研究者情報

キクチ　エイジ   KIKUCHI EIJI   菊地栄次    所属   医学部医学科 腎泌尿器外科学    職種   主任教授
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Role of the MUC1‐C oncoprotein in the acquisition of cisplatin resistance by urothelial carcinoma.
掲載誌名	正式名：Cancer Science 略　 称：Cancer Sci ISSNコード：13479032/13497006
掲載区分	国外
出版社名	John Wiley & Sons Australia
巻・号・頁	111(10),3639-3652頁
著者・共著者	Shigeta Keisuke, Hasegawa Masanori, Kikuchi Eiji, Yasumizu Yota, Kosaka Takeo, Mizuno Ryuichi, Mikami Shuji, Miyajima Akira, Kufe Donald, Oya Mototsugu.
担当区分	責任著者
発行年月	2020/07
概要	Mucin 1 C-terminal subunit (MUC1-C) has been introduced as a key regulator for acquiring drug resistance in various cancers, but the functional role of MUC1-C in urothelial carcinoma (UC) cells remains unknown. We aimed to elucidate the molecular mechanisms underlying the acquisition of cisplatin (CDDP) resistance through MUC1-C oncoprotein in UC cells. MUC1-C expression was examined immunohistochemically in tumor specimens of 159 UC patients who received CDDP-based perioperative chemotherapy. As a result, moderate to high MUC1-C expression was independently associated with poor survival in UC patients. Using human bladder cancer cell lines and CDDP-resistant (CR) cell lines, we compared the expression levels of MUC1-C, multiple drug resistance 1 (MDR1), the PI3K-AKT-mTOR pathway, and x-cystine/glutamate transporter (xCT) to elucidate the biological mechanisms contributing to the acquisition of chemoresistance. MUC1-C was strongly expressed in CR cell lines, followed with MDR1 expression via activation of the PI3K-AKT-mTOR pathway. MUC1-C also stabilized the expression of xCT, which enhanced antioxidant defenses by increasing intracellular glutathione (GSH) levels. MUC1 down-regulation showed MDR1 inhibition along with PI3K-AKT-mTOR pathway suppression. Moreover, it inhibited xCT stabilization and resulted in significant decreases in intracellular GSH levels and increased reactive oxygen species (ROS) generation. The MUC1-C inhibitor restored sensitivity to CDDP in CR cells and UC murine xenograft models. In conclusion, we found that MUC1-C plays a pivotal role in the acquisition of CDDP resistance in UC cells, and therefore the combined treatment of CDDP with a MUC1-C inhibitor may become a novel therapeutic option in CR UC patients.
DOI	doi: 10.1111/cas.14574
PMID	32677159