Liu Yan Tong, Liu Guo Qing, Huang Jing Min
Xi'an Medical University, Xi'an, China.
Qinghai Provincial People's Hospital, Qinghai, China.
Biosci Rep. 2020 Nov 27;40(12). doi: 10.1042/BSR20202054.
Chemotherapy resistance is still a key hurdle in current hepatocellular carcinoma (HCC) treatment. Therefore, clarifying the molecular mechanisms contributing to this acquired resistance is urgent for the effective treatment of liver cancer. In this research, we observed that lncRNA FAM225A expression is dramatically upregulated not only in hepatocellular carcinoma tissues and cell lines but also in sorafenib-resistant HepG2/SOR cells. Moreover, FAM225A knockdown significantly weakened HepG2/SOR cells resistance to sorafenib treatment by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Similar results were obtained from the tumor xenograft model in mice. Further mechanistic researches revealed that the direct interaction between FAM225A and miR-130a-5p, while miR-130a-5p negatively modulated CCNG1 expression by targeting 3'UTR of CCNG1. MiR-130a-5p inhibition or CCNG1 overexpression could partially offset FAM225A knockdown-induced increased viability of HepG2/SOR cells in response to sorafenib challenge. Collectively, our findings provide evidence that FAM225A/miR-130a-5p/CCNG1 interaction network regulates the resistance of HCC cells to sorafenib treatment and could supply a possible strategy for restoring sorafenib sensitivity in HCC therapy.
化疗耐药性仍是当前肝细胞癌（HCC）治疗中的关键障碍。因此，阐明导致这种获得性耐药的分子机制对于肝癌的有效治疗至关重要。在本研究中，我们观察到lncRNA FAM225A的表达不仅在肝癌组织和细胞系中显著上调，而且在索拉非尼耐药的HepG2/SOR细胞中也显著上调。此外，通过MTT（3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐）试验，FAM225A基因敲低显著削弱了HepG2/SOR细胞对索拉非尼治疗的耐药性。在小鼠肿瘤异种移植模型中也获得了类似的结果。进一步的机制研究表明，FAM225A与miR-130a-5p直接相互作用，而miR-130a-5p通过靶向CCNG1的3'UTR负向调节CCNG1的表达。抑制miR-130a-5p或过表达CCNG1可以部分抵消FAM225A基因敲低诱导的HepG2/SOR细胞在索拉非尼刺激下活力的增加。总的来说，我们的研究结果表明FAM225A/miR-130a-5p/CCNG1相互作用网络调节肝癌细胞对索拉非尼治疗的耐药性，并可能为恢复肝癌治疗中索拉非尼的敏感性提供一种可能的策略。
