Exosomal CircRNA-MANBA Mediates Hepatocellular Carcinoma Sorafenib Resistance via miR-1290/CD109/p-STAT3 Axis

Abstract

Abstract Background Sorafenib remains the cornerstone chemotherapeutic treatment for patients with late-stage hepatocellular carcinoma (HCC). Unfortunately, resistance to this drug in the context of the disease is frequent, and the underlying mechanisms remain unclear. In this regard, exosome-contained noncoding RNAs (ncRNAs) have been proven to participate in various diseases. Here, we aimed to identify the exosomal circular RNA (circRNA)-mediated mechanism by which sorafenib resistance develops in HCC. Methods Differential expression of exosomal circRNAs from parental and sorafenib-resistant HCC cells were examined by microarray. Cell viability, colony formation, apoptosis, and TUNEL assays were performed to determine HCC drug resistance following siRNA treatment. Exosomes from sorafenib-resistant HCC cells were harvested and incubated with parental cells. Bioinformatics analysis, quantitative real-time PCR, immunohistochemistry, and Western blot, were performed determine the downstream targets of circRNA. Results CircRNA-MANBA was overexpressed in sorafenib-resistant cell lines, and present in high concentrations in exosomes secreted by resistant cells. Inhibition of circRNA-MANBA significantly increased the cell-killing effect of sorafenib. Analysis of tissue samples from sorafenib-treated HCC patients revealed an association between circRNA-MANBA and poor overall/disease-free survival. The sensitivity of parental HCC was substantially impaired after co-culture with exosomes from resistant cells, and transfection of siRNA targeting circRNA-MANBA could partially reverse the attenuation of sensitization to sorafenib. Mechanically, circRNA-MANBA acted as an “miRNA sponge” to absorb miR-1290, preventing it from interacting with CD109, and therefore upregulating STAT3 phosphorylation (S727). Targeting miR-1290 activation with an inhibitor or mimic could strengthen or reverse the effect of si-circRNA-MANBA on drug sensitivity, respectively. Conclusions Our findings demonstrate the unique role of exosomal circRNA-MANBA in the regulation and transfer of resistance to sorafenib and propose a potential strategy to overcome drug resistance in progressive HCC.