Abstract
Our previous study reported that down-regulation of SIK1 accelerates the growth and invasion of hepatocellular carcinoma (HCC). However, the underlying mechanism leading to SIK1 down-regulation in HCC largely remains to be determined. Herein, we demonstrated that RNF2 expression is negatively correlated with SIK1 levels in HCC tissues. Kaplan-Meier analysis of tumor samples revealed that high RNF2 expression with concurrent low SIK1 expression is associated with poor overall survival. The down-regulation of RNF2 expression in HCC cells significantly reduces tumor cell growth and metastasis, while the simultaneous down-regulation of both RNF2 and SIK1 restores tumor cell growth in vitro and in tumor xenograft models. Mechanistically, we identified RNF2 as an E3 ligase that targets SIK1 for degradation. We further demonstrated that direct physical interaction between RNF2 and SIK1 triggers SIK1 down-regulation in HCC cells. These data suggest that RNF2 is an important upstream negative regulator of SIK1 and that restoration of SIK1 levels induced by loss of RNF2 inhibited HCC cell growth and promoted apoptosis, which may represent a promising therapeutic strategy for HCC treatment.
Highlights
Hepatocellular carcinoma (HCC) is one of the most death causing cancers among the world [1]
For the first time, we investigated the impact of RNF2 on Salt-inducible kinase 1 (SIK1) expression and its role in HCC tumorigenesis
Our data indicate that: 1) A high DNA copy number of RNF2 gene significantly correlated with poor prognosis in HCC. 2) RNF2 overexpression is concurrent with SIK1 down-regulation in HCC patients
Summary
Hepatocellular carcinoma (HCC) is one of the most death causing cancers among the world [1]. Despite advances in the diagnosis and treatment of HCC, the overall survival of patients with HCC remains poor due to a high rate of recurrence and distant metastasis after hepatectomy [2]. The understanding of the underlying molecular mechanisms of HCC remains lacking. It is crucial to explore effective and novel biomarkers for recurrence and metastasis to improve combined treatment strategy for future prognosis. More than 100 putative driver genes had been found to be associated with multiple recurrently altered pathways in HCC and may be potential targets for regulation by therapies [3]. It is necessary to elucidate their role and action mechanisms in HCC growth, invasion and metastasis
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