Wang Yu, Wu Wen-Ze, Hu Yuan-Wen, Yu Qian-Qian, Ge Hai-Long, Yu Wei-Xin, Mo Feng, Chao Chen, Sun Dong-Lin
Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Soochow University Changzhou 213003, Jiangsu, China.
Department of Hepatobiliary Surgery, Jintan Affiliated Hospital of Jiangsu University Changzhou 213200, Jiangsu, China.
Am J Transl Res. 2025 Apr 15;17(4):2445-2466. doi: 10.62347/UJZK5358. eCollection 2025.
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.
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.
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.
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.
DNA损伤修复（DDR）途径的过度激活会导致基因组不稳定，进而引发肝细胞癌（HCC），这是最常见的肝癌形式。长链非编码RNA（lncRNA）肿瘤坏死因子受体相关因子3相互作用蛋白2反义RNA1（TRAF3IP2-AS1）起着肿瘤抑制因子的作用。微小RNA（miR）-374a-5p是TRAF3IP2-AS1的靶标miRNA，而SEL1L内质网相关降解E3连接酶衔接子亚基（SEL1L）是miR-374a-5p的靶标基因。此外，参与DDR的分子核糖体蛋白L6（RPL6）与SEL1L相互作用。在本研究中，我们旨在探讨TRAF3IP3-AS1在HCC中的作用及机制。
体外培养HCC细胞系。在体内，通过向肝脏注射HepG2细胞构建小鼠原位HCC模型。此外，利用临床HCC及癌旁组织验证该通路。
氧化应激下调了HCC细胞中TRAF3IP2-AS1的表达。TRAF3IP2-AS1通过抑制miR-374a-5p水平下调HCC细胞的增殖、迁移和侵袭能力。SEL1L是HCC细胞中miR-374a-5p的靶标基因。miR-374a-5p通过抑制SEL1L促进HCC细胞的增殖、迁移和侵袭。TRAF3IP2-AS1和miR-374a-5p以相反的方式调节HCC细胞中SEL1L与RPL6之间的相互作用以及RPL6的泛素化降解。通过TRAF3IP2-AS1/miR-374a-5p/SEL1L1/RPL6通路，HCC细胞中的DDR被上调。SEL1L表达下调通过上调RPL6的表达促进HCC细胞的增殖、迁移和侵袭。此外，TRAF3IP2-AS1/miR-374a-5p/SEL1L/RPL6通路加剧了小鼠HCC的进展。该通路还通过增强DDR促进体内HCC细胞的增殖、迁移和侵袭。
HCC细胞中的TRAF3IP2-AS1/miR-374a-5p/SEL1L/RPL6通路促进了DDR和HCC的进展。我们的数据确定了TRAF3IP2-AS1在HCC中的作用及机制，并暗示了HCC的治疗靶点。
