FBXW7 modulates malignant potential and cisplatin-induced apoptosis in cholangiocarcinoma through NOTCH1 and MCL1.
FBXW7 modulates malignant potential and cisplatin-induced apoptosis in cholangiocarcinoma through NOTCH1 and MCL1.
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DOI：
10.1111/cas.13829
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发表时间：
2018-12
期刊：
影响因子：
5.7
通讯作者：
Unno M
中科院分区：
文献类型：
--
作者：
Mori A;Masuda K;Ohtsuka H;Shijo M;Ariake K;Fukase K;Sakata N;Mizuma M;Morikawa T;Hayashi H;Nakagawa K;Motoi F;Naitoh T;Fujishima F;Unno M
泛素连接酶F-box和WD重复结构域7（FBXW 7）负责降解多种癌蛋白，被认为是许多人类癌症的肿瘤抑制因子。抑制FBXW 7会增强几种癌症的恶性潜力。本研究旨在探讨FBXW 7在胆管癌中的作用。我们发现FBXW 7表达与胆管癌患者的临床病理结果相关。低FBXW 7组的无病生存率和总生存率均显著低于高FBXW 7组（分别为P = .001和P < .001）。采用考克斯比例风险模型的多变量分析表明，FBXW 7是无病生存期（P = .006）和总生存期（P = .0004）的最重要独立预后因素。我们还发现，两个FBXW 7底物，NOTCH 1和髓细胞白血病序列1（MCL 1），调节胆管癌的进展。FBXW 7的缺失导致NOTCH 1积累并增加胆管癌细胞迁移和自我更新。有趣的是，当用顺式二氨氯铂（II）（顺铂）刺激细胞时，FBXW 7抑制诱导MCL 1上调，这降低了胆管癌细胞对凋亡的敏感性，表明FBXW 7介导的泛素化是环境依赖性的。这些结果表明FBXW 7通过独立调节NOTCH 1和MCL 1来调节胆管癌的恶性潜能。
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.
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影响因子：
64.8
作者：
Inuzuka, Hiroyuki;Shaik, Shavali;Onoyama, Ichiro;Gao, Daming;Tseng, Alan;Maser, Richard S.;Zhai, Bo;Wan, Lixin;Gutierrez, Alejandro;Lau, Alan W.;Xiao, Yonghong;Christie, Amanda L.;Aster, Jon;Settleman, Jeffrey;Gygi, Steven P.;Kung, Andrew L.;Look, Thomas;Nakayama, Keiichi I.;DePinho, Ronald A.;Wei, Wenyi
通讯作者：
Wei, Wenyi
影响因子：
--
作者：
Li Q;Zhan M;Chen W;Zhao B;Yang K;Yang J;Yi J;Huang Q;Mohan M;Hou Z;Wang J
通讯作者：
Wang J
影响因子：
29.4
作者：
Ilyas SI;Gores GJ
通讯作者：
Gores GJ
Notch通路促进肝细胞癌中CD90细胞的癌症干细胞特性。
影响因子：
--
作者：
Luo J;Wang P;Wang R;Wang J;Liu M;Xiong S;Li Y;Cheng B
通讯作者：
Cheng B
影响因子：
56.9
作者：
Nateri, AS;Riera-Sans, L;Behrens, A
通讯作者：
Behrens, A