| RRC ID |
56120
|
| 著者 |
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.
|
| タイトル |
FBXW7 modulates malignant potential and cisplatin-induced apoptosis in cholangiocarcinoma through NOTCH1 and MCL1.
|
| ジャーナル |
Cancer Sci
|
| 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.
|
| 巻・号 |
109(12)
|
| ページ |
3883-3895
|
| 公開日 |
2018-12-1
|
| DOI |
10.1111/cas.13829
|
| PMID |
30302867
|
| PMC |
PMC6272118
|
| MeSH |
Adult
Aged
Aged, 80 and over
Bile Duct Neoplasms / metabolism*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Cholangiocarcinoma / metabolism*
Cisplatin / pharmacology*
Disease Progression
Down-Regulation
F-Box-WD Repeat-Containing Protein 7 / metabolism*
Gene Expression Regulation, Neoplastic
Humans
Middle Aged
Myeloid Cell Leukemia Sequence 1 Protein / metabolism*
Prognosis
Receptor, Notch1 / metabolism*
Survival Analysis
|
| IF |
4.751
|
| 引用数 |
6
|
| リソース情報 |
| ヒト・動物細胞 |
RBE(RCB1292)
HuCCT1(RCB1960)
TFK-1(RCB2537) |
