Chien-Feng Li1,2,3, Ti-Chun Chan1,2, Cheng-Tang Pan4,5, Pichpisith Pierre Vejvisithsakul6,7, Jia-Chen Lai6, Szu-Yu Chen6, Ya-Wen Hsu6, Meng-Shin Shiao8, Yow-Ling Shiue9,10. 1. Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan. 2. National Cancer Research Institute, National Health Research Institutes, Tainan, Taiwan. 3. Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan. 4. Institute of Precision Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan. 5. Department of Mechanical and Electro-Mechanical Engineering, National Sun Yat-sen University, Kaohsiung, Taiwan. 6. Institute of Biomedical Sciences, National Sun Yat-sen University, 70 Lienhai Rd, 80424, Kaohsiung, Taiwan. 7. Section for Translational Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. 8. Research Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. 9. Institute of Precision Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan. shirley@imst.nsysu.edu.tw. 10. Institute of Biomedical Sciences, National Sun Yat-sen University, 70 Lienhai Rd, 80424, Kaohsiung, Taiwan. shirley@imst.nsysu.edu.tw.
Abstract
PURPOSE: Urinary bladder urothelial carcinoma (UBUC) is a common malignant disease, and its high recurrence rates impose a heavy clinical burden. The objective of this study was to identify signaling pathways downstream of epithelial membrane protein 2 (EMP2), which induces cytostasis and apoptosis in UBUC. METHODS: A series of in vitro and in vivo assays using different UBUC-derived cell lines and mouse xenograft models were performed, respectively. In addition, primary UBUC specimens were evaluated by immunohistochemistry. RESULTS: Exogenous expression of EMP2 in J82 UBUC cells significantly decreased DNA replication and altered the expression levels of several TGFβ signaling-related proteins. EMP2 knockdown in BFTC905 UBUC cells resulted in opposite effects. EMP2-dysregulated cell cycle progression was found to be mediated by the TGFβ/TGFBR1/SP1 family member SMAD. EMP2 or purinergic receptor P2X7 (P2RX7) gene expression upregulation induced apoptosis via both intrinsic and extrinsic pathways. In 242 UBUC patient samples, P2RX7 protein levels were found to be significantly and positively correlated with EMP2 protein levels. Low P2RX7 levels conferred poor disease-specific and metastasis-free survival rates, and significantly decreased apoptotic cell rates. EMP2 was found to physically interact with P2RX7. In the presence of a P2RX7 agonist, BzATP, overexpression of both EMP2 and P2RX7 significantly increased apoptotic cell rates compared to overexpression of EMP2 or P2RX7 alone. CONCLUSIONS: EMP2 induces cytostasis via the TGFβ/SMAD/SP1 axis and recruits P2RX7 to enhance apoptosis in UBUC. Our data provide new insights that may be employed for the design of UBUC targeting therapies.
PURPOSE: Urinary bladder urothelial carcinoma (UBUC) is a common malignant disease, and its high recurrence rates impose a heavy clinical burden. The objective of this study was to identify signaling pathways downstream of epithelial membrane protein 2 (EMP2), which induces cytostasis and apoptosis in UBUC. METHODS: A series of in vitro and in vivo assays using different UBUC-derived cell lines and mouse xenograft models were performed, respectively. In addition, primary UBUC specimens were evaluated by immunohistochemistry. RESULTS: Exogenous expression of EMP2 in J82 UBUC cells significantly decreased DNA replication and altered the expression levels of several TGFβ signaling-related proteins. EMP2 knockdown in BFTC905 UBUC cells resulted in opposite effects. EMP2-dysregulated cell cycle progression was found to be mediated by the TGFβ/TGFBR1/SP1 family member SMAD. EMP2 or purinergic receptor P2X7 (P2RX7) gene expression upregulation induced apoptosis via both intrinsic and extrinsic pathways. In 242 UBUC patient samples, P2RX7 protein levels were found to be significantly and positively correlated with EMP2 protein levels. Low P2RX7 levels conferred poor disease-specific and metastasis-free survival rates, and significantly decreased apoptotic cell rates. EMP2 was found to physically interact with P2RX7. In the presence of a P2RX7 agonist, BzATP, overexpression of both EMP2 and P2RX7 significantly increased apoptotic cell rates compared to overexpression of EMP2 or P2RX7 alone. CONCLUSIONS: EMP2 induces cytostasis via the TGFβ/SMAD/SP1 axis and recruits P2RX7 to enhance apoptosis in UBUC. Our data provide new insights that may be employed for the design of UBUC targeting therapies.
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