Department of General Surgery, The First Affiliated Hospital of Soochow University, Soochow, China.
Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, China.
Braz J Med Biol Res. 2021 May 31;54(9):e10390. doi: 10.1590/1414-431X2020e10390. eCollection 2021.
Sorafenib (SOR) resistance is still a significant challenge for the effective treatment of hepatocellular carcinoma (HCC). The mechanism of sorafenib resistance remains unclear. Several microRNAs (miRNAs) have been identified as playing a role in impairing the sensitivity of tumor cells to treatment. We examined the mechanism behind the role of miR-92b in mediating sorafenib resistance in HCC cells. We detected that miR-92b expression was significantly upregulated in SOR-resistant HepG2/SOR cells compared to parental HepG2/WT cells. After transfection with miR-92b inhibitor, the proliferation of HepG2/SOR cells was remarkably weakened and rates of apoptosis significantly increased. PTEN was considered to be a functional target of miR-92b according to a luciferase reporter assay. Knockdown of PTEN significantly impaired the ability of miR-92b inhibitor on increasing sorafenib sensitivity of HepG2/SOR cells. Furthermore, we confirmed by western blotting and immunofluorescence that miR-92b can mediate sorafenib resistance by activating the PI3K/AKT/mTOR pathway in HCC cells by directly targeting PTEN. These findings further validate the mechanism of miR-92b in SOR resistance in HCC treatment.
索拉非尼（sorafenib，SOR）耐药仍然是有效治疗肝细胞癌（hepatocellular carcinoma，HCC）的重大挑战。索拉非尼耐药的机制尚不清楚。已经发现几种 microRNAs（miRNAs）在削弱肿瘤细胞对治疗的敏感性方面发挥作用。我们研究了 miR-92b 在介导 HCC 细胞索拉非尼耐药中的作用机制。我们检测到，与亲本 HepG2/WT 细胞相比，SOR 耐药 HepG2/SOR 细胞中 miR-92b 的表达显著上调。用 miR-92b 抑制剂转染后，HepG2/SOR 细胞的增殖明显减弱，凋亡率显著增加。根据荧光素酶报告基因检测，PTEN 被认为是 miR-92b 的功能靶标。PTEN 敲低显著削弱了 miR-92b 抑制剂增加 HepG2/SOR 细胞索拉非尼敏感性的能力。此外，我们通过 Western blot 和免疫荧光进一步证实，miR-92b 可以通过直接靶向 PTEN 激活 HCC 细胞中的 PI3K/AKT/mTOR 通路来介导索拉非尼耐药。这些发现进一步验证了 miR-92b 在 HCC 治疗中 SOR 耐药中的作用机制。
