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

  • Am J Transl Res. 2025 Apr 15;17(4):2445-2466. doi: 10.62347/UJZK5358.
Yu Wang  1  2 ,  Wen-Ze Wu  3 ,  Yuan-Wen Hu  4 ,  Qian-Qian Yu  5 ,  Hai-Long Ge  2 ,  Wei-Xin Yu  2 ,  Feng Mo  2 ,  Chen Chao  2 ,  Dong-Lin Sun  1
Affiliations
  • 1. Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Soochow University Changzhou 213003, Jiangsu, China.
  • 2. Department of Hepatobiliary Surgery, Jintan Affiliated Hospital of Jiangsu University Changzhou 213200, Jiangsu, China.
  • 3. Department of General Surgery, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University Changzhou 213003, Jiangsu, China.
  • 4. Department of Gastroenterology, Kunshan First People's Hospital Affiliated to Jiangsu University Kunshan 215300, Jiangsu, China.
  • 5. Department of Oncology, Jintan Affiliated Hospital of Jiangsu University Changzhou 213200, Jiangsu, China.
PMID: 40385018 DOI: 10.62347/UJZK5358
Abstract

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.

Keywords
DNA damage repair (DDR); Hepatocellular carcinoma (HCC); MicroRNA (miR)-374a-5p; Ribosomal protein L6 (RPL6); SEL1L ERAD E3 ligase adaptor subunit (SEL1L); Tumor necrosis factor receptor-associated factor 3 interacting protein 2 antisense RNA 1 (TRAF3IP2-AS1).
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