TUG1 targeting enhances anticancer immunity thereby facilitating lenvatinib efficacy in hepatocellular carcinoma.

Abstract

Hepatocellular carcinoma (HCC) is a major cause of cancer death globally, with a poor prognosis. The long non-coding RNA TUG1 has been implicated, but its specific role in HCC remains unclear. RT-qPCR was used to evaluate TUG1 and PD-L1 expression, while GEO and TCGA databases were utilized to compare TUG1 levels between HCC patients and healthy controls. In vitro, including CCK8, colony formation, and transwell, assessed cell growth. CD8 + T cell cytotoxicity was evaluated through HCC cells co-culture experiments, and the interaction of miR-377-3p with TUG1 and PD-L1 was examined using dual-luciferase reporter assays. Results indicated that TUG1 was upregulated in HCC, particularly in advanced-stage disease, and PD-L1 expression positively correlated with TUG1 levels. Notably, lenvatinib (LEN) treatment downregulated both TUG1 and PD-L1 in HCC cells, enhancing CD8 + T cell-mediated cytotoxicity. Overexpression of TUG1 diminished the efficacy of LEN, while TUG1 knockdown enhanced it. Mechanistically, TUG1 was found to sponge miR-377-3p, thereby increasing PD-L1 expression. In vivo, TUG1 knockdown combined with LEN treatment significantly reduced tumor growth and PD-L1 expression. In conclusion, TUG1 promotes HCC progression by enhancing PD-L1 through miR-377-3p, with its knockdown enhancing the therapeutic efficacy of LEN, highlighting TUG1's potential as a novel target for HCC treatment.