miR-486-3p mediates hepatocellular carcinoma sorafenib resistance by targeting FGFR4 and EGFR
miR-486-3p mediates hepatocellular carcinoma sorafenib resistance by targeting FGFR4 and EGFR
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DOI：
10.1038/s41419-020-2413-4
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发表时间：
2020-04-20
影响因子：
9
通讯作者：
Cai Xiujun
中科院分区：
文献类型：
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作者：
Ji Lin;Lin Zhongjie;Cai Xiujun
肝细胞癌是世界范围内常见的恶性肿瘤，手术或局部治疗被认为不足以治疗晚期疾病。索拉非尼是许多激酶的抑制剂，并被证明对晚期HCC患者有益。然而，耐药性在初始治疗后很快出现，限制了索拉非尼的临床益处，其机制仍然难以捉摸。因此，本研究旨在探讨索拉非尼耐药的机制，并为联合治疗提供可能的靶点。通过miRNA测序，我们发现miR-486- 3 p在索拉非尼耐药的肝癌细胞系中下调。细胞活力实验表明，增加miR-486- 3 p表达可诱导细胞凋亡，而通过CRISPR-CAS 9技术敲低miR-486- 3 p可减少索拉非尼处理的细胞凋亡。临床数据还表明，与癌旁正常组织相比，HCC患者肿瘤组织中miR-486- 3 p水平下调。通过荧光素酶报告基因分析，证实了miR-486- 3 p的作用靶点为FGFR 4和EGFR。重要的是，FGFR 4或EGFR选择性抑制剂可以增强索拉非尼在耐药细胞中的功效。此外，体内索拉非尼耐药模型鉴定，通过慢病毒注射过表达miR-486- 3 p可以通过与索拉非尼治疗组合显著抑制肿瘤生长来克服索拉非尼耐药。总之，我们发现miR-486- 3 p是通过靶向FGFR 4和EGFR调节索拉非尼耐药的重要介质，从而为HCC治疗提供了潜在的靶点。
HCC is a common malignancy worldwide and surgery or reginal treatments are deemed insufficient for advanced-stage disease. Sorafenib is an inhibitor of many kinases and was shown to benefit advanced HCC patients. However, resistance emerges soon after initial treatment, limiting the clinical benefit of sorafenib, and the mechanisms still remain elusive. Thus, this study aims to investigate the mechanisms of sorafenib resistance and to provide possible targets for combination therapies. Through miRNA sequencing, we found that miR-486-3p was downregulated in sorafenib resistant HCC cell lines. Cell viability experiments showed increased miR-486-3p expression could induce cell apoptosis while miR-486-3p knockdown by CRISPR-CAS9 technique could reduce cell apoptosis in sorafenib treatment. Clinical data also indicated that miR-486-3p level was downregulated in tumor tissue compared with adjacent normal tissue in HCC patients. Mechanism dissections showed that FGFR4 and EGFR were the targets of miR-486-3p, which was verified by luciferase reporter assay. Importantly, FGFR4 or EGFR selective inhibitor could enhance sorafenib efficacy in the resistant cells. Moreover, in vivo sorafenib resistant model identified that over-expressing miR-486-3p by lentivirus injection could overcome sorafenib resistance by significantly suppressing tumor growth in combination with the treatment of sorafenib. In conclusion, we found miR-486-3p was an important mediator regulating sorafenib resistance by targeting FGFR4 and EGFR, thus offering a potential target for HCC treatment.