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

碩士 === 國立成功大學 === 分子醫學研究所 === 107 === 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...

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Main Authors: Yu-JungLu, 盧昱融
Other Authors: Nan-Haw Chow
Format: Others
Language:en_US
Published: 2019
Online Access:http://ndltd.ncl.edu.tw/handle/msqfca
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spelling ndltd-TW-107NCKU55380062019-10-25T05:24:18Z http://ndltd.ncl.edu.tw/handle/msqfca The Potential Role of Epithelial Membrane Protein 1 in Chemoresistance of Urothelial Carcinoma 探討EMP1在泌尿上皮癌化療藥物抗性中所扮演的角色 Yu-JungLu 盧昱融 碩士 國立成功大學 分子醫學研究所 107 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. Nan-Haw Chow 周楠華 2019 學位論文 ; thesis 31 en_US
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description 碩士 === 國立成功大學 === 分子醫學研究所 === 107 === 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.
author2 Nan-Haw Chow
author_facet Nan-Haw Chow
Yu-JungLu
盧昱融
author Yu-JungLu
盧昱融
spellingShingle Yu-JungLu
盧昱融
The Potential Role of Epithelial Membrane Protein 1 in Chemoresistance of Urothelial Carcinoma
author_sort Yu-JungLu
title The Potential Role of Epithelial Membrane Protein 1 in Chemoresistance of Urothelial Carcinoma
title_short The Potential Role of Epithelial Membrane Protein 1 in Chemoresistance of Urothelial Carcinoma
title_full The Potential Role of Epithelial Membrane Protein 1 in Chemoresistance of Urothelial Carcinoma
title_fullStr The Potential Role of Epithelial Membrane Protein 1 in Chemoresistance of Urothelial Carcinoma
title_full_unstemmed The Potential Role of Epithelial Membrane Protein 1 in Chemoresistance of Urothelial Carcinoma
title_sort potential role of epithelial membrane protein 1 in chemoresistance of urothelial carcinoma
publishDate 2019
url http://ndltd.ncl.edu.tw/handle/msqfca
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