Multilevel regulation of RUVBL2 expression predicts poor prognosis in hepatocellular carcinoma

Abstract

Background Hepatocellular carcinoma (HCC) is the second-most lethal cancer worldwide with a complex pathogenesis. RuvB-like 2 (RUVBL2) was previously found to contribute to hepatocarcinogenesis. However, its expression, regulation and clinical significance have not been systematically evaluated in a large number of clinical samples. Methods Here, we performed a comprehensive analysis of RUVBL2 based on multiple datasets from 371 liver cancer patients of The Cancer Genome Atlas (TCGA) and on immunohistochemical staining in 153 subjects. In addition, the aberrant signaling pathways caused by RUVBL2 overexpression were investigated. Results We demonstrated that promoter hypomethylation, copy number gain, MYC amplification and CTNNB1 mutation were all responsible for RUVBL2 overexpression in HCC. High levels of RUVBL2 mRNA were associated with shorter recurrence-free survival time (RFS) but not overall survival time (OS). Furthermore, RUVBL2 protein was overexpressed in the nucleus and cytoplasm of HCC samples. Univariate and multivariate survival analyses showed that strong nuclear and cytoplasmic staining of RUVBL2 independently predicted worse OS and RFS with a 2.03-fold and a 1.71-fold increase in the hazard ratio, respectively. High levels of RUVBL2 promoted carcinogenesis through the heat shock protein 90 (HSP90)-Cell Division Cycle 37 (CDC37), AKT serine/threonine kinase (AKT) and mitogen-activated protein kinase (ERK/MAPK) pathways. Conclusion The deregulation of RUVBL2 in HCC is influenced at the genomic, epigenetic and transcriptional levels. Our findings highlight the potential roles of RUVBL2 as a promising prognostic marker as well as a therapeutic target for HCC.

Molecular Bases of Drug Resistance in Hepatocellular Carcinoma

“…In healthy cells, these ATPases are located strictly in the nucleus, but in tumor cells, they are also present in the cytoplasm. This dual localization seems to be necessary for tumor cell survival and tumorigenicity [ 77 ], which leads to shorter survival of patients with HCC [ 81 ].…”

A Systematic Analysis Reveals the Prognostic and Immunological Role of Reptin/RUVBL2 in Human Tumors

“…Reptin was overexpressed in gastric tissue ( Li et al, 2010 ), and its high expression was related to advanced nodal disease in colon cancer patients ( Flavin et al, 2011 ). For hepatocellular liver carcinoma, overexpressed Reptin is necessary for hepatocyte proliferation ( Javary et al, 2021 ), and it could be used to predict poor prognosis ( Yan et al, 2019 ). Within the excretory system, a previous study showed that overexpressed Reptin is related to the poor differentiation of RCC cells and portends poor outcomes for patients ( Ren et al, 2013 ).…”

Signatures Based On Tumor Microenvironment Genes Can Reliably Predict The Prognosis of Laryngeal Cancer Patients

“…RUVBL2 represents RuvB-like 2 protein, deregulation of which in hepatocellular carcinoma is in uenced at the genomic, epigenetic and transcriptional levels. It has been suggested as a promising prognostic marker as well as a therapeutic target for hepatocellular carcinoma [33] . Beside these, the connection between the other genes and laryngeal cancer are not clear yet.…”