22 results on '"Xiong X"'
Search Results
2. Targeting type Iγ phosphatidylinositol phosphate kinase inhibits breast cancer metastasis
- Author
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Chen, C, Wang, X, Xiong, X, Liu, Q, Huang, Y, Xu, Q, Hu, J, Ge, G, and Ling, K
- Published
- 2015
- Full Text
- View/download PDF
3. Ribosomal protein S27-like and S27 interplay with p53-MDM2 axis as a target, a substrate and a regulator
- Author
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Xiong, X, Zhao, Y, He, H, and Sun, Y
- Published
- 2011
- Full Text
- View/download PDF
4. RNF126 promotes homologous recombination via regulation of E2F1-mediated BRCA1 expression
- Author
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Wang, Y, primary, Deng, O, additional, Feng, Z, additional, Du, Z, additional, Xiong, X, additional, Lai, J, additional, Yang, X, additional, Xu, M, additional, Wang, H, additional, Taylor, D, additional, Yan, C, additional, Chen, C, additional, Difeo, A, additional, Ma, Z, additional, and Zhang, J, additional
- Published
- 2015
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5. Targeting type Iγ phosphatidylinositol phosphate kinase inhibits breast cancer metastasis
- Author
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Chen, C, primary, Wang, X, additional, Xiong, X, additional, Liu, Q, additional, Huang, Y, additional, Xu, Q, additional, Hu, J, additional, Ge, G, additional, and Ling, K, additional
- Published
- 2014
- Full Text
- View/download PDF
6. Ribosomal protein S27-like and S27 interplay with p53-MDM2 axis as a target, a substrate and a regulator
- Author
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Xiong, X, primary, Zhao, Y, additional, He, H, additional, and Sun, Y, additional
- Published
- 2010
- Full Text
- View/download PDF
7. METTL3-mediated m 6 A modification of lncRNA TSPAN12 promotes metastasis of hepatocellular carcinoma through SENP1-depentent deSUMOylation of EIF3I.
- Author
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Li B, Xiong X, Xu J, Peng D, Nie G, Wen N, Wang Y, and Lu J
- Subjects
- Humans, Cell Line, Tumor, Cell Movement, Cysteine Endopeptidases genetics, Cysteine Endopeptidases metabolism, Epithelial-Mesenchymal Transition, Eukaryotic Initiation Factor-3 genetics, Eukaryotic Initiation Factor-3 metabolism, Gene Expression Regulation, Neoplastic, Methyltransferases genetics, Methyltransferases metabolism, Wnt Signaling Pathway, Carcinoma, Hepatocellular metabolism, Carcinoma, Hepatocellular pathology, Liver Neoplasms pathology, RNA, Long Noncoding genetics, Tetraspanins
- Abstract
In a previous study, we discovered that the level of lnc-TSPAN12 was significantly elevated in hepatocellular carcinoma (HCC) and correlated with a low survival rate. However, the function and mechanism of lnc-TSPAN12 in modulating epithelial-mesenchymal transition (EMT) and metastasis in HCC remains poorly understood. This study demonstrates that lnc-TSPAN12 positively influences migration, invasion, and EMT of HCC cells in vitro and promotes hepatic metastasis in vivo. The modification of N6-methyladenosine, driven by METTL3, is essential for the stability of lnc-TSPAN12, which may partially contribute to the upregulation of lnc-TSPAN12. Mechanistically, lnc-TSPAN12 exhibits direct interactions with EIF3I and SENP1, acting as a scaffold to enhance the SENP1-EIF3I interaction. As a result, the SUMOylation of EIF3I is inhibited, preventing its ubiquitin-mediated degradation. Ultimately, this activates the Wnt/β-catenin signaling pathway, stimulating EMT and metastasis in HCC. Our findings shed light on the regulatory mechanism of lnc-TSPAN12 in HCC metastasis and identify the lnc-TSPAN12-EIF3I/SENP1 axis as a novel therapeutic target for HCC., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2024
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8. UBE3B promotes breast cancer progression by antagonizing HIF-2α degradation.
- Author
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Wang Y, Liu X, Wang M, Wang Y, Wang S, Jin L, Liu M, Zhou J, and Chen Y
- Subjects
- Humans, Female, Basic Helix-Loop-Helix Transcription Factors genetics, Basic Helix-Loop-Helix Transcription Factors metabolism, Von Hippel-Lindau Tumor Suppressor Protein metabolism, Ubiquitination, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Ubiquitin-Protein Ligases genetics, Ubiquitin-Protein Ligases metabolism, Breast Neoplasms genetics, Lung Neoplasms
- Abstract
Mutations in E3 ubiquitin ligase UBE3B have been linked to Kaufman Oculocerebrofacial Syndrome (KOS). Accumulating evidence indicates that UBE3B may play an important role in cancer. However, the precise role of UBE3B in cancer and the underlying mechanism remain largely uncharted. Here, we reported that UBE3B is an E3 ligase for hypoxia-inducible factor 2α (HIF-2α). Mechanically, UBE3B physically interacts with HIF-2α and promotes its lysine 63 (K63)-linked polyubiquitination, thereby inhibiting the Von Hippel-Lindau (VHL) E3 ligase complex-mediated HIF-2α degradation. UBE3B depletion inhibits breast cancer cell proliferation, colony formation, migration, and invasion in vitro and suppresses breast tumor growth and lung metastasis in vivo. We further identified K394, K497, and K503 of HIF-2α as key ubiquitination sites for UBE3B. K394/497/503R mutation of HIF-2α dramatically abolishes UBE3B-mediated breast cancer growth and lung metastasis. Intriguingly, the protein levels of UBE3B are upregulated and positively correlated with HIF-2α protein levels in breast cancer tissues. These findings uncover a critical mechanism underlying the role of UBE3B in HIF-2α regulation and breast cancer progression., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2023
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9. CPEB3 suppresses gastric cancer progression by inhibiting ADAR1-mediated RNA editing via localizing ADAR1 mRNA to P bodies.
- Author
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Chen J, Li L, Liu TY, Fu HF, Lai YH, Lei X, Xu JF, Yu JS, Xia YJ, Zhang TH, Yang DJ, and He YL
- Subjects
- 3' Untranslated Regions genetics, Adenosine Deaminase genetics, Adenosine Deaminase metabolism, Animals, Mice, Nucleotides, RNA, Messenger genetics, RNA, Messenger metabolism, RNA-Binding Proteins genetics, RNA-Binding Proteins metabolism, RNA Editing genetics, Stomach Neoplasms genetics, Stomach Neoplasms pathology
- Abstract
Deciphering the crosstalk between RNA-binding proteins and corresponding RNAs will provide a better understanding of gastric cancer (GC) progression. The comprehensive bioinformatics study identified cytoplasmic polyadenylation element-binding protein 3 (CPEB3) might play a vital role in GC progression. Then we found CPEB3 was downregulated in GC and correlated with prognosis. In addition, CPEB3 suppressed GC cell proliferation, invasion and migration in vitro, as well as tumor growth and metastasis in vivo. Mechanistic study demonstrated CPEB3 interacted with 3'-UTR of ADAR1 mRNA through binding to CPEC nucleotide element, and then inhibited its translation by localizing it to processing bodies (P bodies), eventually leading to the suppression of ADAR1-mediated RNA editing. Microscale thermophoresis assay further revealed that the direct interaction between CPEB3 and GW182, the P-body's major component, was through the 440-698AA region of CPEB3 binding to the 403-860AA region of GW182. Finally, AAV9-CPEB3 was developed and administrated in mouse models to assess its potential value in gene therapy. We found AAV9-CPEB3 inhibited GC growth and metastasis. Besides, AAV9-CPEB3 induced hydropic degeneration in mouse liver, but did not cause kidney damage. These findings concluded that CPEB3 suppresses GC progression by inhibiting ADAR1-mediated RNA editing via localizing ADAR1 mRNA to P bodies., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2022
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10. Correction: Repurposing dextromethorphan and metformin for treating nicotine-induced cancer by directly targeting CHRNA7 to inhibit JAK2/STAT3/SOX2 signaling.
- Author
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Wang L, Du L, Xiong X, Lin Y, Zhu J, Yao Z, Wang S, Guo Y, Chen Y, Geary K, Pan Y, Zhou F, Gao S, Zhang D, Yeung SJ, and Zhang H
- Published
- 2021
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11. The Chk2-PKM2 axis promotes metabolic control of vasculogenic mimicry formation in p53-mutated triple-negative breast cancer.
- Author
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Yu P, Zhu X, Zhu JL, Han YB, Zhang H, Zhou X, Yang L, Xia YZ, Zhang C, and Kong LY
- Subjects
- Humans, Female, Cell Line, Tumor, Animals, Mice, Mutation, Glucose metabolism, Checkpoint Kinase 2 metabolism, Checkpoint Kinase 2 genetics, Thyroid Hormone-Binding Proteins, Tumor Suppressor Protein p53 metabolism, Tumor Suppressor Protein p53 genetics, Triple Negative Breast Neoplasms genetics, Triple Negative Breast Neoplasms pathology, Triple Negative Breast Neoplasms metabolism, Membrane Proteins metabolism, Membrane Proteins genetics, Carrier Proteins metabolism, Carrier Proteins genetics, Thyroid Hormones metabolism, Thyroid Hormones genetics, Neovascularization, Pathologic genetics, Neovascularization, Pathologic metabolism, Neovascularization, Pathologic pathology
- Abstract
Vasculogenic mimicry (VM) formation, which participates in the process of neovascularization, is highly activated in p53-mutated triple-negative breast cancer (TNBC). Here, we show that Chk2 is negatively correlated with VM formation in p53-mutated TNBC. Its activation by DNA-damaging agents such as cisplatin, etoposide, and DPT reduces VM formation. Mechanistically, the Chk2-PKM2 axis plays an important role in the inhibition of VM formation at the level of metabolic regulation. Chk2 promotes the Chk2-PKM2 interaction through the Chk2 SCD (SQ/TQ cluster domain) and the PKM2 C domain. Furthermore, Chk2 promotes the nuclear export of PKM2 by phosphorylating PKM2 at Ser100. P-PKM2 S100 reduces VM formation by decreasing glucose flux, and the PKM2 S100A mutation abolishes the inhibition of glucose flux and VM formation induced by Chk2 activation. Overall, this study proposes a novel strategy of VM suppression through Chk2 induction, which prevents PKM2-mediated glucose flux in p53-mutated TNBC., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2021
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12. Repurposing dextromethorphan and metformin for treating nicotine-induced cancer by directly targeting CHRNA7 to inhibit JAK2/STAT3/SOX2 signaling.
- Author
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Wang L, Du L, Xiong X, Lin Y, Zhu J, Yao Z, Wang S, Guo Y, Chen Y, Geary K, Pan Y, Zhou F, Gao S, Zhang D, Yeung SJ, and Zhang H
- Subjects
- Animals, Carcinogenesis drug effects, Cell Line, Tumor, DNA Methylation drug effects, Dextromethorphan pharmacology, Drug Repositioning, Electronic Nicotine Delivery Systems, Esophageal Squamous Cell Carcinoma chemically induced, Esophageal Squamous Cell Carcinoma genetics, Esophageal Squamous Cell Carcinoma pathology, Female, Gene Expression Regulation, Neoplastic drug effects, Heterografts, Humans, Male, Metformin pharmacology, Mice, Nicotine toxicity, Esophageal Squamous Cell Carcinoma drug therapy, Janus Kinase 2 genetics, SOXB1 Transcription Factors genetics, STAT3 Transcription Factor genetics, alpha7 Nicotinic Acetylcholine Receptor genetics
- Abstract
Smoking is one of the most impactful lifestyle-related risk factors in many cancer types including esophageal squamous cell carcinoma (ESCC). As the major component of tobacco and e-cigarettes, nicotine is not only responsible for addiction to smoking but also a carcinogen. Here we report that nicotine enhances ESCC cancer malignancy and tumor-initiating capacity by interacting with cholinergic receptor nicotinic alpha 7 subunit (CHRNA7) and subsequently activating the JAK2/STAT3 signaling pathway. We found that aberrant CHRNA7 expression can serve as an independent prognostic factor for ESCC patients. In multiple ESCC mouse models, dextromethorphan and metformin synergistically repressed nicotine-enhanced cancer-initiating cells (CIC) properties and inhibited ESCC progression. Mechanistically, dextromethorphan non-competitively inhibited nicotine binding to CHRNA7 while metformin downregulated CHRNA7 expression by antagonizing nicotine-induced promoter DNA hypomethylation of CHRNA7. Since dextromethorphan and metformin are two safe FDA-approved drugs with minimal undesirable side-effects, the combination of these drugs has a high potential as either a preventive and/or a therapeutic strategy against nicotine-promoted ESCC and perhaps other nicotine-sensitive cancer types as well.
- Published
- 2021
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13. Inhibition of protein tyrosine phosphatase receptor type F suppresses Wnt signaling in colorectal cancer.
- Author
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Gan T, Stevens AT, Xiong X, Wen YA, Farmer TN, Li AT, Stevens PD, Golshani S, Weiss HL, Evers BM, and Gao T
- Subjects
- Animals, Cell Line, Tumor, Cell Proliferation genetics, Colorectal Neoplasms genetics, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Humans, Mice, Neoplastic Stem Cells pathology, Oncogene Proteins genetics, Receptor-Like Protein Tyrosine Phosphatases, Class 2 genetics, Xenograft Model Antitumor Assays, Carcinogenesis pathology, Colorectal Neoplasms pathology, Oncogene Proteins metabolism, Receptor-Like Protein Tyrosine Phosphatases, Class 2 metabolism, Wnt Signaling Pathway
- Abstract
Wnt signaling dysregulation promotes tumorigenesis in colorectal cancer (CRC). We investigated the role of PTPRF, a receptor-type tyrosine phosphatase, in regulating Wnt signaling in CRC. Knockdown of PTPRF decreased cell proliferation in patient-derived primary colon cancer cells and established CRC cell lines. In addition, the rate of proliferation as well as colony formation ability were significantly decreased in tumor organoids grown in 3D, whereas the number of differentiated tumor organoids were markedly increased. Consistently, knockdown of PTPRF resulted in a decrease in the expression of genes associated with cancer stem cells downstream of Wnt/β-catenin signaling. Treating PTPRF knockdown cells with GSK3 inhibitor rescued the expression of Wnt target genes suggesting that PTPRF functions upstream of the β-catenin destruction complex. PTPRF was found to interact with LRP6 and silencing PTPRF largely decreased the activation of LRP6. Interestingly, this PTPRF-mediated activation of Wnt signaling was blocked in cells treated with clathrin endocytosis inhibitor. Furthermore, knockdown of PTPRF inhibited xenograft tumor growth in vivo and decreased the expression of Wnt target genes. Taken together, our studies identify a novel role of PTPRF as an oncogenic protein phosphatase in supporting the activation of Wnt signaling in CRC.
- Published
- 2020
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14. DEPTOR is an in vivo tumor suppressor that inhibits prostate tumorigenesis via the inactivation of mTORC1/2 signals.
- Author
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Chen X, Xiong X, Cui D, Yang F, Wei D, Li H, Shu J, Bi Y, Dai X, Gong L, Sun Y, and Zhao Y
- Subjects
- Animals, Cell Movement, Cell Proliferation, Cell Survival, Gene Knockdown Techniques, Heterozygote, Humans, Intracellular Signaling Peptides and Proteins deficiency, Intracellular Signaling Peptides and Proteins genetics, Male, Membrane Proteins deficiency, Membrane Proteins genetics, Mice, Neoplasm Invasiveness, PTEN Phosphohydrolase deficiency, PTEN Phosphohydrolase genetics, Prostatic Neoplasms metabolism, Carcinogenesis, Intracellular Signaling Peptides and Proteins metabolism, Mechanistic Target of Rapamycin Complex 1 metabolism, Mechanistic Target of Rapamycin Complex 2 metabolism, Prostatic Neoplasms pathology, Signal Transduction
- Abstract
The DEPTOR-mTORC1/2 axis has been shown to play an important, but a context dependent role in the regulation of proliferation and the survival of various cancer cells in cell culture settings. The in vivo role of DEPTOR in tumorigenesis remains elusive. Here we showed that the levels of both DEPTOR protein and mRNA were substantially decreased in human prostate cancer tissues, which positively correlated with disease progression. DEPTOR depletion accelerated proliferation and survival, migration, and invasion in human prostate cancer cells. Mechanistically, DEPTOR depletion not only activated both mTORC1 and mTORC2 signals to promote cell proliferation and survival, but also induced an AKT-dependent epithelial-mesenchymal transition (EMT) and β-catenin nuclear translocation to promote cell migration and invasion. Abrogation of mTOR or AKT activation rescued the biological consequences of DEPTOR depletion. Importantly, in a Deptor-KO mouse model, Deptor knockout accelerated prostate tumorigenesis triggered by Pten loss via the activation of mTOR signaling. Collectively, our study demonstrates that DEPTOR is a tumor suppressor in the prostate, and its depletion promotes tumorigenesis via the activation of mTORC1 and mTORC2 signals. Thus, DEPTOR reactivation via a variety of means would have therapeutic potential for the treatment of prostate cancer.
- Published
- 2020
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15. TXNDC9 regulates oxidative stress-induced androgen receptor signaling to promote prostate cancer progression.
- Author
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Feng T, Zhao R, Sun F, Lu Q, Wang X, Hu J, Wang S, Gao L, Zhou Q, Xiong X, Dong X, Wang L, and Han B
- Subjects
- Animals, Benzamides, Cell Proliferation genetics, Disease Progression, Gene Expression Regulation, Neoplastic genetics, Heterografts, Humans, Male, Mice, Nitriles, Oxidative Stress genetics, Peroxiredoxins antagonists & inhibitors, Phenylthiohydantoin analogs & derivatives, Phenylthiohydantoin pharmacology, Prostate metabolism, Prostate pathology, Prostatic Neoplasms, Castration-Resistant genetics, Prostatic Neoplasms, Castration-Resistant pathology, Protein Stability, Proto-Oncogene Proteins c-mdm2 genetics, Quinoxalines pharmacology, Reactive Oxygen Species metabolism, Signal Transduction, Peroxiredoxins genetics, Prostatic Neoplasms, Castration-Resistant drug therapy, Receptors, Androgen genetics, Thioredoxins genetics
- Abstract
Reactive oxygen species (ROS) and ROS-induced oxidative stress are associated with prostate cancer (PCa) development and castrate-resistant tumor progression. This is in part through the activation of the androgen receptor (AR) signaling. However, the molecular underpinning of ROS to activate AR remains poorly understood. Here, we report that the thioredoxin domain-containing 9 (TXNDC9) is an important regulator of ROS to trigger AR signaling. TXNDC9 expression is upregulated by ROS inducer, and increased TXNDC9 expression in patient tumors is associated with advanced clinical stages. TXNDC9 promotes PCa cell survival and proliferation. It is required for AR protein expression and AR transcriptional activity under oxidative stress conditions. Mechanistically, ROS inducers promote TXNDC9 to dissociate from PRDX1, but enhance a protein association with MDM2. Concurrently, PRDX1 enhances its association with AR. These protein interaction exchanges result in not only MDM2 protein degradation, but also PRDX1 mediated AR protein stabilization, and subsequent elevation of AR signaling. Blocking PRDX1 by its inhibitor, Conoidin A (CoA), suppresses AR signaling, PCa cell proliferation, and xenograft tumor growth even under androgen-deprived conditions. These tumor-suppressive effects of CoA were further strengthened when in combination with enzalutamide treatment. Together, these studies demonstrate that the TXNDC9-PRDX1 axis plays an important role for ROS to activate AR functions. It provides a proof-of-principle that co-targeting AR and PRDX1 may be more effective to control PCa growth.
- Published
- 2020
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16. Targeting the TR4 nuclear receptor-mediated lncTASR/AXL signaling with tretinoin increases the sunitinib sensitivity to better suppress the RCC progression.
- Author
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Shi H, Sun Y, He M, Yang X, Hamada M, Fukunaga T, Zhang X, and Chang C
- Subjects
- Animals, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Renal Cell genetics, Carcinoma, Renal Cell pathology, Cell Hypoxia genetics, Cell Line, Tumor, Cell Movement drug effects, Cell Movement genetics, Disease Progression, Drug Resistance, Neoplasm drug effects, Drug Resistance, Neoplasm genetics, Gene Expression Regulation, Neoplastic drug effects, Humans, Kidney Neoplasms genetics, Kidney Neoplasms pathology, Metformin pharmacology, Metformin therapeutic use, Mice, RNA, Long Noncoding metabolism, RNA, Small Interfering metabolism, Receptors, Steroid genetics, Receptors, Thyroid Hormone genetics, Signal Transduction drug effects, Signal Transduction genetics, Sunitinib therapeutic use, Tretinoin pharmacology, Tretinoin therapeutic use, Xenograft Model Antitumor Assays, Axl Receptor Tyrosine Kinase, Antineoplastic Combined Chemotherapy Protocols pharmacology, Carcinoma, Renal Cell drug therapy, Kidney Neoplasms drug therapy, Proto-Oncogene Proteins genetics, RNA, Long Noncoding genetics, Receptor Protein-Tyrosine Kinases genetics, Receptors, Steroid metabolism, Receptors, Thyroid Hormone metabolism, Sunitinib pharmacology
- Abstract
Renal cell carcinoma (RCC) is one of the most lethal urological tumors. Using sunitinib to improve the survival has become the first-line therapy for metastatic RCC patients. However, the occurrence of sunitinib resistance in the clinical application has curtailed its efficacy. Here we found TR4 nuclear receptor might alter the sunitinib resistance to RCC via altering the TR4/lncTASR/AXL signaling. Mechanism dissection revealed that TR4 could modulate lncTASR (ENST00000600671.1) expression via transcriptional regulation, which might then increase AXL protein expression via enhancing the stability of AXL mRNA to increase the sunitinib resistance in RCC. Human clinical surveys also linked the expression of TR4, lncTASR, and AXL to the RCC survival, and results from multiple RCC cell lines revealed that targeting this newly identified TR4-mediated signaling with small molecules, including tretinoin, metformin, or TR4-shRNAs, all led to increase the sunitinib sensitivity to better suppress the RCC progression, and our preclinical study using the in vivo mouse model further proved tretinoin had a better synergistic effect to increase sunitinib sensitivity to suppress RCC progression. Future successful clinical trials may help in the development of a novel therapy to better suppress the RCC progression.
- Published
- 2020
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17. KLF4 as a rheostat of osteolysis and osteogenesis in prostate tumors in the bone.
- Author
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Tassone E, Bradaschia-Correa V, Xiong X, Sastre-Perona A, Josephson AM, Khodadadi-Jamayran A, Melamed J, Bu L, Kahler DJ, Ossowski L, Leucht P, Schober M, and Wilson EL
- Subjects
- Animals, Cell Line, Tumor, Cell Proliferation genetics, Cohort Studies, Heterografts, Humans, Kruppel-Like Factor 4, Kruppel-Like Transcription Factors genetics, Kruppel-Like Transcription Factors metabolism, Male, Mice, Prostatic Neoplasms genetics, Prostatic Neoplasms metabolism, Bone Neoplasms secondary, Kruppel-Like Transcription Factors physiology, Osteolysis physiopathology, Prostatic Neoplasms pathology
- Abstract
We previously showed that KLF4, a gene highly expressed in murine prostate stem cells, blocks the progression of indolent intraepithelial prostatic lesions into aggressive and rapidly growing tumors. Here, we show that the anti-tumorigenic effect of KLF4 extends to PC3 human prostate cancer cells growing in the bone. We compared KLF4 null cells with cells transduced with a DOX-inducible KLF4 expression system, and find KLF4 function inhibits PC3 growth in monolayer and soft agar cultures. Furthermore, KLF4 null cells proliferate rapidly, forming large, invasive, and osteolytic tumors when injected into mouse femurs, whereas KLF4 re-expression immediately after their intra-femoral inoculation blocks tumor development and preserves a normal bone architecture. KLF4 re-expression in established KLF4 null bone tumors inhibits their osteolytic effects, preventing bone fractures and inducing an osteogenic response with new bone formation. In addition to these profound biological changes, KLF4 also induces a transcriptional shift from an osteolytic program in KLF4 null cells to an osteogenic program. Importantly, bioinformatic analysis shows that genes regulated by KLF4 overlap significantly with those expressed in metastatic prostate cancer patients and in three individual cohorts with bone metastases, strengthening the clinical relevance of the findings in our xenograft model.
- Published
- 2019
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18. Radiation-promoted CDC6 protein stability contributes to radioresistance by regulating senescence and epithelial to mesenchymal transition.
- Author
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Yu X, Liu Y, Yin L, Peng Y, Peng Y, Gao Y, Yuan B, Zhu Q, Cao T, Xie B, Sun L, Chen Y, Gong Z, Qiu Y, Fan X, and Li X
- Subjects
- Animals, Antigens, CD biosynthesis, Antigens, CD genetics, Antigens, Differentiation, T-Lymphocyte biosynthesis, Antigens, Differentiation, T-Lymphocyte genetics, Carcinoma radiotherapy, Cell Cycle Checkpoints radiation effects, Cell Line, Tumor, Heterografts, Humans, Ki-67 Antigen biosynthesis, Mice, Mice, Inbred BALB C, Mice, Nude, Nasopharyngeal Neoplasms radiotherapy, Neoplasm Proteins biosynthesis, Neoplasm Proteins genetics, Phosphorylation radiation effects, Protein Stability, Protein Transport radiation effects, RNA Interference, RNA, Small Interfering genetics, Ubiquitination radiation effects, X-Rays, Antigens, CD physiology, Antigens, Differentiation, T-Lymphocyte physiology, Apoptosis radiation effects, Carcinoma pathology, Cellular Senescence physiology, Epithelial-Mesenchymal Transition radiation effects, Nasopharyngeal Neoplasms pathology, Neoplasm Proteins physiology, Protein Processing, Post-Translational radiation effects, Radiation Tolerance physiology
- Abstract
Ionizing radiation (IR) is a conventional cancer therapeutic, to which cancer cells develop radioresistance with exposure. The residual cancer cells after radiation treatment also have increased metastatic potential. The mechanisms by which cancer cells develop radioresistance and gain metastatic potential are still unknown. In this study acute IR exposure induced cancer cell senescence and apoptosis, but after long-term IR exposure, cancer cells exhibited radioresistance. The proliferation of radioresistant cells was retarded, and most cells were arrested in G0/G1 phase. The radioresistant cells simultaneously showed resistance to further IR-induced apoptosis, premature senescence, and epithelial to mesenchymal transformation (EMT). Acute IR exposure steadily elevated CDC6 protein levels due to the attenuation of ubiquitination, while CDC6 overexpression was observed in the radioresistant cells because the insufficiency of CDC6 phosphorylation blocked protein translocation from nucleus to cytoplasm, resulting in subcellular protein accumulation when the cells were arrested in G0/G1 phase. CDC6 ectopic overexpression in CNE2 cells resulted in apoptosis resistance, G0/G1 cell cycle arrest, premature senescence, and EMT, similar to the characteristics of radioresistant CNE2-R cells. Targeting CDC6 with siRNA promoted IR-induced senescence, sensitized cancer cells to IR-induced apoptosis, and reversed EMT. Furthermore, CDC6 depletion synergistically repressed the growth of CNE2-R xenografts when combined with IR. The study describes for the first time cell models for IR-induced senescence, apoptosis resistance, and EMT, three major mechanisms by which radioresistance develops. CDC6 is a novel radioresistance switch regulating senescence, apoptosis, and EMT. These studies suggest that CDC6
high KI67low represents a new diagnostic marker of radiosensitivity, and CDC6 represents a new therapeutic target for cancer radiosensitization.- Published
- 2019
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19. Metformin sensitizes endometrial cancer cells to chemotherapy through IDH1-induced Nrf2 expression via an epigenetic mechanism.
- Author
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Bai M, Yang L, Liao H, Liang X, Xie B, Xiong J, Tao X, Chen X, Cheng Y, Chen X, Feng Y, Zhang Z, and Zheng W
- Subjects
- Epigenesis, Genetic, Female, Gene Expression Regulation, Neoplastic physiology, Glutamates metabolism, Humans, Mixed Function Oxygenases metabolism, Proto-Oncogene Proteins metabolism, Signal Transduction drug effects, Signal Transduction physiology, Antineoplastic Agents pharmacology, Drug Resistance, Neoplasm drug effects, Endometrial Neoplasms genetics, Endometrial Neoplasms metabolism, Endometrial Neoplasms pathology, Isocitrate Dehydrogenase metabolism, Metformin pharmacology, NF-E2-Related Factor 2 biosynthesis
- Abstract
Chemoresistance is the major obstacle to cure endometrial cancer, whereas metformin has demonstrated sensitization to chemotherapy in endometrial cancer. A novel finding states that isocitrate dehydrogenase 1 (IDH1) involves in cancer chemoresistance. Recent studies have revealed that epigenetic modifications facilitate chemoresistance. However, whether IDH1 play a role in metformin-induced endometrial cancer chemosensitivity through epigenetic modification is incompletely understood. Immunohistochemistry and Elisa assays were used to evaluate the expression pattern of IDH1 in endometrial tissue and serum, respectively. Western blot was performed to determine changes in expression of key molecules in the IDH1-ɑ-KG-TET1-Nrf2 signaling pathway after various treatments. Dot blot assays were used to assess global hydroxymethylation levels after metformin administration or plasmid transfection. Antioxidant response element (ARE) activity in the IDH1 promoter region was monitored by luciferase assay. Cancer cell sensitivity to chemotherapy was detected by SRB assay. We found that activation of the IDH1 signaling pathway in endometrial cancer tissue resulting from aberrant expression of IDH1 and its downstream mediators conferred chemoresistance. We found that this effect was abated by metformin treatment. Dot blot and HMeDIP assays revealed that metformin blocked IDH1-ɑ-KG-TET1-mediated enhancement of Nrf2 hydroxymethylation levels, eliminating chemoresistance. Moreover, we observed that chemoresistance was enhanced via a regulatory loop in which Nrf2 activated IDH1-ɑ-KG-TET1-Nrf2 signaling via binding to the ARE sites in the IDH1 promoter region. Our findings highlight a critical role of IDH1-ɑ-KG-TET1-Nrf2 signaling in chemoresistance and suggest that rational combination therapy with metformin and chemotherapeutics has the potential to suppress chemoresistance.
- Published
- 2018
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20. Selectively frequent expression of CXCR5 enhances resistance to apoptosis in CD8(+)CD34(+) T cells from patients with T-cell-lineage acute lymphocytic leukemia.
- Author
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Qiuping Z, Jie X, Youxin J, Qun W, Wei J, Chun L, Jin W, Yan L, Chunsong H, Mingzhen Y, Qingping G, Qun L, Kejian Z, Zhimin S, Junyan L, and Jinquan T
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, CD8-Positive T-Lymphocytes drug effects, Cell Adhesion drug effects, Cell Line, Cell Lineage drug effects, Chemokine CXCL13, Chemokines, CXC metabolism, Chemokines, CXC pharmacology, Chemotaxis drug effects, Humans, Inhibitor of Apoptosis Proteins, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Nuclear Proteins genetics, Nuclear Proteins metabolism, Nuclear Proteins pharmacology, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Receptors, CXCR5, Receptors, Chemokine metabolism, Receptors, Cytokine genetics, Tumor Necrosis Factor-alpha pharmacology, Up-Regulation genetics, Antigens, CD34 metabolism, Apoptosis drug effects, CD8-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes pathology, Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Receptors, Cytokine metabolism
- Abstract
We investigated CD4(+)CD34(+), CD8(+)CD34(+), CD4(+)CD34(-), and CD8(+)CD34(-) T cells from cord blood and from typical patients with T-cell-lineage acute lymphocytic leukemia and T-cell-lineage chronic lymphocytic leukemia in terms of expression and functions of CXCR5/CXCL13. We found that CXCR5 was selectively frequently expressed on T-cell-lineage acute (chronic) lymphocytic leukemia (T-ALL) CD8(+)CD34(+) T cells, but not on T-ALL CD4(+)CD34(+), CD4(+)CD34(-), and CD8(+)CD34(-) T cells. CXCR5 was rarely expressed on all types of CD34(+) and CD34(-) CB or T-CLL T cells. CXCL13/B cells attracting chemokine 1 induced significant resistance to TNF-alpha-mediated apoptosis in T-ALL CD8(+)CD34(+) T cells, instead of induction of chemotactic and adhesive responsiveness. A proliferation-inducing ligand expression in T-ALL CD8(+)CD34(+) T cells was upregulated by CXCL13/BCA-1 (B-cell attracting chemokine 1). The CXCR5/CXCL13 pair by means of activation of APRIL (A proliferation-inducing ligand) induced resistance to apoptosis in T-ALL CD8(+)CD34(+) T cells in livin-dependent manner. In this process, cell-cell contact in culture was necessary. Based on our findings, we suggested that there were differential functions of CXCR5/CXCL13 in distinct types of cells. Normal lymphocytes, especially naive B and T cells, utilized CXCR5/CXCL13 for migration, homing, maturation, and cell homeostasis, as well as secondary lymphoid tissue organogenesis. Meanwhile, certain malignant cells took advantages of CXCR5/CXCL13 for infiltration, resistance to apoptosis, and inappropriate proliferation.
- Published
- 2005
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21. HER2/Neu and the Ets transcription activator PEA3 are coordinately upregulated in human breast cancer.
- Author
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Benz CC, O'Hagan RC, Richter B, Scott GK, Chang CH, Xiong X, Chew K, Ljung BM, Edgerton S, Thor A, and Hassell JA
- Subjects
- Animals, COS Cells, Humans, Promoter Regions, Genetic, Receptor, ErbB-2 genetics, Transcription Factors genetics, Transcription, Genetic, Transfection, Up-Regulation, Breast Neoplasms metabolism, Receptor, ErbB-2 metabolism, Transcription Factors metabolism
- Abstract
HER2/Neu is overexpressed in 25-30% of all human breast cancers as a result of both gene amplification and enhanced transcription. Transcriptional upregulation of HER2/neu leads to a 6-8-fold increased abundance of its mRNA per gene copy and likely results from the elevated activity of transcription factors acting on the HER2/neu promoter. Here we report that transcripts of PEA3, an ETS transcription factor implicated in oncogenesis, were increased in 93% of HER2/Neu-overexpressing human breast tumor samples. Analyses to uncover the molecular basis for elevated PEA3 transcripts in HER2/Neu-positive breast tumors revealed that the HER2/Neu receptor tyrosine kinase initiated an intracellular signaling cascade resulting in increased PEA3 transcriptional activity; transcriptionally-activated PEA3 stimulated HER2/neu and PEA3 gene transcription by binding to sites in the promoters of these genes. PEA3 also activates transcription of genes encoding matrix-degrading proteinases, enzymes required for tumor cell migration and invasion. These findings implicate PEA3 in the initiation and progression of HER2/Neu positive breast cancer, and suggest that PEA3 and signaling proteins affecting its regulation are appropriate therapeutic targets.
- Published
- 1997
- Full Text
- View/download PDF
22. ESX: a structurally unique Ets overexpressed early during human breast tumorigenesis.
- Author
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Chang CH, Scott GK, Kuo WL, Xiong X, Suzdaltseva Y, Park JW, Sayre P, Erny K, Collins C, Gray JW, and Benz CC
- Subjects
- Amino Acid Sequence, Chromosome Mapping, Chromosomes, Human, Pair 1, Female, Gene Expression, Genes, Immediate-Early, Humans, Male, Molecular Sequence Data, Multigene Family, Proto-Oncogene Protein c-ets-1, Proto-Oncogene Proteins chemistry, Proto-Oncogene Proteins c-ets, Receptor, ErbB-2 genetics, Transcription Factors chemistry, Tumor Cells, Cultured, Breast Neoplasms genetics, Carcinoma in Situ genetics, Carcinoma, Ductal, Breast genetics, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins genetics, Transcription Factors genetics
- Abstract
The >30 known members of the Ets multigene family of transcriptional regulators are increasingly being recognized for their involvement in early embryonic development and late tissue maturation, directing stage-specific and tissue-restricted programs of target gene expression. Identifiable primarily by their 85 amino acid ETS DNA-binding domain and dispersed across all metazoan lineages into distinct subfamilies, Ets genes also produce malignancies in humans and other vertebrates when overexpressed or rearranged into chimeras retaining the ETS domain, suggesting that their oncogenic potential is determined by the program of target genes they regulate. Searching for Ets factors that regulate expression of the HER2/neu (c-erbB2) oncogene in human breast cancer, we identified a new epithelium-restricted Ets encoding an ETS domain homologous to the Drosophila E74/human Elf-1 subfamily, an amino-terminal region (A-region or Pointed domain) homologous to the distantly related Ets-1 subfamily, and a serine-rich box homologous to the transactivating domain of the lymphocyte-restricted High Mobility Group (HMG) protein, SOX4. Recombinant protein encoded by ESX (for epithelial-restricted with serine box) exhibits Ets-like DNA binding specificity in electrophoretic mobility shift assays and, in transient transfection assays, transactivates Ets-responsive promoter elements including that found in the HER2/neu oncogene. ESX is located at chromosome 1q32 in a region known to be amplified in 50% of early breast cancers, is heregulin-inducible and overexpressed in HER2/neu activated breast cancer cells. Tissue hybridization suggests that ESX becomes overexpressed at an early stage of human breast cancer development known as ductal carcinoma in situ (DCIS).
- Published
- 1997
- Full Text
- View/download PDF
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