» Articles » PMID: 31721195

Liver Haploinsufficiency of RuvBL1 Causes Hepatic Insulin Resistance and Enhances Hepatocellular Carcinoma Progression

Overview
Journal Int J Cancer
Specialty Oncology
Date 2019 Nov 14
PMID 31721195
Citations 13
Authors
Affiliations
Soon will be listed here.
Abstract

RuvBL1 is an AAA+ ATPase whose expression in hepatocellular carcinoma (HCC) correlates with a poor prognosis. In vitro models suggest that targeting RuvBL1 could be an effective strategy against HCC. However, the role of RuvBL1 in the onset and progression of HCC remains unknown. To address this question, we developed a RuvBL1 mouse model and evaluated the outcome of DEN-induced liver carcinogenesis up to 12 months of progression. We found that RuvBL1 haploinsufficiency initially delayed the onset of liver cancer, due to a reduced hepatocyte turnover in RuvBL1 mice. However, RuvBL1 mice eventually developed HCC nodules that, with aging, grew larger than in the control mice. Moreover, RuvBL1 mice developed hepatic insulin resistance and impaired glucose homeostasis. We could determine that RuvBL1 regulates insulin signaling through the Akt/mTOR pathway in liver physiology in vivo as well as in normal hepatocytic and HCC cells in vitro. Whole transcriptome analysis of mice livers confirmed the major role of RuvBL1 in the regulation of hepatic glucose metabolism. Finally, RuvBL1 expression was found significantly correlated to glucose metabolism and mTOR signaling by bioinformatic analysis of human HCC sample from the publicly available TGCA database. These data uncover a role of RuvBL1 at the intersection of liver metabolism, hepatocyte proliferation and HCC development, providing a molecular rationale for its overexpression in liver cancer.

Citing Articles

Regulation of the β‑catenin/LEF‑1 pathway by the siRNA knockdown of RUVBL1 expression inhibits breast cancer cell proliferation, migration and invasion.

Zhang X, Cui D, Sun W, Yang G, Wang W, Mi C Oncol Rep. 2024; 53(2).

PMID: 39670302 PMC: 11667213. DOI: 10.3892/or.2024.8855.


Molecular Signatures of CB-6644 Inhibition of the RUVBL1/2 Complex in Multiple Myeloma.

Yi W, Dziadowicz S, Mangano R, Wang L, McBee J, Frisch S Int J Mol Sci. 2024; 25(16).

PMID: 39201707 PMC: 11354775. DOI: 10.3390/ijms25169022.


DNA damage repair-related gene signature for identifying the immune status and predicting the prognosis of hepatocellular carcinoma.

Lu Y, Wang S, Chi T, Zhao Y, Guo H, Wang H Sci Rep. 2023; 13(1):18978.

PMID: 37923899 PMC: 10624694. DOI: 10.1038/s41598-023-45999-z.


Emerging and potential use of CRISPR in human liver disease.

Adlat S, Vazquez Salgado A, Lee M, Yin D, Wangensteen K Hepatology. 2023; .

PMID: 37607734 PMC: 10881897. DOI: 10.1097/HEP.0000000000000578.


Tumor subtypes and signature model construction based on chromatin regulators for better prediction of prognosis in uveal melanoma.

Li Y, Xiong C, Wu L, Zhang B, Wu S, Chen Y Pathol Oncol Res. 2023; 29:1610980.

PMID: 37362244 PMC: 10287976. DOI: 10.3389/pore.2023.1610980.