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Hepatology. 2019 Sep 21. doi: 10.1002/hep.30962. [Epub ahead of print]

RPB5-mediating protein promotes cholangiocarcinoma tumorigenesis and drug resistance by competing with NRF2 for KEAP1 binding.

Author information

1
National Center for Liver Cancer, the Second Military Medical University, Shanghai, 201805, P.R. China.
2
No.971 hospital of Peoples' Liberation Army Navy, Qing Dao, 266071, P.R. China.
3
International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai, 200438, P. R. China.
4
Children's Hospital of Soochow University, Suzhou, 215025, P. R. China.
5
Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
6
State Key Laboratory of Oncogenes and related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200127, P.R. China.
7
Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, The Second Military Medical University & Ministry of Education, Shanghai, 200438, P. R. China.

Abstract

Cancer cell survival depends on the balance between reactive oxygen species production and scavenging, which is mainly regulated by NRF2 during tumorigenesis. Here, we demonstrated that deletion of RBP5-mediating protein (RMP) in an autonomous mouse model of intrahepatic cholangiocarcinoma (ICC) delays tumor progression. RMP-overexpressing tumor cells exhibited enhanced tolerance to oxidative stress and apoptosis. Mechanistically, RMP competes with NRF2 for binding to the Kelch domain of KEAP1 via the E**E motif, leading to decreased NRF2 degradation via ubiquitination, thus increasing NRF2 nuclear translocation and downstream transactivation of antioxidant genes. This RMP-KEAP1-NRF2 axis promotes ICC tumorigenesis, metastasis and drug resistance. Consistent with these findings, the RMP level in human ICC is positively correlated with the protein level of NRF2 and is associated with poor prognosis. CONCLUSION: These findings reveal that RMP is involved in the oxidative stress defense program and could be exploited for targeted cancer therapies.

KEYWORDS:

Cholangiocarcinoma; KEAP1; NRF2; RMP; ROS

PMID:
31541481
DOI:
10.1002/hep.30962

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