Downregulated TRAF3IP2-AS1 promotes hepatocellular carcinoma progression through the miR-374a-5p/SEL1L1/RPL6 axis to enhance DNA damage repair.

OBJECTIVES

Excessive activity in the DNA damage repair (DDR) pathway causes genomic instability, leading to the development of hepatocellular carcinoma (HCC), the most common form of liver cancer. The long non-coding RNA (lncRNA) tumor necrosis factor receptor-associated factor 3 interacting protein 2 antisense RNA 1 (TRAF3IP2-AS1) acts as a tumor suppressor. MicroRNA (miR)-374a-5p is a target miRNA for TRAF3IP2-AS1, while SEL1L ERAD E3 ligase adaptor subunit (SEL1L) acts as a target gene of miR-374a-5p. Moreover, DDR-participating molecule ribosomal protein L6 (RPL6) interacts with SEL1L. In this study, we aimed to explore the role and mechanism of TRAF3IP3-AS1 in HCC.

METHODS

In vitro HCC cell lines were cultured. In vivo, a mouse in situ HCC model was constructed using a liver injection of HepG2 cells. Additionally, clinical HCC and adjacent tissues were used to verify the pathway.

RESULTS

Oxidative stress downregulated TRAF3IP2-AS1 in HCC cells. TRAF3IP2-AS1 downregulated the proliferation, migration, and invasion of HCC cells by inhibiting miR-374a-5p levels. SEL1L was a target gene of miR-374a-5p in HCC cells. Mir-374a-5p facilitated the proliferation, migration, and invasion of HCC cells by inhibiting SEL1L. TRAF3IP2-AS1 and miR-374a-5p regulated the interaction between SEL1L and RPL6 as well as RPL6 ubiquitin degradation in HCC cells in an opposite manner. DDR was upregulated in HCC cells through the TRAF3IP2-AS1/miR-374a-5p/SEL1L1/RPL6 pathway. Downregulated SEL1L promoted the proliferation, migration, and invasion of HCC cells by upregulating RPL6 expression. Furthermore, the TRAF3IP2-AS1/miR-374a-5p/SEL1L/RPL6 pathway exacerbated the progression of HCC in mice. This pathway also promoted the proliferation, migration, and invasion of in vivo HCC cells by enhancing DDR.

CONCLUSIONS

TRAF3IP2-AS1/miR-374a-5p/SEL1L/RPL6 pathway in HCC cells promoted DDR and HCC progression. Our data identify the role and mechanism of TRAF3IP2-AS1 in HCC and imply treatment targets for HCC.