38 results on '"Zhu, Z."'
Search Results
2. Tumor cell-derived lactate induces TAZ-dependent upregulation of PD-L1 through GPR81 in human lung cancer cells
- Author
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Feng, J, Yang, H, Zhang, Y, Wei, H, Zhu, Z, Zhu, B, Yang, M, Cao, W, Wang, L, and Wu, Z
- Published
- 2017
- Full Text
- View/download PDF
3. Upregulation of long noncoding RNA ZEB1-AS1 promotes tumor metastasis and predicts poor prognosis in hepatocellular carcinoma
- Author
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Li, T, Xie, J, Shen, C, Cheng, D, Shi, Y, Wu, Z, Deng, X, Chen, H, Shen, B, Peng, C, Li, H, Zhan, Q, and Zhu, Z
- Published
- 2016
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4. p54nrb/NONO regulates lipid metabolism and breast cancer growth through SREBP-1A
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Zhu, Z, Zhao, X, Zhao, L, Yang, H, Liu, L, Li, J, Wu, J, Yang, F, Huang, G, and Liu, J
- Published
- 2016
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5. Rheb activates AMPK and reduces p27Kip1 levels in Tsc2-null cells via mTORC1-independent mechanisms: implications for cell proliferation and tumorigenesis
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Lacher, M D, Pincheira, R, Zhu, Z, Camoretti-Mercado, B, Matli, M, Warren, R S, and Castro, A F
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- 2010
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6. Homeobox gene IRX1 is a tumor suppressor gene in gastric carcinoma
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Guo, X, Liu, W, Pan, Y, Ni, P, Ji, J, Guo, L, Zhang, J, Wu, J, Jiang, J, Chen, X, Cai, Q, Li, J, Zhang, J, Gu, Q, Liu, B, Zhu, Z, and Yu, Y
- Published
- 2010
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7. CSR1 induces cell death through inactivation of CPSF3
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Zhu, Z-H, Yu, Y P, Shi, Y-K, Nelson, J B, and Luo, J-H
- Published
- 2009
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8. IRX1 influences peritoneal spreading and metastasis via inhibiting BDKRB2-dependent neovascularization on gastric cancer
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Jiang, J, Liu, W, Guo, X, Zhang, R, Zhi, Q, Ji, J, Zhang, J, Chen, X, Li, J, Gu, Q, Liu, B, Zhu, Z, and Yu, Y
- Published
- 2011
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9. Suppression of cell-cycle progression by Jun dimerization protein-2 (JDP2) involves downregulation of cyclin-A2
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Pan, J, Nakade, K, Huang, Y-C, Zhu, Z-W, Masuzaki, S, Hasegawa, H, Murata, T, Yoshiki, A, Yamaguchi, N, Lee, C-H, Yang, W-C, Tsai, E-M, Obata, Y, and Yokoyama, K K
- Published
- 2010
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10. Erratum: Suppression of cell-cycle progression by Jun dimerization protein-2 (JDP2) involves downregulation of cyclin-A2
- Author
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Pan, J, Nakade, K, Huang, Y-C, Zhu, Z-W, Masuzaki, S, Hasegawa, H, Murata, T, Yoshiki, A, Yamaguchi, N, Lee, C-H, Yang, W-C, Tsai, E-M, Obata, Y, and Yokoyama, K K
- Published
- 2011
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11. Transducin (β)-like 1 X-linked receptor 1 promotes gastric cancer progression via the ERK1/2 pathway
- Author
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Zhou, Q, primary, Wang, X, additional, Yu, Z, additional, Wu, X, additional, Chen, X, additional, Li, J, additional, Zhu, Z, additional, Liu, B, additional, and Su, L, additional
- Published
- 2016
- Full Text
- View/download PDF
12. p54nrb/NONO regulates lipid metabolism and breast cancer growth through SREBP-1A
- Author
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Zhu, Z, primary, Zhao, X, additional, Zhao, L, additional, Yang, H, additional, Liu, L, additional, Li, J, additional, Wu, J, additional, Yang, F, additional, Huang, G, additional, and Liu, J, additional
- Published
- 2015
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13. RETRACTED ARTICLE: Upregulation of long noncoding RNA ZEB1-AS1 promotes tumor metastasis and predicts poor prognosis in hepatocellular carcinoma
- Author
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Li, T, primary, Xie, J, additional, Shen, C, additional, Cheng, D, additional, Shi, Y, additional, Wu, Z, additional, Deng, X, additional, Chen, H, additional, Shen, B, additional, Peng, C, additional, Li, H, additional, Zhan, Q, additional, and Zhu, Z, additional
- Published
- 2015
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14. Transducin (β)-like 1 X-linked receptor 1 promotes gastric cancer progression via the ERK1/2 pathway
- Author
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Zhou, Q, Wang, X, Yu, Z, Wu, X, Chen, X, Li, J, Zhu, Z, Liu, B, and Su, L
- Abstract
Gastric cancer (GC) is one of the most common types of cancer worldwide, and it involves extensive local tumour invasion, metastasis and poor prognosis. Understanding the mechanisms regulating the progression of GC is necessary for the development of effective therapeutic strategies. Transducin (β)-like 1 X-linked receptor 1 (TBL1XR1) is an important regulator controlling gene activation and repression, which has been thought to be involved in tumorigenesis. However, the role of TBL1XR1 in human GC remains largely unknown. Here, we find that TBL1XR1 is aberrantly expressed in human GC tissues, and TBL1XR1 levels are highly correlated with local tumour invasion, late tumor, lymph node, metastasis (TNM) stage and poor prognosis. Knockdown of TBL1XR1 by shRNA inhibits GC cell proliferation, migration, invasion, epithelial-mesenchymal transition (EMT) in vitro, as well as tumorigenesis and peritoneal metastasis in vivo, whereas overexpression of TBL1XR1 produces the opposite effects. These effects are mediated by activation of the ERK1/2 signalling pathway, and inhibition of this pathway with a specific ERK1/2 inhibitor (U0126) significantly impairs the tumour-promoting effects induced by TBL1XR1. Moreover, TBL1XR1 mediated ERK1/2 activation is dependent on the β-catenin/MMP7/EGFR signalling pathway. In conclusion, TBL1XR1 contributes to GC tumorigenesis and progression through the activation of the β-catenin/MMP7/EGFR/ERK signalling pathway and may act as a new therapeutic target for GC.
- Published
- 2017
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15. CSR1 induces cell death through inactivation of CPSF3
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Zhu, Z-H, primary, Yu, Y P, additional, Shi, Y-K, additional, Nelson, J B, additional, and Luo, J-H, additional
- Published
- 2008
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16. Suppression of cell-cycle progression by Jun dimerization protein-2 (JDP2) involves downregulation of cyclin-A2.
- Author
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Pan, J, Nakade, K, Huang, Y-C, Zhu, Z-W, Masuzaki, S, Hasegawa, H, Murata, T, Yoshiki, A, Yamaguchi, N, Lee, C-H, Yang, W-C, Tsai, E-M, Obata, Y, and Yokoyama, K K
- Subjects
PUBLISHED errata ,CELL cycle regulation ,CYCLINS ,PHYSIOLOGICAL control systems ,NUCLEOTIDE sequence ,PROTEIN analysis ,TRANSCRIPTION factors - Published
- 2011
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17. tiRNA-Val-CAC-2 interacts with FUBP1 to promote pancreatic cancer metastasis by activating c‑MYC transcription.
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Xiong Q, Zhang Y, Xu Y, Yang Y, Zhang Z, Zhou Y, Zhang S, Zhou L, Wan X, Yang X, Zeng Z, Liu J, Zheng Y, Han J, and Zhu Q
- Abstract
Cumulative studies have established the significance of transfer RNA-derived small RNA (tsRNA) in tumorigenesis and progression. Nevertheless, its function and mechanism in pancreatic cancer metastasis remain largely unclear. Here, we screened and identified tiRNA-Val-CAC-2 as highly expressed in pancreatic cancer metastasis samples by tsRNA sequencing. We also observed elevated levels of tiRNA-Val-CAC-2 in the serum of pancreatic cancer patients who developed metastasis, and patients with high levels of tiRNA-Val-CAC-2 exhibited a worse prognosis. Additionally, knockdown of tiRNA-Val-CAC-2 inhibited the metastasis of pancreatic cancer in vivo and in vitro, while overexpression of tiRNA-Val-CAC-2 promoted the metastasis of pancreatic cancer. Mechanically, we discovered that tiRNA-Val-CAC-2 interacts with FUBP1, leading to enhanced stability of FUBP1 protein and increased FUBP1 enrichment in the c-MYC promoter region, thereby boosting the transcription of c-MYC. Of note, rescue experiments confirmed that tiRNA-Val-CAC-2 could influence pancreatic cancer metastasis via FUBP1-mediated c-MYC transcription. These findings highlight a potential novel mechanism underlying pancreatic cancer metastasis, and suggest that both tiRNA-Val-CAC-2 and FUBP1 could serve as promising prognostic biomarkers and potential therapeutic targets for pancreatic cancer., (© 2024. The Author(s).)
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- 2024
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18. TKT-PARP1 axis induces radioresistance by promoting DNA double-strand break repair in hepatocellular carcinoma.
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Geng L, Zhu M, Luo D, Chen H, Li B, Lao Y, An H, Wu Y, Li Y, Xia A, Shi Y, Tong Z, Lu S, Xu D, Wang X, Zhang W, Sun B, and Xu Z
- Subjects
- Humans, Animals, Mice, DNA Breaks, Double-Stranded, Transketolase genetics, DNA Repair, DNA, DNA End-Joining Repair, Recombinational DNA Repair, Poly (ADP-Ribose) Polymerase-1 genetics, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular radiotherapy, Carcinoma, Hepatocellular pathology, Liver Neoplasms genetics, Liver Neoplasms radiotherapy, Liver Neoplasms pathology
- Abstract
Hepatocellular carcinoma (HCC) stands as the fifth most prevalent malignant tumor on a global scale and presents as the second leading cause of cancer-related mortality. DNA damage-based radiotherapy (RT) plays a pivotal role in the treatment of HCC. Nevertheless, radioresistance remains a primary factor contributing to the failure of radiation therapy in HCC patients. In this study, we investigated the functional role of transketolase (TKT) in the repair of DNA double-strand breaks (DSBs) in HCC. Our research unveiled that TKT is involved in DSB repair, and its depletion significantly reduces both non-homologous end joining (NHEJ) and homologous recombination (HR)-mediated DSB repair. Mechanistically, TKT interacts with PARP1 in a DNA damage-dependent manner. Furthermore, TKT undergoes PARylation by PARP1, resulting in the inhibition of its enzymatic activity, and TKT can enhance the auto-PARylation of PARP1 in response to DSBs in HCC. The depletion of TKT effectively mitigates the radioresistance of HCC, both in vitro and in mouse xenograft models. Moreover, high TKT expression confers resistance of RT in clinical HCC patients, establishing TKT as a marker for assessing the response of HCC patients who received cancer RT. In summary, our findings reveal a novel mechanism by which TKT contributes to the radioresistance of HCC. Overall, we identify the TKT-PARP1 axis as a promising potential therapeutic target for improving RT outcomes in HCC., (© 2024. The Author(s).)
- Published
- 2024
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19. LZTFL1 inhibits kidney tumor cell growth by destabilizing AKT through ZNRF1-mediated ubiquitin proteosome pathway.
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Lu J, Fu LM, Cao Y, Fang Y, Cao JZ, Pan YH, Cen JJ, Liang YP, Chen ZH, Wei JH, Huang Y, Mumin MA, Xu QH, Wang YH, Zhu JQ, Liang H, Wang Z, Deng Q, Chen W, Jin XH, Liu ZP, and Luo JH
- Subjects
- Humans, Cell Line, Tumor, Cell Proliferation, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins c-akt metabolism, Transcription Factors metabolism, Ubiquitins metabolism, Carcinoma, Renal Cell pathology, Kidney Neoplasms pathology
- Abstract
LZTFL1 is a tumor suppressor located in chromosomal region 3p21.3 that is deleted frequently and early in various cancer types including the kidney cancer. However, its role in kidney tumorigenesis remains unknown. Here we hypothesized a tumor suppressive function of LZTFL1 in clear cell renal cell carcinoma (ccRCC) and its mechanism of action based on extensive bioinformatics analysis of patients' tumor data and validated it using both gain- and loss-functional studies in kidney tumor cell lines and patient-derive xenograft (PDX) model systems. Our studies indicated that LZTFL1 inhibits kidney tumor cell proliferation by destabilizing AKT through ZNRF1-mediated ubiquitin proteosome pathway and inducing cell cycle arrest at G1. Clinically, we found that LZTFL1 is frequently deleted in ccRCC. Downregulation of LZTFL1 is associated with a poor ccRCC outcome and may be used as prognostic maker. Furthermore, we show that overexpression of LZTFL1 in PDX via lentiviral delivery suppressed PDX growth, suggesting that re-expression of LZTFL1 may be a therapeutic strategy against ccRCC., (© 2023. The Author(s).)
- Published
- 2023
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20. Insufficient ablation induces E3-ligase Nedd4 to promote hepatocellular carcinoma progression by tuning TGF-β signaling.
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Li K, Niu Y, Yuan Y, Qiu J, Shi Y, Zhong C, Qiu Z, Li K, Lin Z, Huang Z, Zhang C, Zuo D, He W, Yuan Y, and Li B
- Subjects
- Cell Line, Tumor, Humans, Nedd4 Ubiquitin Protein Ligases genetics, Transforming Growth Factor beta, Ubiquitin-Protein Ligases genetics, Ubiquitin-Protein Ligases metabolism, Carcinoma, Hepatocellular metabolism, Liver Neoplasms metabolism, Nedd4 Ubiquitin Protein Ligases metabolism
- Abstract
Thermal ablation is a main curative therapy for early-stage hepatocellular carcinoma (HCC). However, insufficient ablation has been shown to promote HCC progression. E3 ligases have been approved to play important roles in malignant tumors. Whether E3 ligases are involved in HCC progression caused by insufficient ablation remains unclear. Herein, using RNA-sequencing coupled with an in vitro loss-of-function screen, we found that the E3 ligase Neuronal Precursor cell-expressed Developmentally Downregulated 4 (Nedd4) was upregulated in HCC insufficient ablation tissues and promoted HCC cells migration. The upregulation of Nedd4 was induced by METTL14-mediated N
6 -methyladenosine modification after sublethal heat treatment. Knockdown of Nedd4 inhibited HCC metastasis and growth in vitro and in vivo. Mechanistically, Nedd4 enhanced TGF-β signal transduction mediated tumor progression by directly binding to TGF-β type I receptor (TGFBR1) and forming K27-linked ubiquitin at Lysine 391. Additionally, the adverse effect on HCC of sublethal heat treatment was mediated by Nedd4. Clinically, high Nedd4 expression was positively correlated with aggressive tumor phenotypes and poor prognosis in HCC patients. Patient-derived xenograft (PDX) model confirmed this conclusion. Collectively, this study demonstrated that Nedd4 induced by insufficient ablation plays a crucial role in promoting HCC progression and provides a novel therapeutic target for HCC., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2022
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21. DARPP-32 promotes ERBB3-mediated resistance to molecular targeted therapy in EGFR-mutated lung adenocarcinoma.
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Alam SK, Zhang Y, Wang L, Zhu Z, Hernandez CE, Zhou Y, Yang N, Lei J, Chen X, Zeng L, Klein MA, and Hoeppner LH
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- Adenocarcinoma of Lung pathology, Animals, Cell Line, Tumor, Humans, Mice, Adenocarcinoma of Lung genetics, Dopamine and cAMP-Regulated Phosphoprotein 32 metabolism, Molecular Targeted Therapy methods, Receptor, ErbB-3 metabolism
- Abstract
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-refractory lung adenocarcinoma (LUAD) progression is a major clinical problem. New approaches to predict and prevent acquired resistance to EGFR TKIs are urgently needed. Here, we show that dopamine and cyclic AMP-regulated phosphoprotein, Mr 32000 (DARPP-32) physically recruits ERBB3 (HER3) to EGFR to mediate switching from EGFR homodimers to EGFR:ERBB3 heterodimers to bypass EGFR TKI-mediated inhibition by potentiating ERBB3-dependent activation of oncogenic signaling. In paired LUAD patient-derived specimens before and after EGFR TKI-refractory disease progression, we reveal that DARPP-32 and kinase-activated EGFR and ERBB3 proteins are overexpressed upon acquired resistance. In mice, DARPP-32 ablation sensitizes gefitinib-resistant xenografts to EGFR TKIs, while DARPP-32 overexpression increases gefitinib-refractory LUAD progression in gefitinib-sensitive lung tumors. We introduce a DARPP-32-mediated, ERBB3-dependent mechanism the LUAD cells use to evade EGFR TKI-induced cell death, potentially paving the way for the development of therapies to better combat therapy-refractory LUAD progression., (© 2021. The Author(s).)
- Published
- 2022
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22. Hypoxic exosomal HIF-1α-stabilizing circZNF91 promotes chemoresistance of normoxic pancreatic cancer cells via enhancing glycolysis.
- Author
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Zeng Z, Zhao Y, Chen Q, Zhu S, Niu Y, Ye Z, Hu P, Chen D, Xu P, Chen J, Hu C, Hu Y, Xu F, Tang J, Wang F, Han S, Huang M, Wang C, and Zhao G
- Subjects
- Animals, Female, Humans, Male, Mice, Cell Hypoxia genetics, Cell Line, Tumor, Deoxycytidine analogs & derivatives, Deoxycytidine pharmacology, Exosomes metabolism, Exosomes genetics, Gene Expression Regulation, Neoplastic, Glycolysis, Mice, Nude, Sirtuin 1 metabolism, Sirtuin 1 genetics, Xenograft Model Antitumor Assays, Drug Resistance, Neoplasm genetics, Gemcitabine therapeutic use, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Hypoxia-Inducible Factor 1, alpha Subunit genetics, MicroRNAs genetics, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms drug therapy, RNA, Circular genetics, RNA, Circular metabolism
- Abstract
Research has indicated that hypoxia profoundly contributes to chemoresistance of pancreatic cancer (PC), while the precise mechanism has not been fully elucidated. In this study, we report a hypoxic exosomal circular RNA (circRNA)-mediated mechanism of conferred chemoresistance in PC cells. Gemcitabine (GEM) resistance was enhanced in normoxic PC cells incubated with exosomes derived from hypoxic PC cells. CircRNA microarray displayed that circZNF91 was remarkably increased in hypoxic exosomes of PC cells compared with normoxic exosomes. Overexpression of circZNF91 obviously stimulated chemoresistance in PC cells, while knockdown of circZNF91 retarded the hypoxic exosome-transmitted chemoresistance. Mechanistically, the hypoxic-induced exosomal circZNF91 transmitted into normoxic PC cells could competitively bind to miR-23b-3p, which deprives the inhibition of miR-23b-3p on expression of deacetylase Sirtuin1 (SIRT1). Consequently, the upregulated SIRT1 enhanced deacetylation-dependent stability of HIF-1α protein, leading to glycolysis and GEM chemoresistance of recipient PC cells. In addition, we revealed that the increased circZNF91 in hypoxic exosome was attributed to the transcriptional regulation by HIF-1α. Coincidently, transmission of hypoxic exosomes into subcutaneous xenografts in nude mice obviously facilitated the chemoresistance of transplanted PC tumor, which could be reversed by depletion of circZNF91 or upregulation of miR-23b-3p. Furthermore, clinical data showed that circZNF91 was significantly upregulated in PC tissues and correlated with overexpression of glycolytic enzymes and short overall survival time. Collectively, exosomal circZNF91 can function as a cargo mediating the signal transmission between hypoxic and normoxic tumor cells to promote GEM chemoresistance of PC and may potentially serve as a therapeutic target., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2021
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23. Dexamethasone suppresses immune evasion by inducing GR/STAT3 mediated downregulation of PD-L1 and IDO1 pathways.
- Author
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Xiang Z, Zhou Z, Song S, Li J, Ji J, Yan R, Wang J, Cai W, Hu W, Zang L, Zhu Z, Zhang Z, Li M, and Yu Y
- Subjects
- Animals, Apoptosis drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Databases, Genetic, Disease Models, Animal, Gene Expression Profiling, Heterografts, Humans, Lymphocyte Count, Mice, Models, Biological, Protein Binding, Protein Transport, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, B7-H1 Antigen metabolism, Dexamethasone pharmacology, Immune Evasion drug effects, Immunosuppressive Agents pharmacology, Indoleamine-Pyrrole 2,3,-Dioxygenase metabolism, STAT3 Transcription Factor metabolism, Signal Transduction drug effects
- Abstract
T cell exhaustion plays critical roles in tumor immune evasion. Novel strategies to suppress immune evasion are in urgent need. We aimed to identify potential compounds to target T cell exhaustion and increase response to immune checkpoint inhibitors (ICIs). Differentially expressed genes (DEGs) were identified between tumors with different immune evasion potential by comparing the transcriptome data. DEGs were then analyzed in the Connectivity Map (CMap) platform to identify potential compounds to increase response to ICIs. Gene set enrichment analysis, LDH release assay, Chromatin immunoprecipitation (ChIP), and Co-IP were performed to explore the potential mechanisms in vitro. Patients derived organoids and humanized xenograft mouse model were utilized to validate the finding ex vivo and in vivo. We identified 25 potential compounds that may play critical roles in regulating tumor immune evasion. We further pinpointed a specific compound, dexamethasone, which shows potent anti-tumor effect in multiple cancer cell lines when cocultured with T cells. Dexamethasone can suppress T cell exhaustion by decreasing the activity of two immune checkpoints simultaneously, including PD-L1 and IDO1. Functional study shows dexamethasone can increase the sensitivity of ICIs in coculture system, 3D organoid model and humanized mouse model. Mechanism study shows dexamethasone mediated transcriptional suppression of PD-L1 and IDO1 depends on the nuclear translocation of GR/STAT3 complex. These findings demonstrate dexamethasone can suppress immune evasion by inducing GR/STAT3 mediated downregulation of PD-L1 and IDO1 pathways., (© 2021. The Author(s).)
- Published
- 2021
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24. Nuclear scaffold protein p54 nrb /NONO facilitates the hypoxia-enhanced progression of hepatocellular carcinoma.
- Author
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Shen M, Zhang R, Jia W, Zhu Z, Zhao X, Zhao L, Huang G, and Liu J
- Subjects
- Carcinoma, Hepatocellular pathology, Cell Nucleus genetics, Disease Progression, Female, Humans, Hypoxia pathology, Liver Neoplasms pathology, Male, Middle Aged, RNA Splicing genetics, RNA, Messenger genetics, Transcription, Genetic genetics, Transcriptional Activation genetics, Up-Regulation genetics, Carcinoma, Hepatocellular genetics, DNA-Binding Proteins genetics, Hypoxia genetics, Liver Neoplasms genetics, Nuclear Matrix-Associated Proteins genetics, RNA-Binding Proteins genetics
- Abstract
Hypoxia and related oxidative stress are closely related to the development and treatment of hepatocellular carcinoma (HCC). However, the mechanism mediated by hypoxia in HCC has not yet been elucidated. Here, we found multifunction scaffold protein p54
nrb /NONO exerted pleiotropic effects to regulate hypoxia transcription signals, thereby enhancing the progression of liver cancer. Extensive analysis of clinical data demonstrated that NONO was significantly upregulated and represented as a poor prognostic indicator of HCC. The crucial role of NONO in driving angiogenesis and glycolysis, two well-known cancer phenotypes mediated by hypoxia, was examined in vitro an in vivo. Mechanistically, NONO interacted with and stabilized both HIF-1 and HIF-2 complexes thus activating the transcription of hypoxia-induced genes. Besides, NONO bound pre-mRNA and subsequent mRNA of these genes to facilitate them splicing and mRNA stability, respectively. Thus, NONO knockout seriously disrupted the expression of a cluster of HIF-1/2 targets and impeded hypoxia-enhanced progression in HCC. In conclusion, NONO functioned as a multipurpose scaffold that interacted with HIF-1/2 complex and their downstream transcripts to facilitate the expression of hypoxia-induced genes, allowing malignant proliferation, indicating that NONO might be a potential therapeutic target for HCC.- Published
- 2021
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25. RBMX suppresses tumorigenicity and progression of bladder cancer by interacting with the hnRNP A1 protein to regulate PKM alternative splicing.
- Author
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Yan Q, Zeng P, Zhou X, Zhao X, Chen R, Qiao J, Feng L, Zhu Z, Zhang G, and Chen C
- Subjects
- Alternative Splicing, Animals, Disease Progression, Female, Heterogeneous Nuclear Ribonucleoprotein A1 genetics, Heterogeneous-Nuclear Ribonucleoproteins genetics, Heterografts, Humans, Male, Mice, Mice, Inbred NOD, Middle Aged, Prognosis, Pyruvate Kinase genetics, Survival Analysis, Urinary Bladder Neoplasms genetics, Urinary Bladder Neoplasms pathology, Heterogeneous Nuclear Ribonucleoprotein A1 metabolism, Heterogeneous-Nuclear Ribonucleoproteins metabolism, Pyruvate Kinase metabolism, Urinary Bladder Neoplasms metabolism
- Abstract
The prognosis for patients with metastatic bladder cancer (BCa) is poor, and it is not improved by current treatments. RNA-binding motif protein X-linked (RBMX) are involved in the regulation of the malignant progression of various tumors. However, the role of RBMX in BCa tumorigenicity and progression remains unclear. In this study, we found that RBMX was significantly downregulated in BCa tissues, especially in muscle-invasive BCa tissues. RBMX expression was negatively correlated with tumor stage, histological grade and poor patient prognosis. Functional assays demonstrated that RBMX inhibited BCa cell proliferation, colony formation, migration, and invasion in vitro and suppressed tumor growth and metastasis in vivo. Mechanistic investigations revealed that hnRNP A1 was an RBMX-binding protein. RBMX competitively inhibited the combination of the RGG motif in hnRNP A1 and the sequences flanking PKM exon 9, leading to the formation of lower PKM2 and higher PKM1 levels, which attenuated the tumorigenicity and progression of BCa. Moreover, RBMX inhibited aerobic glycolysis through hnRNP A1-dependent PKM alternative splicing and counteracted the PKM2 overexpression-induced aggressive phenotype of the BCa cells. In conclusion, our findings indicate that RBMX suppresses BCa tumorigenicity and progression via an hnRNP A1-mediated PKM alternative splicing mechanism. RBMX may serve as a novel prognostic biomarker for clinical intervention in BCa.
- Published
- 2021
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26. Correction: Nuclear receptor HNF4α performs a tumor suppressor function in prostate cancer via its induction of p21-driven cellular senescence.
- Author
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Wang Z, Li Y, Wu D, Yu S, Wang Y, and Chan FL
- Abstract
The original version of this Article contained an error in the spelling of the author Chan FL, which was incorrectly given as leung Chan F. This has now been corrected in both the PDF and HTML versions of the Article.
- Published
- 2020
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27. LAMB3 promotes tumour progression through the AKT-FOXO3/4 axis and is transcriptionally regulated by the BRD2/acetylated ELK4 complex in colorectal cancer.
- Author
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Zhu Z, Song J, Guo Y, Huang Z, Chen X, Dang X, Huang Y, Wang Y, Ou W, Yang Y, Yu W, Liu CY, and Cui L
- Subjects
- Acetylation, Animals, Cell Adhesion Molecules genetics, Cell Cycle Proteins genetics, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, Female, Forkhead Box Protein O3 genetics, Forkhead Transcription Factors genetics, Humans, Male, Mice, Proto-Oncogene Proteins c-akt genetics, Transcription Factors genetics, ets-Domain Protein Elk-4 genetics, Kalinin, Cell Adhesion Molecules metabolism, Cell Cycle Proteins metabolism, Colorectal Neoplasms metabolism, Forkhead Box Protein O3 metabolism, Forkhead Transcription Factors metabolism, Proto-Oncogene Proteins c-akt metabolism, Signal Transduction, Transcription Factors metabolism, ets-Domain Protein Elk-4 metabolism
- Abstract
Aberrant expression of laminin-332 promotes tumour growth and metastasis in multiple cancers. However, the dysregulated expression and mechanism of action of LAMB3, which encodes the β3 subunit of laminin-332, and the mechanism underlying dysregulated LAMB3 expression in CRC remain obscure. Here, we show that LAMB3 is overexpressed in CRC and that this overexpression is correlated with tumour metastasis and poor prognosis. Overexpression of LAMB3 promoted cell proliferation and cell migration in vitro and tumour growth and metastasis in vivo, while knockdown of LAMB3 elicited opposing effects. LAMB3 inhibited the tumour suppressive function of FOXO3/4 by activating AKT in CRC. Both the BET inhibitor JQ1 and the MEK inhibitor U0126 decreased the mRNA level of LAMB3 in multiple CRC cells. Mechanistically, ELK4 cooperated with BRD2 to regulate the transcription of LAMB3 in CRC by directly binding to the ETS binding motifs in the LAMB3 promoter. ELK4 was as acetylated at K125, which enhanced the interaction between ELK4 and BRD2. JQ1 disrupted the interaction between ELK4 and BRD2, resulting in decreased binding of BRD2 to the LAMB3 promoter and downregulation of LAMB3 transcription. Both ELK4 and BRD2 expression was associated with LAMB3 expression in CRC. LAMB3 expression was also negatively correlated with FOXO3/4 in CRC. Our study reveals the pro-tumorigenic role of LAMB3 through the AKT-FOXO3/4 axis and the transcriptional mechanism of LAMB3 in CRC, demonstrating that LAMB3 is a potential therapeutic target that can be targeted by BET inhibitors and MEK inhibitors.
- Published
- 2020
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28. The reciprocal interaction between tumor cells and activated fibroblasts mediated by TNF-α/IL-33/ST2L signaling promotes gastric cancer metastasis.
- Author
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Zhou Q, Wu X, Wang X, Yu Z, Pan T, Li Z, Chang X, Jin Z, Li J, Zhu Z, Liu B, and Su L
- Subjects
- Cell Movement, Epithelial-Mesenchymal Transition, Female, Gene Expression Regulation, Neoplastic, Humans, Male, Middle Aged, Neoplasm Invasiveness, Neoplasm Metastasis, Prognosis, Stomach Neoplasms diagnosis, Stomach Neoplasms metabolism, Cancer-Associated Fibroblasts pathology, Cell Communication, Interleukin-1 Receptor-Like 1 Protein metabolism, Interleukin-33 metabolism, Signal Transduction, Stomach Neoplasms pathology, Tumor Necrosis Factor-alpha metabolism
- Abstract
Gastric cancer (GC) is characterized by extensive local invasion, distant metastasis and poor prognosis. In most cases, GC progression is associated with aberrant expression of cytokines or activation of signaling cascades mediated by tumor-stroma interactions. However, the mechanisms by which these interactions contribute to GC progression are poorly understood. In this study, we find that IL-33 and its receptor ST2L are upregulated in the human GC and served as prognostic markers for poor survival of GC patients. In a co-culture model with GC cells and cancer-associated fibroblasts (CAFs), we further demonstrate that CAFs-derived IL-33 enhances the migration and invasion of GC cells by inducing the epithelial-mesenchymal transition (EMT) through activation of the ERK1/2-SP1-ZEB2 pathway in a ST2L-dependent manner. Furthermore, the secretion of IL-33 by CAFs can be induced by the proinflammatory cytokines TNF-α that is released by GC cells via TNFR2-NF-κB-IRF-1 pathway. Additionally, silencing of IL-33 expression in CAFs or ST2L expression in GC cells inhibits the peritoneal dissemination and metastatic potential of GC cells in nude mice. Taken together, these results characterize a critical role of the interaction between epithelial-stroma mediated by the TNF-α/IL-33/ST2L signaling in GC progression, and provide a rationale for targeting this pathway to treat GC metastasis.
- Published
- 2020
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29. Nuclear receptor HNF4α performs a tumor suppressor function in prostate cancer via its induction of p21-driven cellular senescence.
- Author
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Wang Z, Li Y, Wu D, Yu S, Wang Y, and Leung Chan F
- Subjects
- Cell Cycle Checkpoints, Cell Line, Tumor, Cell Proliferation, Epigenesis, Genetic, Epithelial Cells pathology, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Genes, ras genetics, Hepatocyte Nuclear Factor 4 deficiency, Hepatocyte Nuclear Factor 4 genetics, Humans, Male, Prostatic Neoplasms pathology, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p21 metabolism, Hepatocyte Nuclear Factor 4 metabolism, Prostatic Neoplasms metabolism
- Abstract
Hepatocyte nuclear factor 4α (HNF4α, NR2A1) is a highly conserved member of the nuclear receptor superfamily. Recent advances reveal that it is a key transcriptional regulator of genes, broadly involved in xenobiotic and drug metabolism and also cancers of gastrointestinal tract. However, the exact functional roles of HNF4α in prostate cancer progression are still not fully understood. In this study, we determined the functional significance of HNF4α in prostate cancer. Our results showed that HNF4α exhibited a reduced expression pattern in clinical prostate cancer tissues, prostate cancer cell lines and xenograft model of castration-relapse prostate cancer. Stable HNF4α knockdown not only could promote cell proliferation and suppress doxorubicin (Dox)-induced cellular senescence in prostate cancer cells, but also confer resistance to paclitaxel treatment and enhance colony formation capacity and in vivo tumorigenicity of prostate cancer cells. On the contrary, ectopic overexpression of HNF4α could significantly inhibit the cell proliferation of prostate cancer cells, induce cell-cycle arrest at G
2 /M phase and trigger the cellular senescence in prostate cancer cells by activation of p21 signal pathway in a p53-independent manner via its direct transactivation of CDKN1A. Together, our results show that HNF4α performs a tumor suppressor function in prostate cancer via a mechanism of p21-driven cellular senescence.- Published
- 2020
- Full Text
- View/download PDF
30. Combining CDK4/6 inhibition with taxanes enhances anti-tumor efficacy by sustained impairment of pRB-E2F pathways in squamous cell lung cancer.
- Author
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Cao J, Zhu Z, Wang H, Nichols TC, Lui GYL, Deng S, Rejto PA, VanArsdale T, Hardwick JS, Weinrich SL, and Wei P
- Subjects
- Angiogenesis Inhibitors pharmacology, Animals, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung metabolism, Carcinoma, Squamous Cell metabolism, Cell Line, Cell Line, Tumor, Cell Proliferation drug effects, Female, G2 Phase Cell Cycle Checkpoints drug effects, Gene Expression drug effects, Human Umbilical Vein Endothelial Cells, Humans, Lung Neoplasms metabolism, Mice, Mice, Inbred BALB C, Mice, Nude, Neovascularization, Pathologic drug therapy, Neovascularization, Pathologic metabolism, Piperazines pharmacology, Pyridines pharmacology, Signal Transduction drug effects, Antineoplastic Combined Chemotherapy Protocols pharmacology, Bridged-Ring Compounds pharmacology, Carcinoma, Squamous Cell drug therapy, Cyclin-Dependent Kinase 4 antagonists & inhibitors, Cyclin-Dependent Kinase 6 antagonists & inhibitors, E2F Transcription Factors metabolism, Lung Neoplasms drug therapy, Retinoblastoma Protein metabolism, Taxoids pharmacology
- Abstract
The CDK4/6 inhibitor palbociclib reduces tumor growth by decreasing retinoblastoma (RB) protein phosphorylation and inducing cell cycle arrest at the G1/S phase transition. Palbociclib in combination with anti-hormonal therapy brings significant benefit to breast cancer patients. In this study, novel combination approaches and underlying molecular/cellular mechanisms for palbociclib were explored in squamous cell lung cancer (SqCLC), the second most common subtype of non-small cell lung cancer. While approximate 20% lung patients benefit from immunotherapy, most SqCLC patients who receive platinum-doublet chemotherapy as first-line treatment, which often includes a taxane, are still in need of more effective combination therapies. Our results demonstrated enhanced cytotoxicity and anti-tumor effect with palbociclib plus taxanes at clinically achievable doses in multiple SqCLC models with diverse cancer genetic backgrounds. Comprehensive gene expression analysis revealed a sustained disruption of pRB-E2F signaling by combination that was accompanied with enhanced regulation of pleiotropic biological effects. These included several novel mechanisms such as abrogation of G2/M and mitotic spindle assembly checkpoints, as well as impaired induction of hypoxia-inducible factor 1 alpha (HIF-1α). The decrease in HIF-1α modulated a couple key angiogenic and anti-angiogenic factors, resulting in an enhanced anti-angiogenic effect. This preclinical work suggests a new therapeutic opportunity for palbociclib in lung and other cancers currently treated with taxane based chemotherapy as standard of care.
- Published
- 2019
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31. Hypoxia-induced LncRNA-BX111 promotes metastasis and progression of pancreatic cancer through regulating ZEB1 transcription.
- Author
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Deng SJ, Chen HY, Ye Z, Deng SC, Zhu S, Zeng Z, He C, Liu ML, Huang K, Zhong JX, Xu FY, Li Q, Liu Y, Wang CY, and Zhao G
- Subjects
- Animals, Cell Hypoxia, Cell Line, Tumor, Disease Progression, Epithelial-Mesenchymal Transition genetics, Epithelial-Mesenchymal Transition physiology, Humans, Hypoxia-Inducible Factor 1 genetics, Hypoxia-Inducible Factor 1 metabolism, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Lymphatic Metastasis, Mice, Mice, Inbred BALB C, Mice, Nude, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms physiopathology, Pancreatic Neoplasms secondary, RNA, Long Noncoding metabolism, Transcription, Genetic, Y-Box-Binding Protein 1 genetics, Y-Box-Binding Protein 1 metabolism, Zinc Finger E-box-Binding Homeobox 1 metabolism, Gene Expression Regulation, Neoplastic, Pancreatic Neoplasms genetics, RNA, Long Noncoding physiology, Zinc Finger E-box-Binding Homeobox 1 genetics
- Abstract
The contribution of long noncoding RNAs (lncRNAs) to pancreatic cancer progression and the regulatory mechanisms of their expression are attractive areas. In the present study, the overexpression of lncRNA-BX111887 (BX111) in pancreatic cancer tissues was detected by microarray and further validated in a cohort of pancreatic cancer tissues. We further demonstrated that knockdown or overexpression of BX111 dramatically repressed or enhanced proliferation and invasion of pancreatic cancer cells. Mechanically, BX111 activated transcription of ZEB1, a key regulator for epithelia-mesenchymal transition (EMT), via recruiting transcriptional factor Y-box protein (YB1) to its promoter region. Moreover, we revealed that BX111 transcription was induced by hypoxia-inducible factor (HIF-1α) in response to hypoxia. In addition, BX111 contributed to the hypoxia-induced EMT of pancreatic cells by regulating expression of ZEB1 and its downstream proteins E-cadherin and MMP2. Coincidence with in vitro results, BX111 depletion effectively inhibited growth and metastasis of xenograft tumor in vivo. The clinical samples of pancreatic cancer further confirmed a positive association between BX111 and ZEB1. Moreover, high BX111 expression was correlated with late TNM stage, lymphatic invasion and distant metastasis, as well as short overall survival time in patients. Taken together, our findings implicate a hypoxia-induced lncRNA contributes to metastasis and progression of pancreatic cancer, and suggest BX111 might be applied as a potential biomarker and therapeutic target for pancreatic cancer.
- Published
- 2018
- Full Text
- View/download PDF
32. Nuclear receptor ERRα and transcription factor ERG form a reciprocal loop in the regulation of TMPRSS2:ERG fusion gene in prostate cancer.
- Author
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Xu Z, Wang Y, Xiao ZG, Zou C, Zhang X, Wang Z, Wu D, Yu S, and Chan FL
- Subjects
- Androgens genetics, Animals, Cell Line, Tumor, Gene Expression Regulation, Neoplastic genetics, Humans, Male, Mice, Mice, SCID, Prostate metabolism, Receptors, Androgen genetics, Signal Transduction genetics, Trans-Activators genetics, Transcriptional Regulator ERG genetics, ERRalpha Estrogen-Related Receptor, Oncogene Proteins, Fusion genetics, Prostatic Neoplasms, Castration-Resistant genetics, Receptors, Estrogen genetics, Serine Endopeptidases genetics
- Abstract
The TMPRSS2:ERG (T:E) fusion gene is generally believed to be mainly regulated by the activated androgen receptor (AR) signaling in androgen-dependent prostate cancer. However, its persistent expression in castration-resistant and neuroendocrine prostate cancers implies that other transcription factors might also regulate its expression. Here, we showed that up-regulation of nuclear receptor estrogen-related receptor alpha (ERRα) was closely associated with the oncogenic transcription factor ERG expression in prostate cancer, and their increased coexpression patterns were closely associated with high Gleason scores and metastasis in patients. Both ERRα and ERG exhibited a positive expression correlation in a castration-resistant prostate cancer (CRPC) xenograft model VCaP-CRPC. We showed that ERRα could directly transactivate T:E fusion gene in both AR-positive and -negative prostate cancer cells via both ERR-binding element- and AR-binding element-dependent manners. Ectopic T:E expression under ERRα regulation could promote both in vitro invasion and in vivo metastasis capacities of AR-negative prostatic cells. Intriguingly, ERG expressed by the T:E fusion could also transactivate the ERRα (ESRRA) gene. Hereby, ERRα and ERG can synergistically regulate each other and form a reciprocal regulatory loop to promote the advanced growth of prostate cancer. Inhibition of ERRα activity by ERRα inverse agonist could suppress T:E expression in prostate cancer cells, implicating that targeting ERRα could be a potential therapeutic strategy for treating the aggressive T:E-positive prostate cancer.
- Published
- 2018
- Full Text
- View/download PDF
33. Orphan nuclear receptor TLX contributes to androgen insensitivity in castration-resistant prostate cancer via its repression of androgen receptor transcription.
- Author
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Jia L, Wu D, Wang Y, You W, Wang Z, Xiao L, Cai G, Xu Z, Zou C, Wang F, Teoh JY, Ng CF, Yu S, and Chan FL
- Subjects
- Androgen Antagonists pharmacology, Animals, Apoptosis, Biomarkers, Tumor genetics, Cell Proliferation, Humans, Male, Mice, Mice, SCID, Orphan Nuclear Receptors, Prognosis, Prostatic Neoplasms, Castration-Resistant drug therapy, Prostatic Neoplasms, Castration-Resistant genetics, Receptors, Androgen chemistry, Receptors, Androgen metabolism, Receptors, Cytoplasmic and Nuclear genetics, Transcriptional Activation, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Biomarkers, Tumor metabolism, Gene Expression Regulation, Neoplastic, Prostatic Neoplasms, Castration-Resistant pathology, Receptors, Androgen genetics, Receptors, Cytoplasmic and Nuclear metabolism, Transcription, Genetic
- Abstract
The metastatic castration-resistant prostate cancer (CRPC) is a lethal form of prostate cancer, in which the expression of androgen receptor (AR) is highly heterogeneous. Indeed, lower AR expression and attenuated AR signature activity is shown in CRPC tissues, especially in the subset of neuroendocrine prostate cancer (NEPC) and prostate cancer stem-like cells (PCSCs). However, the significance of AR downregulation in androgen insensitivity and de-differentiation of tumor cells in CRPC is poorly understood and much neglected. Our previous study shows that the orphan nuclear receptor TLX (NR2E1), which is upregulated in prostate cancer, plays an oncogenic role in prostate carcinogenesis by suppressing oncogene-induced senescence. In the present study, we further established that TLX exhibited an increased expression in metastatic CRPC. Further analyses showed that overexpression of TLX could confer resistance to androgen deprivation and anti-androgen in androgen-dependent prostate cancer cells in vitro and in vivo, whereas knockdown of endogenous TLX could potentiate the sensitivity to androgen deprivation and anti-androgen in prostate cancer cells. Our study revealed that the TLX-induced resistance to androgen deprivation and anti-androgen was mediated through its direct suppression of AR gene transcription and signaling in both androgen-stimulated and -unstimulated prostate cancer cells. We also characterized that TLX could bind directly to AR promoter and repress AR transcription by recruitment of histone modifiers, including HDAC1, HDAC3, and LSD1. Together, our present study shows, for the first time, that TLX can contribute to androgen insensitivity in CRPC via repression of AR gene transcription and signaling, and also implicates that targeting the druggable TLX may have a potential therapeutic significance in CRPC management, particularly in NEPC and PCSCs.
- Published
- 2018
- Full Text
- View/download PDF
34. MiRNA-646-mediated reciprocal repression between HIF-1α and MIIP contributes to tumorigenesis of pancreatic cancer.
- Author
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Niu Y, Jin Y, Deng SC, Deng SJ, Zhu S, Liu Y, Li X, He C, Liu ML, Zeng Z, Chen HY, Zhong JX, Ye Z, Wang CY, and Zhao G
- Subjects
- Adult, Aged, Animals, Cell Proliferation genetics, Cells, Cultured, Down-Regulation genetics, Female, Gene Expression Regulation, Neoplastic, Humans, Intracellular Signaling Peptides and Proteins, Male, Mice, Mice, Inbred BALB C, Mice, Nude, Middle Aged, Neoplasm Invasiveness, Pancreatic Neoplasms mortality, Pancreatic Neoplasms pathology, Tumor Hypoxia genetics, Carcinogenesis genetics, Carrier Proteins genetics, Hypoxia-Inducible Factor 1, alpha Subunit genetics, MicroRNAs physiology, Pancreatic Neoplasms genetics
- Abstract
Migration and invasion inhibitory protein (MIIP) is recently identified as an inhibitor in tumor development. However, the regulatory mechanism and biological contributions of MIIP in pancreatic cancer (PC) have been not elucidated. In this study, we demonstrated a negative feedback of MIIP and hypoxia-induced factor-1α (HIF-1α), which was mediated by a hypoxia-induced microRNA. Compared with paracarcinoma tissues, MIIP was downregulated in PC tissues. Overexpression of MIIP significantly impeded the proliferation and invasion of PC cells both in vitro and in mouse xenograft models. We further verified MIIP was downregulated under hypoxia in a HIF-1α-mediated manner. Interestingly, although MIIP promoter containing two putative hypoxia response elements (HREs), the chromatin immunoprecipitation (ChIP) and luciferase reporter assays did not support an active interaction between HIF-1α and MIIP promoter. Meanwhile, microRNA array revealed a hypoxia-induced microRNA, miR-646, impaired stability of MIIP mRNA and consequently inhibited its expression by targeting the coding sequence (CDS). Coincidently, knockdown of miR-646 significantly repressed proliferation and invasion ability of PC cells both in vitro and in vivo by upregulating MIIP expression. Besides, ChIP and luciferase reporter assays further validated that HIF-1α activated transcription of miR-646 in hypoxia condition. Therefore, these results suggested HIF-1α indirectly regulated MIIP expression in post-transcriptional level through upregulating miR-646 transcription. Conversely, our results further revealed that MIIP suppressed deacetylase ability of histone deacetylase 6 (HDAC6) to promote the acetylation and degradation of HIF-1α, by which impairing HIF-1α accumulation. What is more, a specific relationship between downregulated MIIP and upregulated miR-646 expression was validated in PC samples. Moreover, the dysregulated miR-646 and MIIP expression was correlated with advanced tumor stage, lymphatic invasion, metastasis and shorter overall survival in PC patients. Together, our results highlight that the reciprocal loop of HIF-1α/miR-646/MIIP might be implemented as an applicable target for pancreatic cancer therapy.
- Published
- 2018
- Full Text
- View/download PDF
35. Molecular classification of papillary thyroid carcinoma: distinct BRAF, RAS, and RET/PTC mutation-specific gene expression profiles discovered by DNA microarray analysis.
- Author
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Giordano TJ, Kuick R, Thomas DG, Misek DE, Vinco M, Sanders D, Zhu Z, Ciampi R, Roh M, Shedden K, Gauger P, Doherty G, Thompson NW, Hanash S, Koenig RJ, and Nikiforov YE
- Subjects
- Base Sequence, DNA Primers, Humans, Immunohistochemistry, In Situ Hybridization, Fluorescence, Iodide Peroxidase metabolism, Proto-Oncogene Proteins c-ret, Receptors, G-Protein-Coupled, Transcription, Genetic, Gene Expression Profiling, Genes, ras, Mutation, Oligonucleotide Array Sequence Analysis, Oncogene Proteins genetics, Proto-Oncogene Proteins B-raf genetics, Receptor Protein-Tyrosine Kinases genetics, Receptors, Cell Surface genetics, Thyroid Neoplasms genetics
- Abstract
Thyroid cancer poses a significant clinical challenge, and our understanding of its pathogenesis is incomplete. To gain insight into the pathogenesis of papillary thyroid carcinoma, transcriptional profiles of four normal thyroids and 51 papillary carcinomas (PCs) were generated using DNA microarrays. The tumors were genotyped for their common activating mutations: BRAF V600E point mutation, RET/PTC1 and 3 rearrangement and point mutations of KRAS, HRAS and NRAS. Principal component analysis based on the entire expression data set separated the PCs into three groups that were found to reflect tumor morphology and mutational status. By combining expression profiles with mutational status, we defined distinct expression profiles for the BRAF, RET/PTC and RAS mutation groups. Using small numbers of genes, a simple classifier was able to classify correctly the mutational status of all 40 tumors with known mutations. One tumor without a detectable mutation was predicted by the classifier to have a RET/PTC rearrangement and was shown to contain one by fluorescence in situ hybridization analysis. Among the mutation-specific expression signatures were genes whose differential expression was a direct consequence of the mutation, as well as genes involved in a variety of biological processes including immune response and signal transduction. Expression of one mutation-specific differentially expressed gene, TPO, was validated at the protein level using immunohistochemistry and tissue arrays containing an independent set of tumors. The results demonstrate that mutational status is the primary determinant of gene expression variation within these tumors, a finding that may have clinical and diagnostic significance and predicts success for therapies designed to prevent the consequences of these mutations.
- Published
- 2005
- Full Text
- View/download PDF
36. p44/42 MAP kinase-dependent regulation of catalase by autocrine human growth hormone protects human mammary carcinoma cells from oxidative stress-induced apoptosis.
- Author
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Zhu Z, Mukhina S, Zhu T, Mertani HC, Lee KO, and Lobie PE
- Subjects
- Breast Neoplasms metabolism, Cell Line, Tumor, DNA-Binding Proteins physiology, Female, Humans, Hydrogen Peroxide toxicity, Promoter Regions, Genetic, Proto-Oncogene Proteins physiology, Transcription Factors physiology, Transcription, Genetic, ets-Domain Protein Elk-1, Apoptosis, Breast Neoplasms pathology, Catalase genetics, Gene Expression Regulation, Enzymologic, Human Growth Hormone physiology, Mitogen-Activated Protein Kinase 1 physiology, Mitogen-Activated Protein Kinase 3 physiology, Oxidative Stress
- Abstract
Previous microarray expression analyses have indicated autocrine human growth hormone (hGH) regulation of genes involved in the oxidative stress response. Expression analysis of antioxidant enzymes revealed that autocrine hGH increased both the mRNA and protein levels of catalase, superoxide dismutase 1 (SOD1), glutathione peroxidase and glutamylcysteine synthetase but not that of SOD2. As a consequence, autocrine hGH increased the antioxidant capacity of mammary carcinoma cells and protected against oxidative stress-induced apoptosis. Catalase activity was increased by autocrine production of hGH in mammary carcinoma cells and a catalase inhibitor abrogated protection from oxidative stress afforded by autocrine hGH. Autocrine hGH transcriptionally regulated catalase gene expression in a p44/42 MAP kinase-dependent manner and inhibition of MEK concordantly abrogated the protective effect of autocrine hGH against oxidative stress-induced apoptosis. Given that increased cellular oxidative stress is a key effector mechanism of specific chemotherapeutic agents, we propose that antagonism of autocrine hGH will improve the efficacy of chemotherapeutic regimes utilized for human mammary carcinoma.
- Published
- 2005
- Full Text
- View/download PDF
37. Functional contribution of EEN to leukemogenic transformation by MLL-EEN fusion protein.
- Author
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Liu H, Chen B, Xiong H, Huang QH, Zhang QH, Wang ZG, Li BL, Chen Z, and Chen SJ
- Subjects
- Amino Acid Sequence, Animals, Cell Differentiation, Dimerization, HL-60 Cells, Homeodomain Proteins genetics, Humans, Intracellular Signaling Peptides and Proteins, Mice, Mice, Inbred BALB C, Molecular Sequence Data, Myeloid-Lymphoid Leukemia Protein, NIH 3T3 Cells, Neoplasm Proteins genetics, Proteins chemistry, Transcriptional Activation, Carrier Proteins physiology, Cell Transformation, Neoplastic, Leukemia etiology, Nucleocytoplasmic Transport Proteins, Oncogene Proteins, Fusion physiology, Proteins physiology
- Abstract
The EEN (extra eleven nineteen) gene was originally cloned from a case of acute myeloid leukemia M5 subtype with translocation t (11; 19)(q23; p13), in which EEN was fused with MLL. To explore the involvement of EEN in leukemogenesis caused by MLL-EEN, we studied the transformation potential of the MLL-EEN fusion protein. MLL-EEN had oncogenic features, while, as a control, MLLDelta, the truncated form of MLL lacking the EEN moiety, did not show any oncogenic potential. MLL-EEN exerted a dominant-negative effect over wild-type EEN in terms of subcellular localization. Normally, EEN was found in the cytoplasm, but the MLL-EEN fusion protein was located in the nucleus, and EEN could be delocalized by MLL-EEN. This interaction is via a coiled-coil dimerization domain of EEN, which is reserved in the fusion protein. In addition, MLL-EEN might act as a potential transcriptional factor with the MLL part providing the DNA-binding domain and the EEN part providing the transcription activation domain, though EEN seems to have no direct role in transcriptional regulation. As an aberrant transcriptional factor, MLL-EEN could transactivate the promoter of HoxA7, a potential target gene of MLL., (Copyright 2004 Nature Publishing Group)
- Published
- 2004
- Full Text
- View/download PDF
38. Monoclonal antibody therapeutics and apoptosis.
- Author
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Ludwig DL, Pereira DS, Zhu Z, Hicklin DJ, and Bohlen P
- Subjects
- Animals, Antibodies, Monoclonal pharmacology, Antineoplastic Agents pharmacology, Cell Division drug effects, Cell Survival drug effects, Humans, Immunotoxins therapeutic use, Models, Biological, Signal Transduction, Antibodies, Monoclonal therapeutic use, Antineoplastic Agents therapeutic use, Apoptosis drug effects
- Abstract
The potential for disease-specific targeting and low toxicity profiles have made monoclonal antibodies attractive therapeutic drug candidates. Antibody-mediated target cell killing is frequently associated with immune effector mechanisms such as antibody-directed cellular cytotoxicity, but they can also be induced by apoptotic processes. Antibody-directed mechanisms, including antigen crosslinking, activation of death receptors, and blockade of ligand-receptor growth or survival pathways, can elicit the induction of apoptosis in targeted cells. Depending on their mechanism of action, monoclonal antibodies can induce targeted cell-specific killing alone or can enhance target cell susceptibility to chemo- or radiotherapeutics by effecting the modulation of antiapoptotic pathways. This review will focus on the mechanisms by which antibodies are capable of eliciting programmed cell death either directly or indirectly within tumor cells.
- Published
- 2003
- Full Text
- View/download PDF
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