长末端重复（LTR）逆转录转座子衍生的lncRNA与肝细胞癌（HCC）之间的因果关系仍然难以捉摸，这些癌症专有的lncRNA是否有助于当前HCC治疗的有效性还有待探索。在这里，我们研究了 LTR 逆转录转座子衍生的 lncRNA 在多种肝脏疾病中的激活情况。我们发现LTR逆转录转座子衍生的lncRNA主要在HCC中被激活，并且与HCC的增殖状态相关。此外，我们发现 LTR 逆转录转座子衍生的 lncRNA LINC01446 在 HCC 中表现出特异性表达。 LINC01446 表达较高的 HCC 患者的总生存时间较短。体外和体内测定显示 LINC01446 促进 HCC 生长和血管生成。从机制上讲，LINC01446 与丝氨酸/精氨酸蛋白激酶 2 (SRPK2) 结合并激活其下游靶标丝氨酸/精氨酸剪接因子 1 (SRSF1)。此外，SRPK2-SRSF1 轴的激活增加了 VEGF 同工型 A165 (VEGFA165) 的剪接和表达。值得注意的是，抑制 LINC01446 表达会显着损害体内肿瘤生长，并与抗血管生成药物联合使用时产生更好的治疗结果。此外，我们发现转录因子 MESI2 与神秘的 MLT2B3 LTR 启动子结合并驱动 HCC 细胞中的 LINC01446 转录。总而言之，我们的研究结果表明，LTR 逆转录转座子衍生的 LINC01446 通过激活 SRPK2/SRSF1/VEGFA165 轴促进 HCC 的进展，并强调以 LINC01446 为靶点作为 HCC 患者的潜在治疗策略。版权所有 © 2024。由 Elsevier B.V. 出版。

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.Copyright © 2024. Published by Elsevier B.V.