Abstract

Objective Hepatocellular carcinoma (HCC) is fatal, with increasing incidence and mortality rates and resistance to classical chemotherapies. This paper investigates the molecular mechanism of U2SURP with lenvatinib (LEV) resistance in HCC cells. Methods By integrating public database analysis, clinical samples, and cell lines, we elucidated the expression of U2SURP, CREB3L2, and RIOK1 in HCC and their relationship with LEV sensitivity. In vitro , we established corresponding overexpression, knockdown, and rescue models to examine the effects of U2SURP, CREB3L2, and RIOK1 on HCC cell proliferation, migration, invasion, apoptosis, and LEV sensitivity, and analyzed their upstream and downstream regulatory relationships. Xenograft models and rescue models were established to evaluate the impact of the U2SURP/CREB3L2/RIOK1 axis on tumor growth and response to LEV treatment. Results U2SURP, CREB3L2, and RIOK1 were highly expressed in patients with HCC and cell lines and reduced by LEV treatment. Functional studies indicated that upregulation of CREB3L2 expression enhanced the proliferation, migration, and invasion of HCC cells, inhibited apoptosis, and reduced the sensitivity of HCC cells to LEV. CREB3L2 transcriptionally activated RIOK1 expression, and knocking down RIOK1 reversed the LEV-resistant phenotype mediated by CREB3L2. Moreover, U2SURP upregulated CREB3L2 expression by enhancing its mRNA stability, thereby promoting RIOK1 activation and reducing HCC sensitivity to LEV. Knockdown of CREB3L2 significantly attenuated the aforementioned effects mediated by U2SURP. Conclusion U2SURP reduces the sensitivity of HCC cells to LEV by stabilizing CREB3L2 and activating RIOK1. The U2SURP/CREB3L2/RIOK1 axis may serve as a potential intervention target to enhance the efficacy of LEV in HCC.