FBXW7 modulates malignant potential and cisplatin‐induced apoptosis in cholangiocarcinoma through NOTCH1 and MCL1. Issue 12 (5th November 2018)

• Record Type: Journal Article
• Authors: Mori, Akiko; Masuda, Kunihiro; Ohtsuka, Hideo; Shijo, Masahiro; Ariake, Kyohei; Fukase, Koji; Sakata, Naoaki; Mizuma, Masamichi; Morikawa, Takanori; Hayashi, Hiroki; Nakagawa, Kei; Motoi, Fuyuhiko; Naitoh, Takeshi; Fujishima, Fumiyoshi; Unno, Michiaki
• Is Part Of: Cancer science. Volume 109:Issue 12(2018)
• Page Start: 3883
• Page End: 3895
• Publication Date: 2018-11-05
• Subjects: cholangiocarcinoma -- cisplatin -- FBXW7 protein -- myeloid cell leukemia sequence 1 protein -- NOTCH1 protein; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.13829
• Languages: English
• ISSNs: 1347-9032

Abstract

Abstract : The ubiquitin ligase F‐box and WD repeat domain‐containing 7 (FBXW7) is responsible for degrading diverse oncoproteins and is considered a tumor suppressor in many human cancers. Inhibiting FBXW7 enhances the malignant potential of several cancers. In this study, we aimed to investigate the role of FBXW7 in cholangiocarcinoma. We found that FBXW7 expression was associated with clinicopathological outcomes in cholangiocarcinoma patients. Both disease‐free and overall survival were significantly worse in the low‐FBXW7 group than in the high‐FBXW7 group ( P = .001 and P < .001, respectively). Multivariate analysis with the Cox proportional hazards model indicated that FBXW7 was the most important independent prognostic factor for disease‐free ( P = .006) and overall ( P = .0004) survival. We also showed that the two FBXW7 substrates, NOTCH1 and myeloid cell leukemia sequence 1 (MCL1), regulate cholangiocarcinoma progression. Depletion of FBXW7 resulted in NOTCH1 accumulation and increased cholangiocarcinoma cell migration and self‐renewal. Interestingly, when cells were stimulated with cis‐diamminedichloridoplatinum(II) (cisplatin), FBXW7 suppression induced MCL1 upregulation, which reduced the sensitivity of cholangiocarcinoma cells to apoptosis, indicating that FBXW7‐mediated ubiquitylation is context‐dependent. These results indicate that FBXW7 modulates the malignant potential of cholangiocarcinoma through independent regulation of NOTCH1 and MCL1. Abstract : The ubiquitin ligase FBXW7 is associated with prognostic outcome in cholangiocarcinoma patients. FBXW7 was found to regulate the migration and self‐renewal of cholangiocarcinoma cells through modulation of NOTCH1 as well as CDDP‐induced apoptosis through MCL1 accumulation for the first time in cholangiocarcinoma cells. These findings suggest that FBXW7 modulates the malignant potential of cholangiocarcinoma through two signals, NOTCH1 and MCL1.