Sorafenib was originally identified as an inhibitor of multiple oncogenic kinases and remains the first-line systemic therapy for advanced hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) have been reported to play critical roles in the initiation, progression, and drug resistance of HCC. In this study, we aimed to identify sorafenib-induced miRNAs and demonstrate their regulatory roles. First, we identified that the expression of the tumor-suppressive miRNA miR-375 was significantly induced in hepatoma cells treated with sorafenib, and miR-375 could exert its antiangiogenic effect partially via platelet-derived growth factor C (PDGFC) inhibition. Then, we demonstrated that sorafenib inhibited PDGFC expression by inducing the expression of miR-375 and a transcription factor, achaete-scute homolog-1 (ASH1), mediated the induction of miR-375 by sorafeinb administration in hepatoma cells. Finally, we verified that the expression of miR-375 was reduced in sorafenib-resistant cells and that the restoration of miR-375 could resensitize sorafenib-resistant cells to sorafenib partially by the degradation of astrocyte elevated gene-1 (AEG-1). In conclusion, our data demonstrate that miR-375 is a critical determinant of HCC angiogenesis and sorafenib tolerance, revealing a novel miRNA-mediated mechanism underlying sorafenib treatment.

索拉非尼最初被确定为多种致癌激酶的抑制剂，并且仍然是晚期肝细胞癌 (HCC) 的一线全身治疗药物。据报道，MicroRNA (miRNA) 在 HCC 的发生、进展和耐药性中发挥着关键作用。在这项研究中，我们的目的是鉴定索拉非尼诱导的 miRNA 并证明它们的调节作用。首先，我们发现在索拉非尼处理的肝癌细胞中显着诱导肿瘤抑制 miRNA miR-375 的表达，并且 miR-375 可以部分通过抑制血小板源性生长因子 C (PDGFC) 发挥其抗血管生成作用。然后，我们证明索拉非尼通过诱导 miR-375 的表达来抑制 PDGFC 表达，而转录因子 achaete-scute 同源物-1 (ASH1) 则通过在肝癌细胞中施用索拉非尼介导 miR-375 的诱导。最后，我们验证了索拉非尼耐药细胞中miR-375的表达降低，并且miR-375的恢复可以部分通过星形胶质细胞升高基因1（AEG-1）的降解使索拉非尼耐药细胞对索拉非尼重新敏感。总之，我们的数据表明 miR-375 是 HCC 血管生成和索拉非尼耐受的关键决定因素，揭示了索拉非尼治疗背后的新的 miRNA 介导机制。