The Potential Role of Epithelial Membrane Protein 1 in Chemoresistance of Urothelial Carcinoma

Abstract

Bladder cancer is the ninth important male cancer in Taiwan More than 90% of bladder cancer is urothelial carcinoma (UC) Currently standard treatment for UC includes surgery radiotherapy and chemotherapy Combination of gemcitabine and cisplatin is the first-line chemotherapy for advanced UC patients and EGFR inhibitor represents the mainstream of targeted therapy However resistance to chemotherapy or targeted therapy is a major obstacle to treatment; but the underlying mechanisms are still unclear EGFR family related signal pathways have been demonstrated to involve in chemoresistance of UC Therefore discovery of biomarker(s) associated with chemoresistance is imperative in the design of treatment of UC patients EMP1 a transmembrane glycoprotein was recently reported to correlate with gefitinib resistance in non-small cell lung cancer This study was designed to investigate the potential of EMP1 involved in chemoresistance of UC and its underlying mechanism(s) EMP1 overexpression and knockdown stable cell lines were first established from NTUB1 cells and TSGH 8301 cells respectively Then sensitivity to cisplatin doxorubicin methotrexate gemcitabine vincristine sorafenib or gefitinib treatment was measured in vitro EMP1 overexpression enhances the sensitivity to cisplatin and doxorubicin but suppresses the sensitivity to methotrexate and gemcitabine When EGFR/ERK pathway was inhibited EMP1 overexpression stable cells cell showed no significant difference of sensitivity to sorafenib or gefitinib treatment To explain for the dichotomous effect additional drug resistance related pathways were analyzed in vitro The ERCC1 biomarker of cisplatin resistance is significantly down-regulated after cisplatin treatment In contract DHFR and RRM1 biomarker of methorexate and gemcitabine resistance are significantly up-regulated after treatment with methorexate or gemcitabine Then effects of EMP1 expression on native or resistant cell lines with/without targeted therapy agent were examined in vitro EMP1 overexpression stable cell line was established from NP14 (cisplatin resistant) and NG1 5 (gemcitabine resistant) cells respectively We showed that EMP1 enhances the sensitivity of UC cells to cisplatin but suppresses the sensitivity to gemcitabine in vitro The results of our experiments suggest that EMP1 may have potential as a biomarker in the design of treatment planning for UC patients and modulating EMP1 deserves further investigation as a novel chemosensitizer of cisplatin Together we have identified a new avenue to contest chemoresistance in human UC patients

Date of Award	2019
Original language	English
Supervisor	Nan-Haw Chow (Supervisor)