2. Academic Validation
  3. LTR retrotransposon-derived LncRNA LINC01446 promotes hepatocellular carcinoma progression and angiogenesis by regulating the SRPK2/SRSF1/VEGF axis

LTR retrotransposon-derived LncRNA LINC01446 promotes hepatocellular carcinoma progression and angiogenesis by regulating the SRPK2/SRSF1/VEGF axis

  • Cancer Lett. 2024 Jun 28:598:217088. doi: 10.1016/j.canlet.2024.217088.
Yangjun Wu 1,  Jiajia Wang 2,  Jingjing Zhao 2,  Yue Su 2,  Xinrong Li 2,  Zhiao Chen 2,  Xiaohua Wu 3,  Shenglin Huang 4,  Xianghuo He 5,  Linhui Liang 6
Affiliations

Affiliations

  • 1 Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China; Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
  • 2 Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
  • 3 Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
  • 4 Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China; Department of Integrative Oncology, Fudan University Shanghai Cancer Center, China.
  • 5 Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China. Electronic address: xhhe@fudan.edu.cn.
  • 6 Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China. Electronic address: lianglinhui@fudan.edu.cn.
PMID: 38945203 DOI: 10.1016/j.canlet.2024.217088
Abstract

The causal link between long terminal repeat (LTR) retrotransposon-derived lncRNAs and hepatocellular carcinoma (HCC) remains elusive and whether these cancer-exclusive lncRNAs contribute to the effectiveness of current HCC therapies is yet to explore. Here, we investigated the activation of LTR retrotransposon-derived lncRNAs in a broad range of liver diseases. We found that LTR retrotransposon-derived lncRNAs are mainly activated in HCC and is correlated with the proliferation status of HCC. Furthermore, we discovered that an LTR retrotransposon-derived lncRNA, LINC01446, exhibits specific expression in HCC. HCC patients with higher LINC01446 expression had shorter overall survival times. In vitro and in vivo assays showed that LINC01446 promoted HCC growth and angiogenesis. Mechanistically, LINC01446 bound to serine/arginine protein kinase 2 (SRPK2) and activated its downstream target, serine/arginine splicing factor 1 (SRSF1). Furthermore, activation of the SRPK2-SRSF1 axis increased the splicing and expression of VEGF isoform A165 (VEGFA165). Notably, inhibiting LINC01446 expression dramatically impaired tumor growth in vivo and resulted in better therapeutic outcomes when combined with antiangiogenic agents. In addition, we found that the transcription factor MESI2 bound to the cryptic MLT2B3 LTR promoter and drove LINC01446 transcription in HCC cells. Taken together, our findings demonstrate that LTR retrotransposon-derived LINC01446 promotes the progression of HCC by activating the SRPK2/SRSF1/VEGFA165 axis and highlight targeting LINC01446 as a potential therapeutic strategy for HCC patients.

Keywords

Anti-angiogenic therapy; HCC; LINC01446; SRPK2; VEGF.

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