Open AccessFBXW 7 modulates malignant potential and cisplatin‐induced apoptosis in cholangiocarcinoma through NOTCH 1 and MCL 1
Author(s) -
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
Publication year - 2018
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13829
Subject(s) - cancer research , notch signaling pathway , downregulation and upregulation , apoptosis , carcinogenesis , context (archaeology) , myeloid leukemia , cisplatin , myeloid , biology , medicine , immunology , cancer , chemotherapy , gene , receptor , genetics , paleontology
The ubiquitin ligase F‐box and WD repeat domain‐containing 7 ( FBXW 7) is responsible for degrading diverse oncoproteins and is considered a tumor suppressor in many human cancers. Inhibiting FBXW 7 enhances the malignant potential of several cancers. In this study, we aimed to investigate the role of FBXW 7 in cholangiocarcinoma. We found that FBXW 7 expression was associated with clinicopathological outcomes in cholangiocarcinoma patients. Both disease‐free and overall survival were significantly worse in the low‐ FBXW 7 group than in the high‐ FBXW 7 group ( P = .001 and P < .001, respectively). Multivariate analysis with the Cox proportional hazards model indicated that FBXW 7 was the most important independent prognostic factor for disease‐free ( P = .006) and overall ( P = .0004) survival. We also showed that the two FBXW 7 substrates, NOTCH 1 and myeloid cell leukemia sequence 1 ( MCL 1), regulate cholangiocarcinoma progression. Depletion of FBXW 7 resulted in NOTCH 1 accumulation and increased cholangiocarcinoma cell migration and self‐renewal. Interestingly, when cells were stimulated with cis‐diamminedichloridoplatinum( II ) (cisplatin), FBXW 7 suppression induced MCL 1 upregulation, which reduced the sensitivity of cholangiocarcinoma cells to apoptosis, indicating that FBXW 7‐mediated ubiquitylation is context‐dependent. These results indicate that FBXW 7 modulates the malignant potential of cholangiocarcinoma through independent regulation of NOTCH 1 and MCL 1.