1. EMP2 induces cytostasis and apoptosis via the TGFβ/SMAD/SP1 axis and recruitment of P2RX7 in urinary bladder urothelial carcinoma.
- Author
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Li CF, Chan TC, Pan CT, Vejvisithsakul PP, Lai JC, Chen SY, Hsu YW, Shiao MS, and Shiue YL
- Subjects
- Animals, Carcinoma, Transitional Cell metabolism, Carcinoma, Transitional Cell pathology, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Humans, Immunoblotting, Membrane Glycoproteins metabolism, Mice, Inbred NOD, Mice, SCID, Proteins metabolism, Receptors, Purinergic P2X7 metabolism, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction genetics, Smad Proteins genetics, Smad Proteins metabolism, Sp1 Transcription Factor genetics, Sp1 Transcription Factor metabolism, Transforming Growth Factor beta genetics, Transforming Growth Factor beta metabolism, Transplantation, Heterologous, Urinary Bladder Neoplasms metabolism, Urinary Bladder Neoplasms pathology, Mice, Apoptosis genetics, Carcinoma, Transitional Cell genetics, Cell Proliferation genetics, Membrane Glycoproteins genetics, Proteins genetics, Receptors, Purinergic P2X7 genetics, Urinary Bladder Neoplasms genetics
- 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., (© 2021. Springer Nature Switzerland AG.)
- Published
- 2021
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