CircPIK3C3 inhibits hepatocellular carcinoma progression and lenvatinib resistance by suppressing the Wnt/β-catenin pathway via the miR-452-5p/SOX15 axis

Introduction: Resistance to lenvatinib limits the effectiveness of the targeted treatments for HCC. However, the exact mechanism behind this resistance remains elusive. Current research suggests that circular RNA (circRNA) is pivotal in mediating drug resistance during targeted treatments.

Objectives: To investigate the influence of circRNA on HCC progression and its resistance to lenvatinib.

Methods: We identified the crucial circRNA hsa_circ_0005711 (circPIK3C3) through bioinformatics. Study (in-vitro and in-vivo) on the expression of circPIK3C3 (measured by qRT-PCR) and its association with progress of HCC patients including lenvatinib resistance were performed. Techniques such as dual-luciferase reporter assays, RNA FISH, RAP, and AGO2-RIP were employed for discerning circPIK3C3's specific mechanisms related to progression of HCC and its lenvatinib resistance.

Results: Study (in-vitro and in-vivo) revealed that circPIK3C3 exhibited reduced expression and lenvatinib resistance in HCC, which was intimately tied to patient outcomes. Moreover, circPIK3C3 elevated SOX15 expression while suppressing the signaling pathway related to Wnt/β-catenin via inhibition of miR-452-5p through a competitive endogenous RNA (ceRNA) network. This, in turn, mitigated HCC progression and its resistance to lenvatinib.

Conclusion: CircPIK3C3 is instrumental in the disease progression and resistance to Lenvatinib in HCC. It presents a potential therapeutic avenue for patients with lenvatinib-resistant HCC and could serve as a valuable molecular marker for forecasting lenvatinib resistance in HCC patients.