FBXW7 modulates malignant potential and cisplatin-induced apoptosis in cholangiocarcinoma through NOTCH1 and MCL1

Akiko Mori, Kunihiro Masuda, Hideo Ohtsuka, Masahiro Shijo, Kyohei Ariake, Koji Fukase, Naoaki Sakata, Masamichi Mizuma, Takanori Morikawa, Hiroki Hayashi, Kei Nakagawa, Fuyuhiko Motoi, Takeshi Naitoh, Fumiyoshi Fujishima, Michiaki Unno

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3883-3895
Number of pages13
JournalCancer science
Volume109
Issue number12
DOIs
Publication statusPublished - 2018 Dec

Keywords

  • FBXW7 protein
  • NOTCH1 protein
  • cholangiocarcinoma
  • cisplatin
  • myeloid cell leukemia sequence 1 protein

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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