Exosome-derived hsa_circ_0007132 promotes lenvatinib resistance by inhibiting the ubiquitin-mediated degradation of NONO

Abstract

Hepatocellular carcinoma (HCC) is a highly heterogeneous solid tumor, with its incidence showing a troubling upward trend over the past decade. Lenvatinib is one of the first-line medications for treating advanced HCC, however, the development of resistance significantly undermines its potential to improve patient prognosis. In recent years, exosomal circRNAs have been implicated in the resistance mechanisms of various cancers, yet their role in mediating lenvatinib resistance (LR) remains largely unexplored. In this study, we identified hsa_circ_0007132, which is upregulated in the serum exosomes of HCC patients exhibiting progressive disease (PD) following lenvatinib treatment. Subsequently, we employed LR cell lines to conduct both in vitro and in vivo experiments, which provided compelling evidence that hsa_circ_0007132 significantly promotes LR in HCC. Mechanistically, hsa_circ_0007132 interacts with the NONO protein, impairing its ubiquitination and leading to increased stability and upregulation of NONO expression, thereby enhancing NONO-mediated nuclear export of ZEB1 mRNA and elevating ZEB1 protein expression, which ultimately contributes to LR. In summary, our findings unveil a critical mechanism through which HCC mediates tumor progression and LR via exosomal hsa_circ_0007132, while also emphasizing that targeting NONO may represent a promising therapeutic strategy to overcome LR.