515 results on '"Wnt signaling pathway"'
Search Results
2. Retraction: CUL4B promotes bladder cancer metastasis and induces epithelial-to-mesenchymal transition by activating the Wnt/β-catenin signaling pathway.
- Author
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Mao XW, Xiao JQ, Xu G, Li ZY, Wu HF, Li Y, Zheng YC, and Zhang N
- Subjects
- Humans, Neoplasm Metastasis, beta Catenin metabolism, Animals, Epithelial-Mesenchymal Transition, Urinary Bladder Neoplasms pathology, Urinary Bladder Neoplasms metabolism, Urinary Bladder Neoplasms genetics, Wnt Signaling Pathway, Cullin Proteins metabolism, Cullin Proteins genetics
- Published
- 2024
- Full Text
- View/download PDF
3. A role for the vitamin D pathway in non-intestinal lesions in genetic and carcinogen models of colorectal cancer and in familial adenomatous polyposis
- Author
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Bong, Yong-Sik, Assefnia, Shahin, Tuohy, Therese, Neklason, Deborah W, Burt, Randall W, Ahn, Jaeil, De Mesquita, Paul J Bueno, and Byers, Stephen W
- Subjects
Nutrition ,Cancer ,Rare Diseases ,Genetics ,Digestive Diseases ,Colo-Rectal Cancer ,Aetiology ,2.1 Biological and endogenous factors ,Adenocarcinoma ,Adenomatous Polyposis Coli ,Animals ,Azoxymethane ,Cell Transformation ,Neoplastic ,Colorectal Neoplasms ,Disease Models ,Animal ,Disease Progression ,Gardner Syndrome ,Genes ,APC ,Genetic Predisposition to Disease ,Mice ,Inbred C57BL ,Mice ,Knockout ,Mutation ,Phenotype ,Polymorphism ,Single Nucleotide ,Receptors ,Calcitriol ,Risk Factors ,Time Factors ,Vitamin D ,Wnt Signaling Pathway ,beta Catenin ,gardner's syndrome ,anal cancer ,vitamin D receptor ,azoxymethane ,colon cancer ,gardner’s syndrome ,Oncology and Carcinogenesis - Abstract
Vitamin D is implicated in the etiology of cancers of the gastrointestinal tract, usually characterized by alteration in the APC/β-catenin/TCF tumor suppressor pathway. The vitamin D receptor (VDR) is also implicated in cardiovascular and skin diseases as well as in immunity. Activated VDR can indirectly alter β-catenin nuclear localization and directly suppress β-catenin/TCF mediated transcriptional activity. We treated VDR null mice with the carcinogen azoxymethane (AOM) and generated mice bearing a mutated APC (hypomorph) on a VDR null background (Apc1638N/+Vdr-/-). VDR null mice do not develop GI or extra-colonic tumors but loss of VDR decreased intestinal tumor latency and increased progression to adenocarcinoma in both models. AOM treatment of VDR null mice also caused squamous cell carcinoma of the anus. Although levels and distribution of total or activated β-catenin in the epithelial component of tumors were unaffected by loss of VDR, β-catenin dependent cyclin D1 expression was affected suggesting a direct VDR effect on β-catenin co-activator activity. Extra-colonic mucosa manifestations in Apc1638N/+Vdr-/- animals included increased nuclear β-catenin in submucosal stromal cells, spleno- and cardiomegaly and large epidermoid cysts characteristic of the FAP variant, Gardner's syndrome. Consistent with this, SNPs in the VDR, vitamin D binding protein and CYP24 as well as mutations in APC distal to codon 850 were strongly associated with Gardners syndrome in a cohort of 457 FAP patients, This work suggests that alterations in the vitamin D/VDR axis are important in Gardner's syndrome, as well as in the etiology of anal cancer.
- Published
- 2016
4. Effect of perineoplasm perinephric adipose tissues on migration of clear cell renal cell carcinoma cells: a potential role of WNT signaling
- Author
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Zi, Xiaolin, Lusch, Achim, Blair, Christopher A, Okhunov, Zhamshid, Yokoyama, Noriko N, Liu, Shuman, Baker, Molly, Huynh, Victor, and Landman, Jaime
- Subjects
Kidney Disease ,Cancer ,Adipose Tissue ,Aged ,Carcinoma ,Renal Cell ,Cell Line ,Tumor ,Cell Movement ,Culture Media ,Conditioned ,Disease Progression ,Female ,Humans ,Kidney Neoplasms ,Male ,Middle Aged ,Wnt Signaling Pathway ,beta Catenin ,migration ,proliferation ,fat ,renal cell carcinoma ,WNT ,Oncology and Carcinogenesis - Abstract
To investigate the cellular and molecular interactions between clear-cell renal cell carcinoma (ccRCC) and perinephric adipose tissue (PAT), perineoplasm PAT, PAT away from the neoplasm, renal sinus and subcutaneous adipose tissues were collected at the time of renal surgery for renal masses and conditioned medium (CM) was generated from 62 patients. Perineoplasm PAT CMs from 44 out of 62 (about 71%) of patients with ccRCC or benign renal diseases (e.g. oncocytomas, angiomyolipomas, multicystic kidney, interstitial fibrosis, etc.) enhanced the migration of CaKi-2 cells. Perineoplasm PAT CMs from ccRCC significantly increased migration of ACHN and CaKi-2 cells by ~8.2 and ~2.4 folds, respectively, relative to those from benign renal diseases, whereas there is no significant difference in migration between ccRCC and benign renal diseases in CMs collected from culturing PAT away from neoplasm, renal sinus and subcutaneous adipose tissues. High Fuhrman Grade was associated with increased migration of Caki-2 cells by perineoplasm PAT CMs. Perineoplasm PATs from pT3 RCCs overexpressed multiple WNTs and their CMs exhibited higher WNT/ß-catenin activity and increased the migration of Caki-2 cells compared to CMs from benign neoplasms. Addition of secreted WNT inhibitory factor-1 recombinant protein into perineoplasm PAT CMs completely blocked the cell migration. These results indicate that WNT related factors from perineoplasm PAT may promote progression of local ccRCC to locally advanced (pT3) disease by increasing ccRCC cell mobility.
- Published
- 2016
5. LGR5 is associated with tumor aggressiveness in papillary thyroid cancer
- Author
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Michelotti, Gregory, Jiang, Xiaoyin, Sosa, Julie Ann, Diehl, Anna Mae, and Henderson, Brittany Bohinc
- Subjects
Rare Diseases ,Cancer ,Pediatric Research Initiative ,Genetics ,Aetiology ,2.1 Biological and endogenous factors ,Adult ,Biomarkers ,Tumor ,Carcinoma ,Carcinoma ,Papillary ,Cell Line ,Tumor ,Cell Proliferation ,Female ,Gene Knockdown Techniques ,Humans ,Immunohistochemistry ,Lymphatic Metastasis ,Male ,Middle Aged ,Mutation ,Proto-Oncogene Proteins B-raf ,Real-Time Polymerase Chain Reaction ,Receptors ,G-Protein-Coupled ,Sensitivity and Specificity ,Thrombospondins ,Thyroid Cancer ,Papillary ,Thyroid Neoplasms ,Wnt Signaling Pathway ,beta Catenin ,R-spondin ,Wnt ,beta-catenin ,metastasis ,BRAFV600E ,β-catenin ,Oncology and Carcinogenesis - Abstract
PurposeLeucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is a cancer stem cell marker and a down-stream target in Wnt/β-catenin signaling. In human papillary thyroid cancer (PTC), over activation of Wnt/β-catenin has been associated with tumor aggressiveness.Patients and methodsUsing established human cell lines (TPC-1, KTC-1, Nthy-ori-3-1), we report LGR5 and R-spondin (RSPO1-3) overexpression in PTC and manipulate LGR5 and Wnt/β-catenin signaling via both pharmacologic and genetic interventions. We test the association of LGR5 tumor expression with markers of PTC aggressiveness using a Discovery Cohort (n = 26 patients) and a Validation Cohort (n = 157 patients). Lastly, we explore the association between LGR5 and the BRAFV600E mutation (n = 33 patients).ResultsOur results reveal that LGR5 and its ligand, RSPO, are overexpressed in human PTC, whereby Wnt/β-catenin signaling regulates LGR5 expression and promotes cellular migration. In two separate cohorts of patients, LGR5 and RSPO2 were associated with markers of tumor aggressiveness including: lymph node metastases, vascular invasion, increased tumor size, aggressive histology, advanced AJCC TNM stage, microscopic extra thyroidal extension, capsular invasion, and macroscopic invasion. As a biomarker, LGR5 positivity predicts lymph node metastasis with 95.5% sensitivity (95% CI 88.8%-98.7%) and 61% specificity (95% CI: 48.4%-72.4%) and has a negative predictive value (NPV) of 91.3% (95% CI 79.2%-97.5%) for lymph node metastatic disease. In human PTC, LGR5 is also strongly associated with the BRAFV600E mutation (p = 0.005).ConclusionWe conclude that overexpression of LGR5 is associated with markers of tumor aggressiveness in human PTC. LGR5 may serve as a future potential biomarker for patient risk stratification and loco regional metastases in PTC.
- Published
- 2015
6. Retraction: Long non-coding RNA H19 induces hippocampal neuronal apoptosis via Wnt signaling in a streptozotocin-induced rat model of diabetes mellitus.
- Author
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Zhao YH, Ji TF, Luo Q, and Yu JL
- Subjects
- Animals, Rats, Streptozocin, Disease Models, Animal, RNA, Long Noncoding genetics, RNA, Long Noncoding metabolism, Hippocampus metabolism, Hippocampus pathology, Apoptosis, Wnt Signaling Pathway, Diabetes Mellitus, Experimental metabolism, Diabetes Mellitus, Experimental genetics, Diabetes Mellitus, Experimental chemically induced, Diabetes Mellitus, Experimental pathology, Neurons metabolism, Neurons pathology
- Published
- 2024
- Full Text
- View/download PDF
7. Resistance of MMTV-NeuT/ATTAC mice to anti-PD-1 immune checkpoint therapy is associated with macrophage infiltration and Wnt pathway expression
- Author
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Hongyan, Yuan, Lu, Jin, Handan, Xiang, Anannya, Bhattacharya, Philip E, Brandish, Gretchen, Baltus, Alexander, Tong, Changyan, Zhou, and Robert I, Glazer
- Subjects
Mice ,Epithelial-Mesenchymal Transition ,Oncology ,Neoplasms ,Macrophages ,Cell Line, Tumor ,Tumor Microenvironment ,Animals ,Antineoplastic Agents ,Wnt Signaling Pathway - Abstract
One of the central challenges for cancer therapy is the identification of factors in the tumor microenvironment that increase tumor progression and immune tolerance. In breast cancer, fibrosis is a histopathologic criterion for invasive cancer and poor survival that results from inflammatory factors and remodeling of the extracellular matrix to produce an immune tolerant microenvironment. To determine whether tolerance is associated with the immune checkpoint, Programmed Cell Death 1 (PD-1), NeuT/ATTAC mice, a conditional model of mammary fibrosis that we recently developed, were administered a murine-specific anti-PD-1 mAb related to pembrolizumab, and drug response was monitored by tumor development, imaging mass cytometry, immunohistochemistry and tumor gene expression by RNAseq. Tumor progression in NeuT/ATTAC mice was unaffected by weekly injection of anti-PD-1 over four months. Insensitivity to anti-PD-1 was associated with several processes, including increased tumor-associated macrophages (TAM), epithelial to mesenchymal transition (EMT), fibroblast proliferation, an enhanced extracellular matrix and the Wnt signaling pathway, including increased expression of Fzd5, Wnt5a, Vimentin, Mmp3, Col2a1 and Tgfβ1. These results suggest potential therapeutic avenues that may enhance PD-1 immune checkpoint sensitivity, including the use of tumor microenvironment targeted agents and Wnt pathway inhibitors.
- Published
- 2022
8. Dishevelled-1 DIX and PDZ domain lysine residues regulate oncogenic Wnt signaling
- Author
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Isabel Castro-Piedras, Fahmida Rasha, Vadivel Ganapathy, Kevin Pruitt, Sabarish Ramachandran, Kathryn L. Furr, Sharilyn Almodovar, Matthew B. Grisham, Souad R. Sennoune, Monica Sharma, and Rakhshanda Layeequr Rahman
- Subjects
chemistry.chemical_classification ,Homeobox protein NANOG ,dishevelled (DVL) ,PDZ domain ,Wnt signaling pathway ,Cell migration ,lysine residue ,Subcellular localization ,Dishevelled ,Cell biology ,post-translational modification ,Oncology ,chemistry ,Acetylation ,Gene expression ,gene expression ,chromatin immunoprecipitation (ChIP) ,Research Paper - Abstract
DVL proteins are central mediators of the Wnt pathway and relay complex input signals into different branches of the Wnt signaling network. However, molecular mechanism(s) that regulate DVL-mediated relay of Wnt signals still remains unclear. Here, for the first time, we elucidate the functional significance of three DVL-1 lysines (K/Lys) which are subject to post-translational acetylation. We demonstrate that K34 Lys residue in the DIX domain regulates subcellular localization of β-catenin, thereby influencing downstream Wnt target gene expression. Additionally, we show that K69 (DIX domain) and K285 (PDZ domain) regulate binding of DVL-1 to Wnt target gene promoters and modulate expression of Wnt target genes including CMYC, OCT4, NANOG, and CCND1, in cell line models and xenograft tumors. Finally, we report that conserved DVL-1 lysines modulate various oncogenic functions such as cell migration, proliferation, cell-cycle progression, 3D-spheroid formation and in-vivo tumor growth in breast cancer models. Collectively, these findings highlight the importance of DVL-1 domain-specific lysines which were recently shown to be acetylated and characterize their influence on Wnt signaling. These site-specific modifications may be subject to regulation by therapeutics already in clinical use (lysine deacetylase inhibitors such as Panobinostat and Vorinostat) or may possibly have prognostic utility in translational efforts that seek to modulate dysfunctional Wnt signaling.
- Published
- 2021
9. Evidence for functional and regulatory cross-talk between Wnt/β-catenin signalling and Mre11-Rad50–Nbs1 complex in the repair of cisplatin-induced DNA cross-links
- Author
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Kalappa Muniyappa and Sanjeev Pasadi
- Subjects
0301 basic medicine ,Cisplatin ,Mre11–Rad50–Nbs1 complex ,DNA repair ,DNA damage ,Chemistry ,cisplatin-induced DNA crosslinks ,Wnt signaling pathway ,Hedgehog signaling pathway ,Cell biology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,MRN complex ,030220 oncology & carcinogenesis ,Rad50 ,Cancer cell ,medicine ,cancer ,cisplatin resistance ,Wnt/β-catenin signalling ,Research Paper ,medicine.drug - Abstract
The canonical Wnt/β-catenin signalling pathway plays a crucial role in a variety of functions including cell proliferation and differentiation, tumorigenic processes and radioresistance in cancer cells. The Mre11-Rad50-Nbs1 (MRN) complex has a pivotal role in sensing and repairing DNA damage. However, it remains unclear whether a connection exists between Wnt/β-catenin signalling and the MRN complex in the repair of cisplatin-induced DNA interstrand cross-links (ICLs). Here, we report that (1) cisplatin exposure results in a significant increase in the levels of MRN complex subunits in human tumour cells; (2) cisplatin treatment stimulates Wnt/β-catenin signalling through increased β-catenin expression; (3) the functional perturbation of Wnt/β-catenin signalling results in aberrant cell cycle dynamics and the activation of DNA damage response and apoptosis; (4) a treatment with CHIR99021, a potent and selective GSK3β inhibitor, augments cisplatin-induced cell death in cancer cells. On the other hand, inactivation of the Wnt/β-catenin signalling with FH535 promotes cell survival. Consistently, the staining pattern of γH2AX-foci is significantly reduced in the cells exposed simultaneously to cisplatin and FH535; and (5) inhibition of Wnt/β-catenin signalling impedes cisplatin-induced phosphorylation of Chk1, abrogates the G2/M phase arrest and impairs recombination-based DNA repair. Our data further show that Wnt signalling positively regulates the expression of β-catenin, Mre11 and FANCD2 at early time points, but declining thereafter due to negative feedback regulation. These results support a model wherein Wnt/β-catenin signalling and MRN complex crosstalk during DNA ICL repair, thereby playing an important role in the maintenance of genome stability.
- Published
- 2020
10. WNT-pathway medulloblastoma: what constitutes low-risk and how low can one go?
- Author
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Mani S, Chatterjee A, Dasgupta A, Shirsat N, Epari S, Chinnaswamy G, and Gupta T
- Subjects
- Adolescent, Child, Humans, Young Adult, Neoplasm Recurrence, Local, Prospective Studies, Risk Factors, Wnt Signaling Pathway, Cerebellar Neoplasms genetics, Medulloblastoma genetics
- Abstract
Novel biological insights have established that medulloblastoma is a heterogenous disease comprising four broad molecular subgroups - WNT, SHH, Group 3, and Group 4 respectively, resulting in the incorporation of molecular/genetic information in 5th edition of WHO classification and contemporary risk-stratification. Concerns regarding therapy-related late toxicity in long-term survivors have led to systematic attempts at treatment de-intensification in good-risk medulloblastoma. Given the excellent survival (>90%) of WNT-pathway medulloblastoma, prospective clinical trials have focused on optimization of therapy to balance survival versus quality of survival. The currently accepted definition of low-risk WNT-pathway medulloblastoma includes children <16 years of age with residual tumour <1.5 cm
2 and no evidence of metastases. This systematically excludes adolescents and young adults who have been perceived to have worse outcomes. We have previously reported long-term survival of our adolescent and young adult cohort that were largely comparable to childhood medulloblastoma. We now report on molecularly characterized WNT-subgroup patients treated between 2004-2020 with risk-stratified multi-modality therapy to identify differences between childhood (<15 years) versus adolescent and young adults (>15 years). Despite modest differences in disease status at presentation and treatment modality, there were no significant differences in patterns of failure or survival between childhood versus adolescent and young adult WNT-pathway medulloblastoma. Two de-intensification trials in low-risk WNT-pathway medulloblastoma - first testing omission of upfront craniospinal irradiation and second a primary chemotherapy approach after surgery - had to be terminated prematurely due to unacceptably high relapse rates suggesting that craniospinal irradiation remains an integral component of treatment. The presence of TP53 mutations and OTX2 gains have recently been reported as independent negative prognostic factors in a multi-institutional cohort of WNT-pathway medulloblastoma raising questions on eligibility of such patients for de-escalation trials. The definition of low-risk WNT-pathway medulloblastoma may need to be refined in light of recent clinical data and newer biological information.- Published
- 2023
- Full Text
- View/download PDF
11. The role of Kras and canonical Wnt pathways for tumorigenesis of extrahepatic biliary system.
- Author
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Nagao M, Fukuda A, and Seno H
- Subjects
- Humans, Cell Transformation, Neoplastic, Carcinogenesis genetics, Genes, ras, Proto-Oncogene Proteins p21(ras) genetics, Wnt Signaling Pathway, Bile Ducts, Extrahepatic
- Published
- 2023
- Full Text
- View/download PDF
12. PARP-1 inhibitor modulate β-catenin signaling to enhance cisplatin sensitivity in cancer cervix
- Author
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Ashok Sharma, Ritu Gupta, Neerja Bhatla, Sunesh Kumar, Lalit Kumar, Minakshi Mann, Sachin Kumar, Sameer Bakhshi, and Shyam S. Chauhan
- Subjects
0301 basic medicine ,DNA repair ,cervical cancer ,cisplatin ,PARP-1 ,Metastasis ,HeLa ,03 medical and health sciences ,0302 clinical medicine ,PJ34 ,Medicine ,Cisplatin ,biology ,business.industry ,Wnt signaling pathway ,Cancer ,Cell cycle ,β-catenin ,biology.organism_classification ,medicine.disease ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,business ,medicine.drug ,Research Paper - Abstract
Cisplatin is a keystone for treatment of both recurring and locally advanced cervical cancer. However toxic side effects and acquired resistance limits its efficacy. Enhanced DNA repair is one of the mechanisms through which cancer cells acquire cisplatin resistance. Inhibitors of PARP, which is a DNA damage repair enzyme, have been approved for use in BRCA mutated cancers like breast and ovary cancer. However little is known about the therapeutic efficacy of PARP inhibitors in cervical cancer, either as a single agent or in combination with cisplatin. We hypothesized that PARP-1 inhibition might improve the sensitivity of cervical cancer cells to cisplatin by diminishing DNA repair. To ascertain this, we determined effect of PARP-1 inhibition on cisplatin cytotoxicity in HeLa and SiHa cell lines. Combination of cisplatin with PJ34, a phenanthridinone-derived PARP-1 inhibitor, augmented cisplatin toxicity in vitro by decreasing cell proliferation, enhancing cell cycle block and cell death, and decreasing invasion and metastasis, when compared with either of the single agent alone. We further show that PARP-1 inhibition inhibited β-catenin signaling and its downstream components such as c-Myc, cyclin D1 and MMPs indicating a possible link between single strand base damage repair and WNT signaling. In conclusion, PARP-1 inhibition might augment cisplatin cytotoxicity in cervical cancer cells by modulating β-catenin signaling pathway. Combining PARP-1 inhibitors with cisplatin might be a promising approach to overcome cisplatin resistance and to achieve a better therapeutic effect.
- Published
- 2019
13. P-cadherin mutations are associated with high basal Wnt activity and stemness in canine mammary tumor cell lines
- Author
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Timmermans-Sprang, Elpetra, Collin, Rob, Henkes, Arjen, Philipsen, Meike, Mol, Jan A, dCSCA RMSC-2, Biochemisch laboratorium, dCSCA AVR, Onderzoek, dCSCA RMSC-2, Biochemisch laboratorium, dCSCA AVR, and Onderzoek
- Subjects
0301 basic medicine ,Mammary tumor ,cancer stem cell ,CDH3 ,canine mammary tumor exome-sequencing ,Cell ,Wnt signaling pathway ,Correction ,cSRC ,Biology ,Cell morphology ,Phenotype ,Cell biology ,03 medical and health sciences ,Wnt ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,Cancer stem cell ,030220 oncology & carcinogenesis ,Gene expression ,medicine ,Gene silencing ,Research Paper - Abstract
Purpose: To find underlying mutations causing highly-activated Wnt activity in mammary tumor cell lines associated with rounded morphology indicative of stemness/EMT. Methods: Stemness of high Wnt cell lines was confirmed using qPCR on selected genes and microRNA profiling, followed by whole-exome sequencing of 3 high Wnt canine mammary tumor cell lines and 5 low/absent Wnt cell lines. Candidate genes were identified and their involvement in Wnt activity investigated using siRNA silencing. Results: The high Wnt cell lines had morphological and gene expression characteristics reminiscent of stemness. All individual cell lines had about 4000 mutations in the exome in comparison to the reference canine genome. The three high basal Wnt cell lines had 167 unique exome mutations. Seven of these mutations resulted in a SIFT score
- Published
- 2019
14. Global gene expression of histologically normal primary skin cells from BCNS subjects reveals 'single-hit' effects that are influenced by rapamycin
- Author
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Mohammad Athar, Levy Kopelovich, James A. Crowell, Brittney-Shea Herbert, Allen E. Bale, Amruta Phatak, and David Leffel
- Subjects
0301 basic medicine ,Patched ,medicine.medical_specialty ,03 medical and health sciences ,0302 clinical medicine ,basal cell carcinoma ,Molecular genetics ,medicine ,Basal cell carcinoma ,patched ,HH signaling ,rapamycin ,business.industry ,Wnt signaling pathway ,medicine.disease ,Gorlin syndrome ,3. Good health ,Gene expression profiling ,030104 developmental biology ,Oncology ,PTCH1 ,Hippo signaling ,030220 oncology & carcinogenesis ,Cancer research ,Stem cell ,business ,Research Paper - Abstract
// Amruta Phatak 1 , Mohammad Athar 2 , James A. Crowell 3 , David Leffel 4 , Brittney-Shea Herbert 1 , Allen E. Bale 5 and Levy Kopelovich 6 1 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA 2 Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA 3 NCI-DCTD-DTP, Bethesda, MD, USA 4 Department of Dermatology, Yale School of Medicine, New Haven, CT, USA 5 Department of Genetics, Yale School of Medicine, New Haven, CT, USA 6 Department of Medicine, Weill Cornell Medical College, New York, NY, USA Correspondence to: Levy Kopelovich, email: kopelovichl@gmail.com Allen E. Bale, email: allen.bale@yale.edu Keywords: Gorlin syndrome; basal cell carcinoma; patched; HH signaling; rapamycin Received: December 09, 2018 Accepted: January 11, 2019 Published: February 15, 2019 ABSTRACT Studies of dominantly heritable cancers enabled insights about tumor progression. BCNS is a dominantly inherited disorder that is characterized by developmental abnormalities and postnatal neoplasms, principally BCCs. We performed an exploratory gene expression profiling of primary cell cultures derived from clinically unaffected skin biopsies of BCNS gene-carriers ( PTCH1 +/- ) and normal individuals. PCA and HC of untreated keratinocytes or fibroblasts failed to clearly distinguish BCNS samples from controls. These results are presumably due to the common suppression of canonical HH signaling in vitro . We then used a relaxed threshold (p-value
- Published
- 2019
15. MERIT40-dependent recruitment of tankyrase to damaged DNA and its implication for cell sensitivity to DNA-damaging anticancer drugs
- Author
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Mika Kuroiwa, Tomokazu Ohishi, Hiroyuki Seimiya, Shun-ichiro Iemura, Keiji Okamoto, and Tohru Natsume
- Subjects
0301 basic medicine ,Gene knockdown ,biology ,DNA repair ,Chemistry ,Poly ADP ribose polymerase ,Wnt signaling pathway ,DNA damage response ,tankyrase ,MERIT40 ,cancer chemotherapy ,Cell biology ,Telomere ,03 medical and health sciences ,030104 developmental biology ,Oncology ,biology.protein ,Ankyrin repeat ,Homologous recombination ,Polymerase ,Research Paper - Abstract
Tankyrase, a member of the poly(ADP-ribose) polymerase (PARP) family, regulates various intracellular responses, such as telomere maintenance, Wnt/β-catenin signaling and cell cycle progression through its interactions with multiple target proteins. Tankyrase contains a long stretch of 24 ankyrin repeats that are further divided into five subdomains, called ANK repeat clusters (ARCs). Each ARC works as an independent ligand-binding unit, which implicates tankyrase as a platform for multiple protein-protein interactions. Furthermore, tankyrase distributes to various intracellular loci, suggesting potential distinct but yet unidentified physiological functions. To explore the novel functions of tankyrase, we performed liquid chromatography-mass spectrometry analysis and identified the BRE-BRCC36-MERIT40 complex, a regulator of homologous recombination, as tankyrase-binding proteins. Among the complex components, MERIT40 was directly associated with tankyrase via a tankyrase-binding consensus motif, as previously reported. In X-ray-irradiated non-small cell lung cancer cells, tankyrase localized to DNA double-stranded break sites in a MERIT40-dependent manner. MERIT40 knockdown increased the cell sensitivity to X-ray, whereas the wild-type, but not the tankyrase-unbound mutant, MERIT40 rescued the phenotype of the knockdown cells. Tankyrase inhibitors, such as G007-LK and XAV939, increased the cellular sensitivity to X-ray irradiation and anticancer drugs that induce DNA double-stranded breaks. These observations suggest that tankyrase plays a role in the DNA damage repair response and implicates a potential therapeutic utility of tankyrase inhibitors in combination treatments with DNA-damaging anticancer drugs.
- Published
- 2018
16. Differential gene expression in human tissue resident regulatory T cells from lung, colon, and blood
- Author
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Bastian R. Angermann, Rajneesh Malhotra, Elisabeth Israelsson, Maryam Clausen, Céline Dumont, Magdalena Niedzielska, Matthew C. Catley, and Benjamin S. Sidders
- Subjects
0301 basic medicine ,Cell type ,Regeneration (biology) ,mucosal tissue ,Wnt signaling pathway ,Cancer ,chemical and pharmacologic phenomena ,Biology ,tissue microenvironment ,medicine.disease ,Phenotype ,Epithelium ,Transcriptome ,03 medical and health sciences ,030104 developmental biology ,Immune system ,medicine.anatomical_structure ,Oncology ,human regulatory T cell ,Cancer research ,medicine ,RNA-seq ,transcriptome ,Research Paper - Abstract
As we learn more about how immune responses occur in situ, it is becoming clear that each organ/tissue is characterized with its own anatomy and microenvironment which may affect and even determine the outcome of the immune responses. With emerging data from animal studies showing that regulatory T cells infiltrating non-lymphoid tissues exhibit unique phenotypes and transcriptional signatures and display functions beyond their well-established suppressive roles, there is an urgent need to explore the function of tissue Treg cells in humans. Here we characterized the transcriptome of Treg residing at the human mucosal tissue obtained from the normal area of cancer resections and their peripheral blood counterparts, identifying human lung and colon tissue Treg signature genes and their upstream regulators. Pathway analysis highlighted potential differences in the cross-talk between tissue Treg cells and other non-immune tissue-specific cell types. For example, genes associated with wnt pathway were differentially regulated in lung Treg cells compared to blood or colon indicating a potential role for lung Treg cells in epithelium repair and regeneration. Moreover, we identified several non-coding RNAs specifically expressed by tissue-resident Tregs. These results provide a comprehensive view of lung and colon tissue Treg transcriptional landscape.
- Published
- 2018
17. Resistance of MMTV-NeuT/ATTAC mice to anti-PD-1 immune checkpoint therapy is associated with macrophage infiltration and Wnt pathway expression.
- Author
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Yuan H, Jin L, Xiang H, Bhattacharya A, Brandish PE, Baltus G, Tong A, Zhou C, and Glazer RI
- Subjects
- Mice, Animals, Wnt Signaling Pathway, Epithelial-Mesenchymal Transition, Macrophages, Tumor Microenvironment, Cell Line, Tumor, Neoplasms, Antineoplastic Agents pharmacology
- Abstract
One of the central challenges for cancer therapy is the identification of factors in the tumor microenvironment that increase tumor progression and immune tolerance. In breast cancer, fibrosis is a histopathologic criterion for invasive cancer and poor survival that results from inflammatory factors and remodeling of the extracellular matrix to produce an immune tolerant microenvironment. To determine whether tolerance is associated with the immune checkpoint, Programmed Cell Death 1 (PD-1), NeuT/ATTAC mice, a conditional model of mammary fibrosis that we recently developed, were administered a murine-specific anti-PD-1 mAb related to pembrolizumab, and drug response was monitored by tumor development, imaging mass cytometry, immunohistochemistry and tumor gene expression by RNAseq. Tumor progression in NeuT/ATTAC mice was unaffected by weekly injection of anti-PD-1 over four months. Insensitivity to anti-PD-1 was associated with several processes, including increased tumor-associated macrophages (TAM), epithelial to mesenchymal transition (EMT), fibroblast proliferation, an enhanced extracellular matrix and the Wnt signaling pathway, including increased expression of Fzd5, Wnt5a, Vimentin, Mmp3, Col2a1 and Tgfβ1. These results suggest potential therapeutic avenues that may enhance PD-1 immune checkpoint sensitivity, including the use of tumor microenvironment targeted agents and Wnt pathway inhibitors.
- Published
- 2022
- Full Text
- View/download PDF
18. The role of miRNA-133b and its target gene SIRT1 in FAP-derived desmoid tumor
- Author
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Maria Grazia Refolo, Domenico Piscitelli, Catia Lippolis, Donato F. Altomare, Arcangelo Picciariello, Maria Teresa Rotelli, and Aldo Cavallini
- Subjects
0301 basic medicine ,Microarray ,desmoid tumor ,Wnt signaling pathway ,Wnt pathway ,Biology ,medicine.disease ,Familial adenomatous polyposis ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Real-time polymerase chain reaction ,Oncology ,Mrna level ,030220 oncology & carcinogenesis ,familial adenomatous polyposis ,microRNA ,medicine ,Cancer research ,Target gene ,Signal transduction ,B-catenin ,Research Paper ,miRNA - Abstract
Signaling pathways have a key role in driving the uncontrolled development of familial adenomatous polyposis (FAP)- associated and sporadic desmoid tumors (DTs). The relationship between the Wnt/b-catenin signaling pathway and DTs has been extensively studied, but no reliable biomarkers able to detect their histological subtype have been identified for the accurate diagnosis. In this study we studied the differences in miRNA expression between sporadic (20 patients) and FAP-associated DTs (7 patients) using microarray confirmed by quantitative PCR (qPCR). The analysis showed 19 dysregulated miRNAs. Among them miR-133b levels were significantly lower in FAP-associated DT than in sporadic DT. Therefore, two mRNAs, associated to miR-133b and β-catenin expression, the SIRT1 and ELAVL1were analyzed. The qPCR analysis showed that SIRT1 mRNA levels were significantly up-regulated in FAP-associated DT than in sporadic DT, whereas no differences in ELAVL1 expression was observed between these two DT types. In addition, a negative correlation was observed between miR-133b and SIRT1 in FAP-associated DTs, but not in sporadic DTs. The miR-133b-SIRT1-β-catenin axis may represent a novel mechanism underlying progression of FAP-associated DT.
- Published
- 2020
19. Increased CHST15 follows decline in arylsulfatase B (ARSB) and disinhibition of non-canonical WNT signaling: potential impact on epithelial and mesenchymal identity
- Author
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Sumit Bhattacharyya, Fuming Zhang, Xiaorui Han, Ke Xia, Joanne K. Tobacman, Robert J. Linhardt, and Leo Feferman
- Subjects
0301 basic medicine ,Arylsulfatase B ,Stromal cell ,Sulfatase ,Carbohydrate sulfotransferase ,Wnt signaling pathway ,EMT ,sulfotransferase ,sulfatase ,Cell biology ,03 medical and health sciences ,chemistry.chemical_compound ,Wnt ,030104 developmental biology ,0302 clinical medicine ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Chondroitin ,Chondroitin sulfate ,Signal transduction ,Research Paper ,chondroitin sulfate - Abstract
Expression of CHST15 (carbohydrate sulfotransferase 15; chondroitin 4-sulfate-6-sulfotransferase; BRAG), the sulfotransferase enzyme that adds 6-sulfate to chondroitin 4-sulfate (C4S) to make chondroitin 4,6-disulfate (chondroitin sulfate E, CSE), was increased in malignant prostate epithelium obtained by laser capture microdissection and following arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) silencing in human prostate epithelial cells. Experiments in normal and malignant human prostate epithelial and stromal cells and tissues, in HepG2 cells, and in the ARSB-null mouse were performed to determine the pathway by which CHST15 expression is up-regulated when ARSB expression is reduced. Effects of Wnt-containing prostate stromal cell spent media and selective inhibitors of WNT, JNK, p38, SHP2, β-catenin, Rho, and Rac-1 signaling pathways were determined. Activation of WNT signaling followed declines in ARSB and Dickkopf WNT Signaling Pathway Inhibitor (DKK)3 and was required for increased CHST15 expression. The increase in expression of CHST15 followed activation of non-canonical WNT signaling and involved Wnt3A, Rac-1 GTPase, phospho-p38 MAPK, and nuclear DNA-bound GATA-3. Inhibition of JNK, Sp1, β-catenin nuclear translocation, or Rho kinase had no effect. Consistent with higher expression of CHST15 in prostate epithelium, disaccharide analysis showed higher levels of CSE and chondroitin 6-sulfate (C6S) disaccharides in prostate epithelial cells. In contrast, chondroitin 4-sulfate (C4S) disaccharides were greater in prostate stromal cells. CSE may contribute to increased C4S in malignant epithelium when GALNS (N-aceytylgalactosamine-6-sulfate sulfatase) is increased and ARSB is reduced. These effects increase chondroitin 4-sulfates and reduce chondroitin 6-sulfates, consistent with enhanced stromal characteristics and epithelial-mesenchymal transition.
- Published
- 2020
20. Sulforaphane inhibits growth and blocks Wnt/β-catenin signaling of colorectal cancer cells
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Martina Brückner, Jürgen Behrens, Dominic B. Bernkopf, and Gabriele Daum
- Subjects
0301 basic medicine ,Colorectal cancer ,Wnt signaling pathway ,LGR5 ,Cancer ,sulforaphane ,colorectal cancer ,TCF ,β-catenin ,medicine.disease ,Wnt signaling ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,AXIN2 ,medicine ,Cancer research ,Growth inhibition ,Transcription factor ,Sulforaphane ,Research Paper - Abstract
The naturally occurring isothiocyanate sulforaphane (SFN) from cruciferous vegetables is associated with growth inhibition of various cancer types, including colorectal cancer. Colorectal cancer is most frequently driven by hyperactive Wnt/β-catenin signaling. Here, we show that SFN treatment reduced growth of three unrelated colorectal cancer cell lines (SW480, DLD1 and HCT116) via induction of cell death and inhibition of proliferation. Importantly, SFN inhibits Wnt/β-catenin signaling in colorectal cancer cells as shown by inhibition of β-catenin-dependent luciferase reporters and repression of β-catenin target genes (AXIN2, LGR5). SFN inhibits Wnt signaling downstream of β-catenin degradation and induces the formation of nuclear β-catenin structures associated with closed chromatin. Co-expression of the transcription factors LEF1 or TCF4 prevented formation of these structures and rescued inhibition of Wnt/β-catenin signaling by SFN. Our findings provide a molecular basis explaining SFN effects in colorectal cancer cells and underline its potential for prevention and therapy of colorectal cancer.
- Published
- 2018
21. Increased expression of the thyroid hormone nuclear receptor TRα1 characterizes intestinal tumors with high Wnt activity
- Author
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Luiz O. F. Penalva, Pierre Laurent-Puig, Pierre Martinez, Michelina Plateroti, Joel Uchuya-Castillo, Alain Puisieux, Nicolas Aznar, Jean-Yves Scoazec, Laetitia Marisa, Carla Frau, Clementine Le Nevé, Stéphane Ansieau, Jacques Samarut, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
0301 basic medicine ,[SDV]Life Sciences [q-bio] ,Wnt pathway ,intestinal cancer ,WIF1 ,Biology ,medicine.disease_cause ,03 medical and health sciences ,medicine ,Transcription factor ,ComputingMilieux_MISCELLANEOUS ,Thyroid ,Wnt signaling pathway ,thyroid hormone nuclear receptor ,Wnt antagonist ,thyroid hormone ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Nuclear receptor ,Frzb ,Cancer research ,Carcinogenesis ,Hormone ,Research Paper - Abstract
Our previous work demonstrated a key function of the thyroid hormone nuclear receptor TRα1, a T3-modulated transcription factor, in controlling intestinal development and homeostasis via the Wnt and Notch pathways. Importantly, increased expression of TRα1 in the intestinal epithelium in a mutated Apc genetic background (vil-TRα1/Apc+/1638N mice) accelerated tumorigenesis and contributed to a more aggressive tumor phenotype compared to that of the Apc mutants alone. Therefore, the aim of this study was to determine the relevance of this synergistic effect in human colorectal cancers and to gain insights into the mechanisms involved. We analyzed cohorts of patients by in silico and experimental approaches and observed increased TRα1 expression and a significant correlation between TRα1 levels and Wnt activity. TRα1 loss-of-function and gain-of-function in Caco2 cell lines not only confirmed that TRα1 levels control Wnt activity but also demonstrated the role of TRα1 in regulating cell proliferation and migration. Finally, upon investigation of the molecular mechanisms responsible for the Wnt-TRα1 association, we described the repression by TRα1 of several Wnt inhibitors, including Frzb, Sox17 and Wif1. In conclusion, our results underline an important functional interplay between the thyroid hormone nuclear receptor TRα1 and the canonical Wnt pathway in intestinal cancer initiation and progression. More importantly, we show for the first time that the expression of TRα1 is induced in human colorectal cancers.
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- 2018
22. ISG15 induction is required during L1-mediated colon cancer progression and metastasis
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Avri Ben-Ze'ev, Nancy Gavert, Sayon Basu, Thomas Brabletz, Harry Doernberg, Gal Haase, and Sanith Cheriyamundath
- Subjects
0301 basic medicine ,ISG15 ,Colorectal cancer ,Wnt signaling pathway ,colorectal cancer ,Biology ,L1 ,medicine.disease ,digestive system diseases ,Metastasis ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Ectodomain ,Stroma ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,metastasis ,Receptor ,Cell adhesion ,Research Paper - Abstract
Hyperactivation of Wnt/β-catenin target gene expression is a hallmark of colorectal cancer (CRC) development. We identified L1-CAM (L1) and Nr-CAM, members of the immunoglobulin family of nerve cell adhesion receptors, as target genes of the Wnt/β-catenin pathway in CRC cells. L1 overexpression in CRC cells enhances their motile and tumorigenic capacity and promotes liver metastasis. L1 is often localized at the invasive edge of CRC tissue. Using gene arrays and proteomic analyses we identified downstream signaling pathways and targets of L1-mediated signaling. Here, we found that the expression of interferon-stimulated gene 15 (ISG15) that operates much like ubiquitin (is conjugated to proteins by ISGylation), is elevated in the conditioned medium and in CRC cells overexpressing L1. Suppression of endogenous ISG15 levels in L1-expressing cells blocked the increased proliferative, motile, tumorigenic and liver metastatic capacities of CRC cells. ISG15 overexpression, on its own, could enhance these properties in CRC cells, but only to a much lower extent compared to L1. We show that NF-κB signaling is involved in the L1-mediated increase in ISG15, since blocking the NF-κB pathway abolished the induction of ISG15 by L1. Point mutations in the L1 ectodomain that interfere with its binding to L1 ligands, also inhibited the increase in ISG15. We detected high levels of ISG15 in human CRC tissue cells and in the adjacent stroma, but not in the normal mucosa. The results suggest that ISG15 is involved in L1-mediated CRC development and is a potential target for CRC therapy.
- Published
- 2019
23. The immune-related microRNA miR-146b is upregulated in glioblastoma recurrence
- Author
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Xiaowei Wang, Shahed N. Badiyan, Jiayi Huang, Chunyu Cai, and Shariq S. Khwaja
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,recurrence ,GBM ,03 medical and health sciences ,Immune system ,Downregulation and upregulation ,glioma ,Internal medicine ,Glioma ,microRNA ,gene expression profiling ,Medicine ,Gene ,business.industry ,Wnt signaling pathway ,medicine.disease ,3. Good health ,Gene expression profiling ,miR-146b ,030104 developmental biology ,business ,Chemoradiotherapy ,Research Paper - Abstract
// Shariq S. Khwaja 1 , Chunyu Cai 2 , Shahed N. Badiyan 3 , Xiaowei Wang 4 and Jiayi Huang 4 1 Department of Neurosurgery, UTHealth McGovern School of Medicine, Mischer Neuroscience Associates, Houston, TX, USA 2 Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA 3 Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, USA 4 Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA Correspondence to: Jiayi Huang, email: jiayi.huang@wustl.edu Keywords: miR-146b; GBM; glioma; recurrence; gene expression profiling Received: March 09, 2017 Accepted: May 16, 2018 Published: June 26, 2018 ABSTRACT Background: Glioblastoma (GBM) has a high rate of local recurrence despite chemoradiotherapy (CRT). Genome-wide expression profiling was performed on patient tumors before and after chemoradiotherapy to identify genes and gene pathways associated with recurrence. Results: Median time to recurrence was 8.9 months with median time to second surgery of 9.6 months. The microRNA (miRNA) analysis identified 9 oncologic and immune-related miRNAs to be differentially expressed, including the hypoxia-related miR-210 and the immune-modulatory miR-146b. More than 1200 differentially-expressed genes were identified with RNA-sequencing (RNA-seq). Gene set enrichment analysis (GSEA) identified p53 signaling, Notch, Wnt, VEGF, and MEK gene sets enriched in recurrent GBM. Consistent with the miRNA profiling data, the miR-146b target gene set from GSEA analysis was also associated with recurrence. Methods: Fourteen patients with GBM recurrence after CRT who had available tumor tissue from the initial diagnosis as well as recurrence were selected. Total RNA was isolated from formalin-fixed paraffin-embedded (FFPE) tumor specimens. Genome-wide expression profiling using RT-PCR for miRNA analysis and RNA-seq for messenger RNA (mRNA) analysis were conducted to identify differentially-expressed genes. GSEA was performed on the differential expression data. Conclusions: Genome-wide expression profiling identifies multiple oncologic and immune-related gene sets associated with GBM recurrence. In particular, immune-related miR-146b is upregulated in recurrence and deserves further investigation.
- Published
- 2018
24. Frequently rearranged and overexpressed δ-catenin is responsible for low sensitivity of prostate cancer cells to androgen receptor and β-catenin antagonists
- Author
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George Vasmatzis, Piyan Zhang, Janet Schaefer-Klein, John C. Cheville, and Irina V. Kovtun
- Subjects
0301 basic medicine ,treatment ,Cell growth ,Chemistry ,Wnt signaling pathway ,delta catenin ,prostate cancer ,medicine.disease ,Androgen receptor ,03 medical and health sciences ,Prostate cancer ,disease progression ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Catenin Delta-2 ,Downregulation and upregulation ,030220 oncology & carcinogenesis ,Catenin ,Cancer research ,medicine ,Delta catenin ,Research Paper - Abstract
The mechanism of prostate cancer (PCa) progression towards the hormone refractory state remains poorly understood. Treatment options for such patients are limited and present a major clinical challenge. Previously, δ-catenin was reported to promote PCa cell growth in vitro and its increased level is associated with PCa progression in vivo. In this study we show that re-arrangements at Catenin Delta 2 (CTNND2) locus, including gene duplications, are very common in clinically significant PCa and may underlie δ-catenin overexpression. We find that δ-catenin in PCa cells exists in a complex with E-cadherin, p120, and α- and β-catenin. Increased expression of δ-catenin leads to its further stabilization as well as upregulation and stabilization of its binding partners. Resistant to degradation and overexpressed δ-catenin isoform activates Wnt signaling pathway by increasing the level of nuclear β-catenin and subsequent stimulation of Tcf/Lef transcription targets. Evaluation of responses to treatments, with androgen receptor (AR) antagonist and β-catenin inhibitors revealed that cells with high levels of δ-catenin are more resistant to killing with single agent treatment than matched control cells. We show that combination treatment targeting both AR and β-catenin networks is more effective in suppressing tumor growth than targeting a single network. In conclusion, targeting clinically significant PCa with high levels of δ–catenin with anti-androgen and anti β-catenin combination therapy may prevent progression of the disease to a castration-resistant state and, thus, represents a promising therapeutic strategy.
- Published
- 2018
25. Inhibition of Wnt/beta-catenin signaling downregulates expression of aldehyde dehydrogenase isoform 3A1 (ALDH3A1) to reduce resistance against temozolomide in glioblastoma in vitro
- Author
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Karl Köhrer, Jaroslaw Maciaczyk, Philippe Aretz, Ulf Dietrich Kahlert, Guido Reifenberger, Hans-Jakob Steiger, Constanze Uhlmann, Abigail K. Suwala, Isabella Ogorek, Dayana Herrera Rios, Katharina Koch, Jörg Felsberg, and René Deenen
- Subjects
0301 basic medicine ,temozolomide ,Stem cell marker ,Wnt ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,SOX2 ,glioma ,Glioma ,medicine ,ALDH3A1 ,neoplasms ,Temozolomide ,Wnt signaling pathway ,chemoresistance ,medicine.disease ,030104 developmental biology ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,Growth inhibition ,Stem cell ,Signal transduction ,Research Paper ,medicine.drug - Abstract
Glioblastoma is the most aggressive type of glioma. The Wingless (Wnt) signaling pathway has been shown to promote stem cell properties and resistance to radio- and chemotherapy in glioblastoma. Here, we demonstrate that pharmacological Wnt pathway inhibition using the porcupine inhibitor LGK974 acts synergistically with temozolomide (TMZ), the chemotherapeutic drug currently used as standard treatment for glioblastoma, to suppress in vitro growth of glioma cells. Synergistic growth inhibition was independent of the O6-alkylguanine DNA alkyltransferase (MGMT) promoter methylation status. Transcriptomic analysis revealed that expression of aldehyde dehydrogenase 3A1 (ALDH3A1) was significantly down-regulated when cells were treated with LGK974 and TMZ. Suppressing ALDH3A1 expression increased the efficacy of TMZ and reduced clonogenic potential accompanied by decreased expression of stem cell markers CD133, Nestin and Sox2. Taken together, our study suggests that previous observations concerning Wnt signaling blockade to reduce chemoresistance in glioblastoma is at least in part mediated by inhibition of ALDH3A1.
- Published
- 2018
26. LRP5 regulates the expression of STK40, a new potential target in triple-negative breast cancers
- Author
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David Gentien, Bérengère Marty-Prouvost, Tania Tahtouh, Didier Decaudin, Sergio Roman-Roman, Mengliang Ye, Leanne de Koning, Guillem Rigaill, Aurélie Dumont, Maïté Noizet, Fariba Nemati, Amélie Brisson, Gordon C. Tucker, Sylvie Maubant, Virginie Maire, Bruno Tesson, Sardar Faisal Mahmood, Thierry Dubois, and Francisco Cruzalegui
- Subjects
LRP6 ,0301 basic medicine ,LRP5 ,medicine.medical_treatment ,Translational research ,Biology ,medicine.disease_cause ,Targeted therapy ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,medicine ,Triple-negative breast cancer ,Kinase ,Wnt signaling pathway ,Cancer ,targeted therapy ,medicine.disease ,3. Good health ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,triple-negative breast cancer ,Cancer research ,STK40 ,Carcinogenesis ,Research Paper - Abstract
// Sylvie Maubant 1, * , Tania Tahtouh 1, * , Amelie Brisson 1 , Virginie Maire 1 , Fariba Nemati 2 , Bruno Tesson 1, 3 , Mengliang Ye 1 , Guillem Rigaill 4, 5 , Maite Noizet 1 , Aurelie Dumont 1 , David Gentien 6 , Berengere Marty-Prouvost 1 , Leanne de Koning 7 , Sardar Faisal Mahmood 1 , Didier Decaudin 2 , Francisco Cruzalegui 8 , Gordon C. Tucker 8 , Sergio Roman-Roman 9 and Thierry Dubois 1 1 Institut Curie, PSL Research University, Translational Research Department, Breast Cancer Biology Group, Paris, France 2 Institut Curie, PSL Research University, Translational Research Department, Preclinical Investigation Laboratory, Paris, France 3 Institut Curie, PSL Research University, INSERM U900, Paris, France 4 Institute of Plant Sciences Paris-Saclay (IPS2), UMR 9213/UMR 1403, CNRS, INRA, Universite Paris-Sud, Universite d’Evry, Universite Paris-Diderot, Sorbonne Paris-Cite, Orsay, France 5 Laboratoire de Mathematiques et Modelisation d’Evry (LaMME), Universite d’Evry Val d’Essonne, UMR CNRS 8071, ENSIIE, USC INRA, Evry, France 6 Institut Curie, PSL Research University, Translational Research Department, Genomics Platform, Paris, France 7 Institut Curie, PSL Research University, Translational Research Department, Reverse-Phase Protein Array Platform, Paris, France 8 Oncology Research and Development Unit, Institut de Recherches SERVIER, Croissy-Sur-Seine, France 9 Institut Curie, PSL Research University, Translational Research Department, Paris, France * These authors have contributed equally to this work Correspondence to: Thierry Dubois, email: thierry.dubois@curie.fr Keywords: triple-negative breast cancer; LRP5; LRP6; STK40; targeted therapy Received: January 18, 2018 Accepted: April 04, 2018 Published: April 27, 2018 ABSTRACT Triple-negative breast cancers (TNBCs) account for a large proportion of breast cancer deaths, due to the high rate of recurrence from residual, resistant tumor cells. New treatments are needed, to bypass chemoresistance and improve survival. The WNT pathway, which is activated in TNBCs, has been identified as an attractive pathway for treatment targeting. We analyzed expression of the WNT coreceptors LRP5 and LRP6 in human breast cancer samples. As previously described, LRP6 was overexpressed in TNBCs. However, we also showed, for the first time, that LRP5 was overexpressed in TNBCs too. The knockdown of LRP5 or LRP6 decreased tumorigenesis in vitro and in vivo , identifying both receptors as potential treatment targets in TNBC. The apoptotic effect of LRP5 knockdown was more robust than that of LRP6 depletion. We analyzed and compared the transcriptomes of cells depleted of LRP5 or LRP6, to identify genes specifically deregulated by LRP5 potentially implicated in cell death. We identified serine/threonine kinase 40 (STK40) as one of two genes specifically downregulated soon after LRP5 depletion. STK40 was found to be overexpressed in TNBCs, relative to other breast cancer subtypes, and in various other tumor types. STK40 depletion decreased cell viability and colony formation, and induced the apoptosis of TNBC cells. In addition, STK40 knockdown impaired growth in an anchorage-independent manner in vitro and slowed tumor growth in vivo . These findings identify the largely uncharacterized putative protein kinase STK40 as a novel candidate treatment target for TNBC.
- Published
- 2018
27. Ferric citrate and ferric EDTA but not ferrous sulfate drive amphiregulin-mediated activation of the MAP kinase ERK in gut epithelial cancer cells
- Author
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Dora I. A. Pereira, Nathalie Scheers, Jonathan J. Powell, and Nuno Faria
- Subjects
inorganic chemicals ,0301 basic medicine ,MAPK/ERK pathway ,Cell signaling ,Chemistry ,Cell growth ,ferric EDTA ,Wnt signaling pathway ,Molecular biology ,ferric citrate ,Ferrous ,03 medical and health sciences ,iron ,pERK ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Amphiregulin ,030220 oncology & carcinogenesis ,Cancer cell ,medicine ,Ferric ,amphiregulin ,Research Paper ,medicine.drug - Abstract
Ferric chelates may be used as oral iron supplements or phosphate binders but both ferric citrate and ferric EDTA have been shown to promote tumor burden in murine models of colon cancer. Here we studied their effects on cancer cell growth, at typical supplemental iron levels encountered in the gastrointestinal tract (0.01-0.2 mM). Caco-2 and/or Hutu-80 cells were exposed to these forms of chelated iron or to ferrous sulfate and outcomes were assessed using cell proliferation assays, proteome profiler arrays, western blot, and ELISA. Ferric EDTA and ferric citrate increased cellular levels of the onco-protein amphiregulin and its receptor (EGFr) which in turn stimulated the activation of the MAP kinase ERK. Simultaneously, the expression of the negative Wnt regulator, DKK-1, increased suggesting that cell proliferation through the Wnt pathway may be less pronounced in the presence of ferric EDTA and ferric citrate, unlike for ferrous sulfate. Moreover, ferrous sulfate did not increase levels of cellular amphiregulin or EGFr. We conclude that specific iron compounds affect cell signaling differently and some may increase the risk of colon cancer advancement in an amphiregulin-dependent fashion. Further scrutiny of safe oral iron use is merited.
- Published
- 2018
28. Depleting ovarian cancer stem cells with calcitriol
- Author
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Qi-En Wang, Altaf A. Wani, Tiantian Cui, Yanfang Zheng, Ananya Banerjee, Asim Rizvi, Chunhua Han, Imrana Naseem, and Amit Kumar Srivastava
- Subjects
calcitriol ,0301 basic medicine ,cancer stem cells (CSCs) ,Calcitriol ,Population ,Wnt pathway ,Calcitriol receptor ,03 medical and health sciences ,0302 clinical medicine ,Cancer stem cell ,polycyclic compounds ,Medicine ,education ,education.field_of_study ,biology ,business.industry ,CD44 ,Wnt signaling pathway ,Cancer ,medicine.disease ,3. Good health ,ovarian cancer ,030104 developmental biology ,Oncology ,vitamin D receptor (VDR) ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,lipids (amino acids, peptides, and proteins) ,business ,Ovarian cancer ,Research Paper ,medicine.drug - Abstract
// Amit Kumar Srivastava 1, 5, * , Asim Rizvi 1, 2, * , Tiantian Cui 1 , Chunhua Han 1 , Ananya Banerjee 1, 3 , Imrana Naseem 2 , Yanfang Zheng 4 , Altaf A. Wani 1 and Qi-En Wang 1 1 Department of Radiology, College of Medicine, The Ohio State University, Columbus, OH 43210, USA 2 Department of Biochemistry, Faculty of Life Sciences, The Aligarh Muslim University, Aligarh, Uttar Pradesh, 202002, India 3 School of Biotechnology, KIIT University, Bhubaneswar, Odisha, 751024, India 4 Oncology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510282, China 5 Current address: Biological Science and Technology Division, CSIR-North East Institute of Science and Technology (CSIR-NEIST), Jorhat, Assam, 785006, India * These authors have contributed equally to this work Correspondence to: Qi-En Wang, email: wang.771@osu.edu Keywords: calcitriol; cancer stem cells (CSCs); vitamin D receptor (VDR); Wnt pathway; ovarian cancer Received: September 25, 2017 Accepted: February 10, 2018 Epub: February 16, 2018 Published: March 06, 2018 ABSTRACT Cancer stem cells (CSCs) represent the root of many solid tumors including ovarian cancer. Eradication of CSCs represents a novel cancer therapeutic strategy. Calcitriol, also known as 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], is an active metabolite of vitamin D, functioning as a potent steroid hormone. Calcitriol has shown anti-tumor effects in various cancers by regulating multiple signaling pathways. It has been reported that calcitriol can regulate the properties of normal and CSCs. However, the effect of calcitriol on the ovarian cancer growth and ovarian CSCs is still unclear. Here, by using a mouse subcutaneous xenograft model generated with human ovarian cancer cells, we have demonstrated that administration of calcitriol is able to strikingly delay the tumor growth. Calcitriol treatment can also deplete the ovarian CSC population characterized by ALDH + and CD44 + CD117 + ; decrease their capacity to form sphere under the CSC culture condition, and reduce the frequency of tumor-initiating cells, as evaluated by in vivo limiting dilution analysis. Mechanistic investigation revealed that calcitriol depletes CSCs via the nuclear vitamin D receptor (VDR)-mediated inhibition of the Wnt pathway. Furthermore, the activation of VDR pathway is more sensitive to calcitriol in ovarian CSCs than in non-CSCs, although the expression levels of VDR are comparable. Taken together, our data indicate that calcitriol is able to deplete the ovarian CSC population by inhibiting their Wnt signaling pathway, consequently, impeding the growth of xenograft tumors.
- Published
- 2018
29. Hepatocyte specific expression of an oncogenic variant of β-catenin results in lethal metabolic dysfunction in mice
- Author
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Claudia D. Fuchs, Christian Schöfer, Christopher Gerner, Makoto Mark Taketo, Gerda Egger, Ursula Lemberger, Tatjana Stojakovic, Andrea Bileck, Michael Trauner, and Christoph H. Österreicher
- Subjects
0301 basic medicine ,medicine.medical_specialty ,glucose metabolism ,education ,Mitochondrion ,Wnt signaling pathway ,liver cancer ,03 medical and health sciences ,Internal medicine ,lipid metabolism ,mitochondrial disorder ,medicine ,Tissue homeostasis ,Lipid metabolism ,Hepatology ,medicine.disease ,humanities ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Hepatocyte ,Catenin ,Cancer research ,Liver cancer ,Research Paper - Abstract
// Ursula J. Lemberger 1, 2 , Claudia D. Fuchs 2 , Christian Schofer 3 , Andrea Bileck 4 , Christopher Gerner 4 , Tatjana Stojakovic 5 , Makoto M. Taketo 6 , Michael Trauner 2 , Gerda Egger 1, 7 and Christoph H. Osterreicher 8 1 Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria 2 Hans Popper Laboratory for Molecular Hepatology, Department of Internal Medicine, Medical University of Vienna, Vienna, Austria 3 Department of Cell and Developmental Biology, Medical University of Vienna, Vienna, Austria 4 Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria 5 Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria 6 Division of Experimental Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan 7 Ludwig Boltzmann Institute Applied Diagnostics, Vienna, Austria 8 Institute of Pharmacology, Medical University Vienna, Vienna, Austria Correspondence to: Ursula J. Lemberger, email: ursula.lemberger@meduniwien.ac.at , ursula.lemberger@gmx.at Keywords: Wnt signaling pathway; liver cancer; lipid metabolism; glucose metabolism; mitochondrial disorder Received: August 31, 2017 Accepted: January 25, 2018 Published: January 30, 2018 ABSTRACT Background: Wnt/β-catenin signaling plays a crucial role in embryogenesis, tissue homeostasis, metabolism and malignant transformation of different organs including the liver. Continuous β-catenin signaling due to somatic mutations in exon 3 of the Ctnnb1 gene is associated with different liver diseases including cancer and cholestasis. Results: Expression of a degradation resistant form of β-catenin in hepatocytes resulted in 100% mortality within 31 days after birth. Ctnnb1 CA hep mice were characterized by reduced body weight, significantly enlarged livers with hepatocellular fat accumulation around central veins and increased hepatic triglyceride content. Proteomics analysis using whole liver tissue revealed significant deregulation of proteins involved in fat, glucose and mitochondrial energy metabolism, which was also reflected in morphological anomalies of hepatocellular mitochondria. Key enzymes involved in transport and synthesis of fatty acids and cholesterol were significantly deregulated in livers of Ctnnb1 CA hep mice. Furthermore, carbohydrate metabolism was substantially disturbed in mutant mice. Conclusion: Continuous β-catenin signaling in hepatocytes results in premature death due to severe disturbances of liver associated metabolic pathways and mitochondrial dysfunction. Methods: To investigate the influence of permanent β-catenin signaling on liver biology we analyzed mice with hepatocyte specific expression of a dominant stable form of β-catenin ( Ctnnb1 CA hep ) and their WT littermates by serum biochemistry, histology, electron microscopy, mRNA profiling and proteomic analysis of the liver.
- Published
- 2018
30. Three-dimensional organoid culture reveals involvement of Wnt/β-catenin pathway in proliferation of bladder cancer cells
- Author
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Trinity J. Bivalacqua, Nikolai A. Sopko, Takahiro Yoshida, Max Kates, David J. McConkey, Xiaopu Liu, and Gregory Joice
- Subjects
0301 basic medicine ,Bladder cancer ,organoid ,Wnt signaling pathway ,β-catenin ,Biology ,medicine.disease ,Wnt ,03 medical and health sciences ,Cytokeratin ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Downregulation and upregulation ,spheroid ,030220 oncology & carcinogenesis ,Catenin ,Cancer cell ,Organoid ,medicine ,Cancer research ,bladder cancer ,Urothelium ,Research Paper - Abstract
There has been increasing awareness of the importance of three-dimensional culture of cancer cells. Tumor cells growing as multicellular spheroids in three-dimensional culture, alternatively called organoids, are widely believed to more closely mimic solid tumors in situ. Previous studies concluded that the Wnt/β-catenin pathway is required for regeneration of the normal urothelium after injury and that β-catenin is upregulated in human bladder cancers, but no clear evidence has been advanced to support the idea that the Wnt/β-catenin pathway is directly involved in deregulated proliferation and the other malignant characteristics of bladder cancer cells. Here we report that the Wnt/β-catenin pathway activator, CHIR99021, promoted proliferation of established human bladder cancer cell lines when they were grown in organoid culture but not when they were grown in conventional adherent cultures. CHIR99021 activated Wnt/β-catenin pathway in bladder cancer cell lines in organoid culture. CHIR99021 also stimulated proliferation and the Wnt/b-catenin pathway in primary human bladder cancer organoids. RNAi-mediated knockdown of β-catenin blocked growth of organoids. The effects of CHIR99021 were associated with decreased expression of the urothelial terminal differentiation marker, cytokeratin 20. Our data suggest that the Wnt/β-catenin pathway is required for the proliferation of bladder cancer cells in three-dimensional organoid culture and provide a concrete example of why organoid culture is important for cancer research.
- Published
- 2018
31. Bufalin inhibits gastric cancer invasion and metastasis by down-regulating Wnt/ASCL2 expression
- Author
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Yi-ming Jiang, Peihao Yin, Jie Xu, Qingshong Zuo, Han Cai, Yue Xia, Shiying Wang, Chao Chen, Ronghua Zhao, Yong Zhang, Jie Wang, Teng Chen, and Likai Xing
- Subjects
0301 basic medicine ,MMP2 ,business.industry ,gastric cancer ,EMT ,Wnt signaling pathway ,Cancer ,Bufalin ,MMP9 ,medicine.disease ,invasion and metastasis ,Metastasis ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,medicine ,Wnt/ASCL2 signaling ,Stem cell ,bufalin ,business ,Research Paper - Abstract
// Jie Wang 1, * , Han Cai 1, * , Yue Xia 1, * , Shiying Wang 2 , Likai Xing 1 , Chao Chen 1 , Yong Zhang 1 , Jie Xu 1 , Peihao Yin 1 , Yiming Jiang 1 , Ronghua Zhao 3 , Qingshong Zuo 1 and Teng Chen 1, 4 1 Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China 2 Department of Gastroenterology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China 3 Department of Medical, Virogin Biotech Ltd., Vancouver, British Columbia V6S 2L9, Canada 4 Shanghai Putuo Central School of Clinical Medicine, Anhui Medical University, Shanghai 200062, China * These authors have contributed equally to this work Correspondence to: Teng Chen, email: 13801842406@163.com Qingshong Zuo, email: zqsadsl123@sina.com Keywords: bufalin; gastric cancer; invasion and metastasis; Wnt/ASCL2 signaling; EMT Received: September 28, 2017 Accepted: January 02, 2018 Epub: January 11, 2018 Published: May 04, 2018 ABSTRACT Achaete-scute-like 2 (ASCL2) is a transcription factor containing a basic helix-loop-helix (bHLH) domain and is a downstream target of Wnt signaling in intestinal stem cells. Bufalin is the primary active ingredient in Chan Su, a traditional Chinese medicine obtained from the skin and parotid venom glands of toads. The purpose of this study was to research the anti-invasion and anti-metastasis activity of bufalin in gastric cancer and to identify the potential mechanism. Bufalin inhibited gastric cancer cell invasion and metastasis, suppressed cancer cell colony formation, and inhibited the growth of subcutaneous xenografted tumors in nude mice. Furthermore, bufalin inhibited ASCL2 expression and down-regulated the expression of invasion-related genes such as MMP2, MMP9, and vimentin, thereby suppressing epithelial-mesenchymal transition (EMT) in gastric cancer. A Wnt signaling inhibitor (XAV939) down-regulated invasion and the expression of ASCL2, β-catenin, and vimentin but up-regulated E-cadherin expression. In nude mice, bufalin inhibited the tumorigenic behavior of gastric cancer cells, induced cancer cell apoptosis, and regulated invasion-related gene expression. Together, our results suggest that bufalin arrests invasion and metastasis and that its mechanism of action may involve down-regulating Wnt/ASCL2 expression.
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- 2018
32. HMGA2 enhances 5-fluorouracil chemoresistance in colorectal cancer via the Dvl2/Wnt pathway
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Maode Lai, Xi Xu, Hong Deng, Jingjing Wu, Yunfeng Wang, and Chungang Liu
- Subjects
0301 basic medicine ,HMGA2 ,Colorectal cancer ,colorectal cancer ,Drug resistance ,03 medical and health sciences ,Transcription (biology) ,In vivo ,medicine ,5-FU ,biology ,business.industry ,Wnt signaling pathway ,chemoresistance ,medicine.disease ,Regimen ,030104 developmental biology ,Dvl2 ,Oncology ,Fluorouracil ,Cancer research ,biology.protein ,business ,Research Paper ,medicine.drug - Abstract
Drug resistance is one of the main hurdles to overcome for the improvement of cancer patient survival. However, the underlying mechanisms remain largely unknown, and therapeutic options are limited. Here, we demonstrate a strong correlation between HMGA2 expression and chemosensitivity to 5-fluorouracil (5-FU), a widely used first-line systemic chemotherapy regimen for colorectal cancer (CRC) patients. Overexpression of HMGA2 enhances chemoresistance to 5-FU of CRC both in vitro and in vivo. Further experiments indicate that HMGA2 directly binds to the promoter of Dvl2 and induces its transcription, which leads to increased activation of the Wnt/β-catenin pathway. Taken together, our data suggest that HMGA2 enhances the chemoresistance to 5-FU in CRC via activating the Dvl2/Wnt pathway. Therefore, HMGA2 may serve as a predictive biomarker and a potential therapeutic target in CRC.
- Published
- 2018
33. Consecutive epigenetically-active agent combinations act in ID1-RUNX3-TET2 and HOXA pathways for Flt3ITD+ve AML
- Author
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Katie J. Sargent, Hamid Sayar, Chirayu P. Goswami, Rajasubramaniam Shanmugam, Yan Liu, Rui Gao, Feng Pan, Lang Li, H. Scott Boswell, Attaya Suvannasankha, Larry D. Cripe, Jill Weisenbach, Mohammad Abu Zaid, Heiko Konig, Reuben Kapur, Mingjiang Xu, and Mehdi Nassiri
- Subjects
Oncology ,Sorafenib ,medicine.medical_specialty ,Hematology ,epigenetics ,business.industry ,Bortezomib ,bortezomib ,Wnt signaling pathway ,Cancer ,Context (language use) ,medicine.disease ,AML ,vorinostat ,Internal medicine ,medicine ,sorafenib ,business ,Vorinostat ,Veterans Affairs ,Research Paper ,medicine.drug - Abstract
// Hamid Sayar 1,* , Yan Liu 4,* , Rui Gao 4 , Mohammad Abu Zaid 1 , Larry D. Cripe 1 , Jill Weisenbach 5 , Katie J. Sargent 5 , Mehdi Nassiri 2 , Lang Li 3 , Heiko Konig 1 , Attaya Suvannasankha 1 , Feng Pan 4 , Rajasubramaniam Shanmugam 1,7 , Chirayu Goswami 3 , Reuben Kapur 4 , Mingjiang Xu 4 and H. Scott Boswell 1,6 1 Indiana University Melvin and Bren Simon Cancer Center, Department of Medicine, Hematology/Oncology Division, Indiana University School of Medicine, Indianapolis, IN, USA 2 Department of Hematopathology, Indiana University School of Medicine, Indianapolis, IN, USA 3 Biostatistics and Computational Biology, Indiana University School of Medicine, Indianapolis, IN, USA 4 Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA 5 Indiana University Health Systems, Indianapolis, IN, USA 6 Veterans Affairs Medical Center, Indianapolis, IN, USA 7 ICMR, National Institute for Research in Tribal Health, Jabalpur, India * These authors contributed equally to this work Correspondence to: Hamid Sayar, email: // Yan Liu, email: // Keywords : AML; sorafenib; vorinostat; bortezomib; epigenetics Received : August 25, 2017 Accepted : October 25, 2017 Published : December 25, 2017 Abstract Co-occurrence of Flt3ITD and TET2 mutations provoke an animal model of AML by epigenetic repression of Wnt pathway antagonists, including RUNX3, and by hyperexpression of ID1, encoding Wnt agonist. These affect HOXA over-expression and treatment resistance. A comparable epigenetic phenotype was identified among adult AML patients needing novel intervention. We chose combinations of targeted agents acting on distinct effectors, at the levels of both signal transduction and chromatin remodeling, in relapsed/refractory AML’s, including Flt3ITD+ve, described with a signature of repressed tumor suppressor genes, involving Wnt antagonist RUNX3 , occurring along with ID1 and HOXA over-expressions. We tracked patient response to combination of Flt3/Raf inhibitor, Sorafenib, and Vorinostat, pan-histone deacetylase inhibitor, without or with added Bortezomib, in consecutive phase I trials. A striking association of rapid objective remissions (near-complete, complete responses) was noted to accompany induced early pharmacodynamic changes within patient blasts in situ, involving these effectors, significantly linking RUNX3 /Wnt antagonist de-repression (80%) and ID1 downregulation (85%), to a response, also preceded by profound HOXA9 repression. Response occurred in context of concurrent TET2 mutation/hypomorphy and Flt3ITD+ve mutation (83% of complete responses). Addition of Bortezomib to the combination was vital to attainment of complete response in Flt3ITD+ve cases exhibiting such Wnt pathway dysregulation.
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- 2017
34. The microtubule-associated protein PRC1 is a potential therapeutic target for lung cancer
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Jonas Malkmus, Steffen Hanselmann, Stefan Gaubatz, and Patrick Wolter
- Subjects
0301 basic medicine ,mitotic kinesins ,Wnt signaling pathway ,therapeutic target ,Cancer ,macromolecular substances ,Biology ,lung adenocarcinoma ,medicine.disease ,medicine.disease_cause ,PRC1 ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,medicine ,Cancer research ,Adenocarcinoma ,Lung cancer ,Carcinogenesis ,Cytokinesis ,Research Paper - Abstract
// Steffen Hanselmann 1 , Patrick Wolter 1 , Jonas Malkmus 1 and Stefan Gaubatz 1 1 Theodor Boveri Institute, Biocenter, University of Wuerzburg and Comprehensive Cancer Center Mainfranken, University of Wuerzburg, University of Wuerzburg, Wuerzburg, Germany Correspondence to: Stefan Gaubatz, email: stefan.gaubatz@biozentrum.uni-wuerzburg.de Keywords: PRC1; mitotic kinesins; lung adenocarcinoma; therapeutic target Received: August 05, 2017 Accepted: December 01, 2017 Published: December 22, 2017 ABSTRACT In this study, we investigated whether proteins that are involved in cytokinesis are potential targets for therapy of lung cancer. We find that the microtubule-associated protein PRC1 (protein required for cytokinesis 1), which plays a key role in organizing anti-parallel microtubule in the central spindle in cytokinesis, is overexpressed in lung cancer cell lines compared to normal cells. Increased expression of PRC1 is correlated with a poor prognosis of human lung adenocarcinoma patients. Lentiviral delivered, inducible RNAi of PRC1 demonstrated that proliferation of lung cancer cell lines strongly depends on PRC1. Significantly, we also show that PRC1 is required for tumorigenesis in vivo using a mouse model for non-small cell lung cancer driven by oncogenic K-RAS and loss of p53. When PRC1 is depleted by in vivo RNA interference, lung tumor formation is significantly reduced. Although PRC1 has been suggested to regulate Wnt/s-catenin signaling in cancer cells, we find no evidence for a role of PRC1 in this pathway in lung cancer. Instead, we show that the depletion of PRC1 results in a strong increase in bi- and multinuclear cells due to defects in cytokinesis. This ultimately leads to apoptosis and senescence. Together these data establish PRC1 as a potential target for therapy of lung cancer.
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- 2017
35. Peptide inhibition of the SETD6 methyltransferase catalytic activity
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Michal Feldman and Dan Levy
- Subjects
0301 basic medicine ,chemistry.chemical_classification ,Methyltransferase ,Chemistry ,Cell growth ,Lysine ,Wnt signaling pathway ,Peptide ,Methylation ,SETD6 ,Amino acid ,03 medical and health sciences ,030104 developmental biology ,Oncology ,Biochemistry ,Lysine methylation ,Cell-penetrating peptide ,Research Paper - Abstract
A large body of evidence accumulating in the past few years indicates the physiological significance of non-histone proteins lysine methylation, catalyzed by protein lysine methyl transferases (PKMTs). Dysregulation of these enzymes was shown to contribute to the development and progression of numerous diseases. SETD6 lysine methylatransferase was recently shown to participate in essential cellular processes, such as the NFkB pathway, oxidative stress and also the Wnt signaling cascade. In order to test the effect of blocking SETD6 catalytic activity, we used the peptide inhibition method, which is considered highly specific and can potentially target almost any protein. We designed a 15 amino acids peptide based on the sequence of the RelA protein (residues 302-316), containing the lysine that is methylated by SETD6. To enable cellular intake, the designed peptide was fused to a cell penetrating peptide (CPP) vp22. The vp22-RelA302-316 peptide showed direct and specific interaction with SETD6 in vitro. This interaction was shown to inhibit SETD6 methyltransferase activity. SETD6 catalytic blockage by the peptide was also observed in cells upon treatment with the vp22-RelA302-316, resulting in induced cellular migration and proliferation. This new insight into the activity of a methylation inhibitory peptide could represent a milestone in the development of therapeutic tools, which can be of use in physiological cases where administration of cell proliferation is required.
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- 2017
36. Genomic landscape of colitis-associated cancer indicates the impact of chronic inflammation and its stratification by mutations in the Wnt signaling
- Author
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Naohiro Tomita, Masashi Fujita, Ayako Oosawa, Satoru Miyano, Hidewaki Nakagawa, Hiroki Ikeuchi, Raúl Nicolás Mateos, Seiichi Hirota, Mayuko Furuta, Hiroko Tanaka, Aya Oku-Sasaki, Ikuo Matsuda, Kazuhiro Maejima, Akihiro Fujimoto, Kenta Nakai, Yuichi Shiraishi, Tomoki Yamano, Kaoru Nakano, and Nagahide Matsubara
- Subjects
0301 basic medicine ,endocrine system diseases ,Colorectal cancer ,medicine.disease_cause ,Inflammatory bowel disease ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,inflammatory bowel disease ,medicine ,cardiovascular diseases ,Exome sequencing ,business.industry ,Wnt signaling pathway ,nutritional and metabolic diseases ,Cancer ,medicine.disease ,Ulcerative colitis ,APC ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,colitis-associated cancer ,RNF43 ,cardiovascular system ,Cancer research ,population characteristics ,next-generation sequencing ,KRAS ,business ,Research Paper - Abstract
Inflammatory bowel disease (IBD) increases the risk of colorectal cancer, known as colitis-associated cancer (CAC). It is still unclear what driver mutations are caused by chronic inflammation and lead to CAC development. To get insight into this issue, we investigated somatic alterations in CAC. We performed exome sequencing of 22 fresh CACs and targeted sequencing of 43 genes on 90 archive specimens from Japanese CAC patients, of which 58 were ulcerative colitis (UC) and 32 were Crohn’s disease (CD). Consistently with the previous reports, TP53 was commonly mutated (66%) whereas APC, KRAS and SMAD4 were mutated less frequently (16%, 11% and 11%, respectively). Mucinous CD-CACs in the anus, an Asian-specific subtype of CD-CAC, had less somatic mutations in our target genes. We also found that RNF43, a negative regulator of the Wnt signaling, was somatically mutated in a significant fraction of CACs (10 of 90; 11%). Two lines of evidence indicated that somatic mutations of RNF43 were related to chronic inflammation. First, somatic mutations of RNF43 were significantly associated with longer duration of IBD. Second, clinico-pathological features suggested many of the APC-mutated CACs were actually sporadic colorectal cancer whereas RNF43-mutated CACs did not have this tendency. RNA-Seq analysis showed that RNF43-mutated CACs had elevated expression of c-Myc and its target genes, suggesting that RNF43 is a bona fide driver of CAC development. This study provides evidence that somatic mutation of RNF43 is the driver genetic alteration that links chronic inflammation and cancer development in about 10% of CACs.
- Published
- 2017
37. ETV4 collaborates with Wnt/β-catenin signaling to alter cell cycle activity and promote tumor aggressiveness in gastrointestinal stromal tumor
- Author
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Timothy G. Bowler, Ronald P. DeMatteo, Michael J. Cavnar, Nesteene J. Param, Shan Zeng, Ferdinand Rossi, Benjamin D. Medina, Teresa S. Kim, Gerardo A. Vitiello, Jennifer K. Loo, Adrian M. Seifert, and Jennifer Q. Zhang
- Subjects
0301 basic medicine ,GiST ,ETV4 ,Wnt signaling pathway ,PDGFRA ,Cell cycle ,Biology ,gastrointestinal stromal tumor ,digestive system diseases ,3. Good health ,03 medical and health sciences ,030104 developmental biology ,Oncology ,Growth factor receptor ,Tumor progression ,Cancer research ,Stromal tumor ,neoplasms ,Transcription factor ,Research Paper ,Wnt/β-catenin signaling - Abstract
Gastrointestinal stromal tumor (GIST) is the most common sarcoma, often resulting from a KIT or platelet-derived growth factor receptor alpha (PDGFRA) mutation. The lineage transcription factor ETV1 is expressed similarly in GISTs regardless of malignant potential. Although the related transcription factor ETV4 has been associated with metastasis and tumor progression in other cancers, its role in GIST is unknown. In this study, we found that ETV4 levels were high in a subset of human GISTs and correlated with high mitotic rate. Through Gene Set Enrichment Analysis in selected human GISTs, we identified a relationship between ETV4 levels and β-catenin signaling, especially in advanced GISTs. GIST specimens with high ETV4 levels overexpressed cell cycle regulating genes and had aberrant activation of the canonical Wnt pathway. In human GIST cell lines, ETV4 RNA interference suppressed cell cycle genes and Wnt/β-catenin signaling. ETV4 knockdown also reduced tumor cell proliferation, invasion, and tumor growth in vivo. Conversely, ETV4 overexpression increased cyclin D1 expression and Wnt/β-catenin signaling. Moreover, we determined that ETV4 knockdown destabilized nuclear β-catenin and increased its degradation via COP1, an E3 ligase involved in both ETV4 and β-catenin turnover. Aberrant accumulation of ETV4 and nuclear β-catenin was found in patient derived xenografts created from metastatic GISTs that became resistant to tyrosine kinase inhibitors. Collectively, our findings highlight the significance of ETV4 expression in GIST and identify ETV4 as a biomarker in human GISTs.
- Published
- 2017
38. Up-regulation of lncRNA SNHG1 indicates poor prognosis and promotes cell proliferation and metastasis of colorectal cancer by activation of the Wnt/β-catenin signaling pathway
- Author
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Zhuo Liu, Lai Jiang, Dechuan Li, Bo Li, Min Lv, Gang Wang, and Yu-ping Zhu
- Subjects
0301 basic medicine ,Wnt/β-catenin ,Oncogene ,Colorectal cancer ,Cell growth ,proliferation ,Wnt signaling pathway ,colorectal cancer ,SNHG1 ,Biology ,medicine.disease ,medicine.disease_cause ,Metastasis ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Cyclin D1 ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,medicine ,metastasis ,Gene silencing ,Carcinogenesis ,Research Paper - Abstract
Recently, the lncRNA small nucleolar RNA host gene (SNHG1) has been exhibited to be upregulated, which plays a crucial role in the development and prognosis of several cancers. However, the role of the biology and clinical significance of SNHG1 in the tumorigenesis of colorectal cancer (CRC) has rarely been reported. In this work, we firstly found that SNHG1 expression levels were upregulated aberrantly in colorectal cancer tissues and colorectal cancer cell lines. By Kaplan-Meier survival analysis, patients with high SNHG1 expression level had poorer overall survival (OS) and progression-free survival (PFS) than those with low SNHG1 expression. In multivariate analysis, increased SNHG1 expression was proved to be an independent unfavorable prognostic indicator for CRC. In vitro experiments revealed that SNHG1 silencing inhibited the growth and metastasis and induced apoptosis of CRC cell lines. Finally, we found that SNHG1 may induce the activation of the WNT/β-catenin pathway through regulating β-catenin expression and transcription factor-4 (TCF-4), cyclin D1 and MMP-9. Altogether, our findings demonstrated that lncRNA SNHG1, was high expressed in colorectal cancer tissues and may serve as a tumor oncogene through regulating WNT/β-catenin signal pathway, which provided a candidate diagnostic biomarker and a promising therapeutic target for patients with CRC.
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- 2017
39. Pathway-focused PCR array profiling of CAL-27 cell with over-expressed ZNF750
- Author
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Cong Xu, Haiying Chen, Wenqiang Tang, Keyi Li, Shuangfeng Chen, Hongli Yang, Zhen Meng, and Li Pan
- Subjects
0301 basic medicine ,PCR array ,Cell ,Wnt signaling pathway ,Biology ,Cell cycle ,FOSL1 ,Gene expression profiling ,03 medical and health sciences ,stomatognathic diseases ,030104 developmental biology ,medicine.anatomical_structure ,Cyclin D1 ,Oncology ,oral squamous cell carcinoma (OSCC) ,medicine ,Cancer research ,Zinc-finger protein 750 (ZNF750) ,Signal transduction ,Gene ,signal transduction ,Research Paper - Abstract
Zinc-finger protein 750 (ZNF750) is the potential anti-cancer gene in oral squamous cell carcinoma (OSCC). The present study was to investigate the expression changes of ZNF750 in OSCC tissue and to reveal the induction of altered mRNA expression profiles caused by over-expressed ZNF750 in CAL-27 cell. The expression level of ZNF750 in tissue specimens from OSCC patients was detected by immunohistochemistry. Gene expression profiling was performed using Human Signal Transduction PathwayFinder RT2 Profiler™ PCR Array. The expression changes of 84 key genes representing 10 signal transduction pathways in human following over-expressed ZNF750 in CAL-27 cell was examined. The expression of ZNF750 protein was reduced in OSCC tissues. The R2 PCR Array analysis revealed that 39 of the 84 examined genes that changed at least a two-fold between control and ZNF750 groups. These genes related to oxidative stress, WNT, JAK/STAT, TGFβ, NF-kappaB (NFκB), p53, Notch, Hedgehog, PPAR and Hypoxia signaling. ZNF750 could inhibit the candidate genes ATF4, SQSTM1, HMOX1, CCND1, TNF-alpha, TNFSF10 and FOSL1 but activate CDKN1A and EMP1. Our studies suggest that ZNF750 can regulate signaling pathways that related to proliferation, cell cycle, inflammation and oxidative stress in CAL-27 cell.
- Published
- 2017
40. MEF2 signaling and human diseases
- Author
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Murugavel Ponnusamy, Zhijuan Lin, Bing Gao, Xiao Chen, and Jia Liu
- Subjects
0301 basic medicine ,Mef2 ,human diseases ,signaling pathway ,Protein family ,Wnt signaling pathway ,Review ,Biology ,musculoskeletal system ,microRNAs ,03 medical and health sciences ,030104 developmental biology ,Oncology ,microRNA ,Signal transduction ,MEF2 ,Neuroscience ,Protein kinase B ,Function (biology) ,PI3K/AKT/mTOR pathway - Abstract
The members of myocyte Enhancer Factor 2 (MEF2) protein family was previously believed to function in the development of heart and muscle. Recent reports indicate that they are also closely associated with development and progression of many human diseases. Although their role in cancer biology is well established, the molecular mechanisms underlying their action is yet largely unknown. MEF2 family is closely associated with various signaling pathways, including Ca2+ signaling, MAP kinase signaling, Wnt signaling, PI3K/Akt signaling, etc. microRNAs also contribute to regulate the activities of MEF2. In this review, we summarize the known molecular mechanism by which MEF2 family contribute to human diseases.
- Published
- 2017
41. Dishevelled1-3 contribute to multidrug resistance in colorectal cancer via activating Wnt/β-catenin signaling
- Author
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Ping Yang, Xiaozhen Dai, Yuanyuan Wang, Liaotian Peng, Junjie Gou, Houyi Huang, Mengju Jiang, Quekun Peng, Kun Zhang, Linpeng Li, Yuhan Yang, Jie Yang, Minhui Li, Ting Li, Tao Zhang, Linyi Chen, and Li Feng
- Subjects
0301 basic medicine ,chemistry.chemical_classification ,Wnt/β-catenin ,Abcg2 ,biology ,Colorectal cancer ,Multidrug resistance-associated protein 2 ,dishevelled ,Wnt signaling pathway ,colorectal cancer ,medicine.disease ,Dishevelled ,03 medical and health sciences ,030104 developmental biology ,Oncology ,chemistry ,Multidrug Resistance Protein 1 ,multidrug resistance ,Survivin ,Cancer research ,biology.protein ,medicine ,Gene silencing ,drug sensitivity ,Research Paper - Abstract
Multidrug resistance is a great obstacle in successful chemotherapy of colorectal cancer. However, the molecular mechanism underlying multidrug resistance is not fully understood. Dishevelled, a pivot in Wnt signaling, has been linked to cancer progression, while its role in chemoresistance remains unclear. Here, we found that Dishevelled1-3 was over-expressed in multidrug-resistant colorectal cancer cells (HCT-8/VCR) compared to their parental cells. Silencing Dishevelled1-3 resensitized HCT-8/VCR cells to multiple drugs including vincristine, 5-fluorouracil and oxaliplatin. Moreover, Dishevelled1-3 increased the protein levels of multidrug resistance protein 1 (P-gp/MDR1), multidrug resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP), Survivin and Bcl-2 which are correlated with multidrug resistance. shβ-catenin abolished Dishevelled-mediated these protein expressions. Unexpectedly, none of Dishevelled1-3 controlled β-catenin accumulation and nuclear translocation. Furthermore, the nuclear translocations of Dishevelled1-3 were promoted in HCT-8/VCR cells compared to HCT-8. Dishevelled1-3 bound to β-catenin in nucleus, and promoted nuclear complex formation and transcription activity of β-catenin/TCF. Taken together, Dishevelled1-3 contributed to multidrug resistance in colorectal cancer via activating Wnt/β-catenin signaling and inducing the expressions of P-gp, MRP2, BCRP, Survivin and Bcl-2, independently of β-catenin accumulation and nuclear translocation. Silencing Dishevelled1-3 resensitized multidrug-resistant colorectal cancer cells, providing a novel therapeutic target for successful chemotherapy of colorectal cancer.
- Published
- 2017
42. Recombinant frizzled1 protein attenuated cardiac hypertrophy after myocardial infarction via the canonical Wnt signaling pathway
- Author
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Stefan E. Hardt, Min Zhang, Lin Qiu, Johannes Riffel, Soeren Meryer, Lin Wang, Ben Ma, Dao Wen Wang, Hongyu Qiu, Marco Hagenmueller, Jingjing Fan, Ning Zhou, and Hongyang Shu
- Subjects
0301 basic medicine ,Cardiac function curve ,FZD1 ,medicine.medical_specialty ,030204 cardiovascular system & hematology ,Sudden death ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Myocardial infarction ,Receptor ,Glycogen synthase ,wnt signaling pathway ,biology ,business.industry ,cardiac hypertrophy ,fungi ,Wnt signaling pathway ,medicine.disease ,3. Good health ,030104 developmental biology ,Endocrinology ,myocardial infarction ,Oncology ,Heart failure ,biology.protein ,business ,recombinant protein ,Research Paper ,frizzled1 - Abstract
Postinfarct cardiac hypertrophy is an independent risk factor for heart failure and sudden death. Regression of cardiac hypertrophy has emerged as a promising strategy in the treatment of myocardial infarction (MI). Here we hypothesized that frizzled1 (FZD1), a receptor of the canonical Wnt signaling pathway, is a novel mediator of ischemia-associated cardiac hypertrophy. MI was induced in mice by left anterior descending (LAD) coronary occlusion. One week after MI, the expression of FZD1 was found to be notably increased in the left ventricles (LVs) of the MI-mice compared to shams. Mouse recombinant FZD1 protein (RFP) was subcutaneously injected in the mice to provoke autoimmunization response. Anti-FZD1 antibody titer was significantly increased in the plasma of RFP-treated mice. RFP significantly mitigated the MI-induced cardiac hypertrophy and improved cardiac function in the MI mouse hearts. Moreover, increased heart and LV weights, myocardial size and the expression of β-myosin heavy chain in the MI-mice were also found to be attenuated by RFP. FZD1 was found to be significantly up-regulated in hypoxia-treated neonatal rat cardiomyocytes (NRCMs). Silencing FZD1 by siRNA transfection notably repressed the hypoxia-induced myocardial hypertrophy in NRCMs. Mechanistically, activation of canonical Wnt signaling induced by MI, e.g., β-catenin and glycogen synthase kinase-3β, was restrained in the LVs of the MI-mice treated by RFP, these inhibition on canonical Wnt signaling was further confirmed in hypoxic NRCMs transfected with FZD1 siRNA. In conclusion, immunization of RFP attenuated cardiac hypertrophy and improved cardiac function in the MI mice via blocking the canonical Wnt signaling pathway.
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- 2017
43. Colon cancer-induced interleukin-35 inhibits beta-catenin-mediated pro-oncogenic activity
- Author
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Yueqiang Jiang, JianHai Sun, RuiChao Li, and Yanling Ma
- Subjects
0301 basic medicine ,Beta-catenin ,biology ,business.industry ,Colorectal cancer ,Wnt signaling pathway ,Cancer ,medicine.disease ,Metastasis ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Cancer stem cell ,030220 oncology & carcinogenesis ,Interleukin 35 ,biology.protein ,Colon neoplasm ,Cancer research ,Medicine ,business - Abstract
The occurrence and development of colon cancer is closely related to inflammation. Therefore, this study was conducted a current retrospective research to study the effect of IL-35 (interleukin 35), a newly identified anti-infective factor, on colon cancer development. The expression of IL-35 in colon cancer samples and their adjacent normal mucosa by real-time PCR, ELISA (enzyme-linked immunosorbent assay). The effect of IL-35 on patient survival, colon cancer progression, and its effect on Wnt/β-catenine signaling pathway was also assessed. IL-35 is minimally expressed in colon cancer tissues but is highly expressed in adjacent normal tissues. The down-regulation of IL-35 was significantly associated with the American Cancer Joint Committee stage and overall survival of colon cancer patients. The overexpression of IL-35 in colon cancer cells inhibits cell migration, invasion, proliferation, colony formation and cancer stem cells by inhibiting beta-catenin. IL-35 inhibits colon neoplasms in mouse. Our results suggest that IL-35 has an inhibitory effect on the development of colon cancer as a novel prognostic indicator and potential therapeutic target.
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- 2017
44. Expression of Wnt-signaling pathway genes and their associations with miRNAs in colorectal cancer
- Author
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Martha L. Slattery, Lori C. Sakoda, John R. Stevens, Roger K. Wolff, Lila E. Mullany, Wade S. Samowitz, Jennifer S. Herrick, and Impact Journals
- Subjects
0301 basic medicine ,Colorectal cancer ,colorectal cancer ,Biology ,Cell and Developmental Biology ,03 medical and health sciences ,0302 clinical medicine ,Gene expression ,microRNA ,medicine ,Gene ,Cancer Biology ,miRNA ,Messenger RNA ,Wnt signaling pathway ,medicine.disease ,Fold change ,3. Good health ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,gene expression ,Signal transduction ,Mathematics ,wnt-signaling ,Research Paper - Abstract
The Wnt-signaling pathway functions in regulating cell growth and thus is involved in the carcinogenic process of several cancers, including colorectal cancer. We tested the hypothesis that multiple genes in this signaling pathway are dysregulated and that miRNAs are associated with these dysregulated genes. We used data from 217 colorectal cancer (CRC) cases to evaluate differences in Wnt-signaling pathway gene expression between paired CRC and normal mucosa and identify miRNAs that are associated with these genes. Gene expression data from RNA-Seq and miRNA expression data from Agilent Human miRNA Microarray V19.0 were analyzed. We focused on genes most strongly associated with CRC (fold change (FC) of >1.5 or 1.50) after adjusting for multiple comparisons. Thirteen of the 66 Wnt-signaling genes that were differentially expressed in CRC tumors were associated with differential expression of miRNAs. A total of 93 miRNA:mRNA associations were detected for these 13 genes. Of these 93 associations, 36 miRNA seed-region matches were observed, suggesting that miRNAs have both direct and indirect effects on Wnt-signaling pathway genes. In summary, our data supports the hypothesis that the Wnt-signaling pathway is dysregulated in CRC and suggest that miRNAs may importantly influence that dysregulation.
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- 2017
45. Ubiquitin Specific Peptidase 15 (USP15) suppresses glioblastoma cell growth via stabilization of HECTD1 E3 ligase attenuating WNT pathway activity
- Author
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Maria Oikonomaki, Monika E. Hegi, and Pierre Bady
- Subjects
0301 basic medicine ,HECT domain ,WNT pathway ,biology ,Tumor suppressor gene ,HECTD1 ,tumor suppressor ,USP15 ,glioblastoma ,Mutant ,Wnt signaling pathway ,Ubiquitin ligase ,03 medical and health sciences ,030104 developmental biology ,Oncology ,Ubiquitin ,biology.protein ,Cancer research ,AXIN2 ,Ectopic expression ,Research Paper - Abstract
// Maria Oikonomaki 1 , Pierre Bady 1, 2, 3 and Monika E. Hegi 1 1 Department of Clinical Neurosciences, University Hospital Lausanne, Lausanne, Switzerland 2 Department of Research and Education, University Hospital Lausanne, Lausanne, Switzerland 3 Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland Correspondence to: Monika E. Hegi, email: Monika.Hegi@CHUV.ch Keywords: glioblastoma; USP15; HECTD1; tumor suppressor; WNT pathway Received: September 12, 2017 Accepted: November 13, 2017 Published: November 30, 2017 ABSTRACT Expression based prediction of new genomic alterations in glioblastoma identified the de-ubiquitinase Ubiquitin Specific Peptidase 15 ( USP15 ) as potential tumor suppressor gene associated with genomic deletions (11%). Ectopic expression of USP15 in glioblastoma cell-lines reduced colony formation and growth in soft agar, while overexpression of its functional mutant had the opposite effect. Evaluation of the protein binding network of USP15 by Mass Spectrometry in glioblastoma cells uncovered eight novel interacting proteins, including HECT Domain Containing E3 Ubiquitin Protein Ligase 1 (HECTD1), whose mouse homologue has been associated with an inhibitory effect on the WNT-pathway. USP15 de-ubiquitinated and thereby stabilized HECTD1 in glioblastoma cells, while depletion of USP15 led to decreased HECTD1 protein levels. Expression of USP15 in glioblastoma cells attenuated WNT-pathway activity, while expression of the functional mutant enhanced the activity. Modulation of HECTD1 expression pheno-copied the effects observed for USP15. In accordance, human glioblastoma display a weak but significant negative correlation between USP15 and AXIN2 expression. Taken together, the data provide evidence that USP15 attenuates the canonical WNT pathway mediated by stabilization of HECTD1, supporting a tumor suppressing role of USP15 in a subset of glioblastoma.
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- 2017
46. Exon 3 mutations ofCTNNB1drive tumorigenesis: a review
- Author
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Wei Zhang, Russell Broaddus, Chao Gao, Yingmei Wang, Longhao Sun, and Fengxia Xue
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0301 basic medicine ,Wnt signaling pathway ,Cancer ,Biology ,medicine.disease_cause ,medicine.disease ,3. Good health ,Cell biology ,03 medical and health sciences ,Exon ,030104 developmental biology ,Oncology ,medicine ,Progenitor cell ,Signal transduction ,Carcinogenesis ,Reprogramming ,Gene - Abstract
The canonical Wnt/β-catenin signaling pathway, an important modulator of progenitor cell proliferation and differentiation, is highly regulated for the maintenance of critical biological homeostasis. Decades of studies in cancer genetics and genomics have demonstrated that multiple genes encoding key proteins in this signaling pathway serve as targets for recurrent mutational alterations. Among these proteins, β-catenin and adenomatosis polyposis coli (APC) are two key nodes. β-catenin contributes in transporting extracellular signals for nuclear programming. Mutations of the CTNNB1 gene that encodes β-catenin occur in a wide spectrum of cancers. These mutations alter the spatial characteristics of the β-catenin protein, leading to drastic reprogramming of the nuclear transcriptional network. Among the outcomes of this reprogramming are increased cell proliferation, enhanced immunosuppression, and disruption of metabolic regulation. Herein we review the current understanding of CTNNB1 mutations, their roles in tumorigenesis and discuss their possible therapeutic implications for cancer.
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- 2017
47. Silencing ROR1 and ROR2 inhibits invasion and adhesion in an organotypic model of ovarian cancer metastasis
- Author
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Claire Henry, Neville F. Hacker, and Caroline E. Ford
- Subjects
epithelial ovarian cancer ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Stromal cell ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,omentum ,Internal medicine ,medicine ,metastasis ,Cell adhesion ,ROR1 ,ROR2 ,business.industry ,Cell growth ,Wnt signaling pathway ,Cell migration ,medicine.disease ,body regions ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Ovarian cancer ,business ,Research Paper - Abstract
// Claire Henry 1 , Neville Hacker 2 and Caroline Ford 1 1 Gynaecological Cancer Research Group, Lowy Cancer Research Centre and School of Women’s and Children’s Health, Faculty of Medicine, University of New South Wales, Sydney, Australia 2 Gynaecological Cancer Centre, Royal Hospital for Women, Sydney, Australia Correspondence to: Caroline Ford, email: caroline.ford@unsw.edu.au Keywords: ROR2; ROR1; epithelial ovarian cancer; omentum; metastasis Received: August 29, 2017 Accepted: October 27, 2017 Published: November 20, 2017 ABSTRACT OBJECTIVE: Elevated expression of the ROR1 and ROR2 Wnt receptors has been noted in both the tumour and stromal compartments of ovarian cancer patient tissue samples. In vitro studies have suggested these receptors play a role in ovarian cancer metastasis. However, these previous studies have utilised simple 2D in vitro models to investigate cancer cell growth and migration, which does not allow investigation of stromal involvement in Wnt driven metastasis. AIM: To investigate targeting ROR1 and ROR2 using a primary co-culture 3D model of epithelial ovarian cancer dissemination to the omentum. METHODS: Primary fibroblasts (NOF) and mesothelial (HPMC) cells were isolated from fresh samples of omentum collected from women with benign or non-metastatic conditions and cultured with collagen to produce a organotypic 3D model. Stable shRNA knockdown of ROR1, ROR2 and double ROR1/ROR2 in OVCAR4 cells were plated onto the 3D model to measure adhesion, or using a transwell to measure invasion. Gene expression changes in primary cells upon OVCAR4 interaction was evaluated using indirect transwell co-culture. RESULTS: Double knockdown of ROR1 and ROR2 strongly inhibited cell adhesion (p
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- 2017
48. Identification of WT1 as determinant of heptatocellular carcinoma and its inhibition by Chinese herbal medicine Salvia chinensis Benth and its active ingredient protocatechualdehyde
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Ning Wang, Yibin Feng, Yau-Tuen Chan, Wei Guo, Hor-Yue Tan, and Sha Li
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0301 basic medicine ,Pharmacology ,03 medical and health sciences ,0302 clinical medicine ,Transcription (biology) ,Carcinoma ,Wnt/β-catenin pathway ,Medicine ,Gene knockdown ,biology ,business.industry ,Cell growth ,Wnt signaling pathway ,hepatocellular carcinoma ,biology.organism_classification ,medicine.disease ,In vitro ,WT1 ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,molecular docking-guided bioactive ingredient identification ,Salvia chinensis ,Chinese herbal medicine ,business ,Research Paper - Abstract
Candidates from Chinese herbal Medicine might be preferable in drug discovery as the abundant experiences of traditional use usually hint the clinical efficacy. In this study, we screened the anti-tumour effect of several commonly used Chinese herbal Medicines on human hepatocellular carcinoma cells (HCC). We identified that Salvia chinensia Benth. (Shijianchuan in Chinese, SJC) exhibited prominent in vitro inhibition of HCC cells and suppressed the orthotopic growth of HCC in the liver of mice and repressed the lung metastasis of tumour cells. Using a pathway-specific PCR array and Gene Ontology analysis, we identified that Wnt/β-catenin pathway was associated with the suppressive effect of SJC on HCC cell proliferation and cell cycle progression. SJC repressed transcription activity of Wnt/β-catenin pathway and reduced expression of β-catenin in GSK-3β-independent but promoter-specific transcription inhibition mechanism. The suppressive effect of SJC on β-catenin expression and its transcription activity was associated with Wilms’ tumor 1 (WT1) protein. WT1 was overexpressed in HCC tissues, and was negatively correlated to the overall survival of HCC patients. WT1 promoted proliferation and invasion of HCC cells, as well as β-catenin-dependent transcription activation of Wnt products, while knockdown of WT1 had the opposite effect. Docking experiment revealed that protocatechualdehyde (PCA) might be the active component of the herb. PCA suppressed transcription activity of Wnt/β-catenin pathway in WT1-dependent manner. Our study sheds light on the potential of PCA from commonly used anti-cancer Chinese herbal Medicine SJC as a lead compound targeting WT1 in the discovery of anti-HCC drugs.
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- 2017
49. Ascl2 activation by YAP1/KLF5 ensures the self-renewability of colon cancer progenitor cells
- Author
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Xiaolong Wei, Haoyuan Chen, Li Liu, Jun Ye, Yangyang Shang, Shanxi Liu, and Rongquan Wang
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0301 basic medicine ,YAP1 ,Hippo signaling pathway ,Gene knockdown ,biology ,Chemistry ,Hippo signaling ,CD44 ,Wnt signaling pathway ,colorectal cancer ,progenitor cells ,Wnt signaling ,Cell biology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Cancer stem cell ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Progenitor cell ,achaete scute-like 2 ,Research Paper - Abstract
// Xiaolong Wei 1 , Jun Ye 1 , Yangyang Shang 1 , Haoyuan Chen 1 , Shanxi Liu 1 , Li Liu 1 and Rongquan Wang 1 1 Institute of Gastroenterology of PLA, Southwest Hospital, Third Military Medical University, Chongqing, China Correspondence to: Rongquan Wang, email: rongquanw@hotmail.com Keywords: achaete scute-like 2; Wnt signaling; Hippo signaling; colorectal cancer; progenitor cells Received: June 21, 2017 Accepted: November 08, 2017 Published: November 27, 2017 ABSTRACT Achaete scute-like 2 (Ascl2) is the Wnt signaling target, its regulation by other signaling is undefined. Now we demonstrated that CD133 + /CD44 + cell population from HT-29 or Caco-2 cells exhibited cancer stem cell (CSC) properties with highly expressed Ascl2, which is related to the Hippo signaling pathway. YAP1 interference in CD133 + /CD44 + HT-29 or Caco-2 cells reduced their proliferation, colony-forming ability and tumorsphere formation in vitro and inhibited the ‘stemness’-associated genes and Ascl2 expression. Enforcing YAP1 expression in HT-29 or Caco-2 cells triggered the opposite changes. Ascl2 interference reversed the phenotype of YAP1-enforced expressed HT-29 or Caco-2 cells. Kruppel-like factor 5 (KLF5) protein, not KLF5 mRNA levels, were increased due to YAP1 overexpression which is reported to prevent KLF5 degradation. Co-immunoprecipitation (Co-IP) assays demonstrated that YAP1 bound with KLF5 in HT-29 and Caco-2 cells. Luciferase and chromatin immunoprecipitation (ChIP) assays indicated that both YAP1 and KLF5 bound to the first two loci with GC-boxes in Ascl2 promoter and induced Ascl2 transcription. The decreased Ascl2 transcription by YAP1 interference required an intact KLF5 binding site (GC-box) within Ascl2 promoter, KLF5 knockdown reduced YAP1 binding and Ascl2 luciferase reporter activity upon YAP1 overexpression. Positive correlation among YAP1 and Ascl2 mRNA levels was observed in colorectal cancer (CRC) samples. Thus, our study demonstrated that Ascl2, a fate decider of CRC progenitor cells can be activated by the Hippo signaling pathway in CRC progenitor cells, and ensured their self-renewability.
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- 2017
50. LRP6 promotes invasion and metastasis of colorectal cancer through cytoskeleton dynamics
- Author
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Haijing Liu, Wei Hou, Qian Yao, Bo Zhang, Lin Hou, Yu An, Yanan Cao, Hong Zhang, Mengfei Yao, and Ningning Ma
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0301 basic medicine ,LRP6 ,Colorectal cancer ,Wnt signaling pathway ,Actin remodeling ,RAC1 ,colorectal cancer ,cytoskeleton ,Biology ,medicine.disease ,Wnt signaling ,Metastasis ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,MACF1 ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,Phosphorylation ,metastasis ,Research Paper - Abstract
Low density lipoprotein (LDL) receptor-related protein-6 (LRP6) is an important co-receptor of Wnt pathway, which plays a predominant role in development and progression of colorectal cancer. Recently, dysregulation of LRP6 has proved to be involved in the progression of cancers, but its biological role and clinical significance in colorectal cancer remain unclear. In present study, we revealed that phosphorylation of LRP6 was aberrantly upregulated in colorectal carcinoma correlating with TNM or Dukes staging and worse prognosis. In addition, phosphorylated LRP6 was positively correlated with nuclear accumulation of β-catenin. Overexpression or activation of LRP6 could activate Wnt signaling and promote tumor cell migration in vitro. The activation of LRP6 could induce microtubule dynamics and actin remodeling, probably through regulation of microtubule-associated protein 1B (MAP1B), microtubule actin cross-linking factor 1 (MACF1) and Rho GTPase--RhoA and Rac1. The investigation suggests that LRP6 may be a potential prognostic marker and therapeutic target in the progression of colorectal cancers.
- Published
- 2017
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