Abstract
BackgroundHepatocellular carcinoma (HCC) is the third cause of cancer death in the world, and few molecularly targeted anticancer therapies have been developed to treat it. The E3 ubiquitin ligase RNF152 has been reported to regulate the activity of the mechanistic target of rapamycin complex 1 (mTORC1), induce autophagy and apoptosis. However, the relationship between RNF152 and HCC is unclear.MethodsTranscriptome RNA-sequencing data of HCC samples and normal tissues were used to detect the mRNA expression of RNF152. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were used to determine the transcriptional regulation of RNF152 in HCC by FoxO1. RNAi, cell proliferation, colony formation and transwell assays were used to determine the in vitro functions of RNF152. Mouse xenograft models were used to study the in vivo effects of RNF152. The immunoprecipitation assay was used to determine the interaction between RNF152 and TSPAN12. The in vivo ubiquitination assay was performed to determine the regulation of TSPAN12 by RNF152.ResultsWe found that RNF152 is significantly down-regulated in clinic HCC samples, and its down-regulation is associated with pool overall survival (OS), progression-free survival (PFS) and disease-specific survival (DSS) in HCC patients. The transcription factor FoxO1 was significantly positively correlated RNF152 expression in HCC tissues. FoxO1 recognizes a classic insulin response element (IRE) on the RNF152 promoter to regulate its expression in HCC. RNF152 suppressed HCC cell proliferation, clonogenic survival, invasion in vitro, and tumorigenesis in vivo. Mechanistically, RNF152 interacted with TSPAN12 and targeted it for ubiquitination and proteasomal degradation, thereby inhibiting TSPAN12-dependent CXCL6 expression and HCC progression.ConclusionCollectively, our data revealed a tumor suppressor role of RNF152 and a connection between RNF152 and FoxO1 in HCC. Our results support an important role of the FoxO1-RNF152-TSPAN12 axis in the development of HCC. Therapeutic targeting this axis may be an effective means of treating HCC.
Highlights
Hepatocellular carcinoma (HCC) is one of the top five solid malignancies with the highest incidence in the world, and it is the third cause of cancer death [1]
RNF152 is down‐regulated in HCC, and its downregulation is associated with a poor prognosis for HCC patients To investigate the role of RNF152 in HCC, we first analyzed the mRNA expression levels of RNF152 in HCC tissues from the Cancer Genome Atlas (TCGA) database
We analyzed the mRNA expression of RNF152 in the Cancer Cell Line Encyclopedia (CCLE) database and found that RNF152 was significantly low expressed in most HCC cell lines (Fig. 1d)
Summary
Hepatocellular carcinoma (HCC) is one of the top five solid malignancies with the highest incidence in the world, and it is the third cause of cancer death [1]. There are about 800,000 newly diagnosed cases of HCC each year, and only China accounts for more than 50% [2]. The 5-year recurrence rate after resection is up to 70% [3]. Current studies have found that the median survival time of patients with advanced HCC who received sorafenib is longer than that of patients who took placebo, there are still many limitations in the current targeted therapy for HCC [4]. Hepatocellular carcinoma (HCC) is the third cause of cancer death in the world, and few molecularly targeted anticancer therapies have been developed to treat it.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
