miR-486-3p mediates hepatocellular carcinoma sorafenib resistance by targeting FGFR4 and EGFR

Abstract

HCC is a common malignancy worldwide and surgery or reginal treatments are deemed insufficient for advancedstage 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.

lncRNA‐POIR promotes epithelial–mesenchymal transition and suppresses sorafenib sensitivity simultaneously in hepatocellular carcinoma by sponging miR‐182‐5p

“…Furthermore, several miRNAs were reported to be involved in the response to SOR in HCC. [37][38][39][40] miR-423-5p was demonstrated to be upregulated in SOR-treated HCC cells, and its increase was positively correlated with response to therapy. 39 Moreover, miR-125a-5p was found to mediate the antiproliferative activity of SOR in HCC cells by suppression of sirtuin-7 and subsequently inducing p21/p27-dependent cell cycle arrest, 38 offering another category of possible targets to overcome SOR resistance in HCC.…”

Sophoridine suppresses lenvatinib‐resistant hepatocellular carcinoma growth by inhibiting RAS/MEK/ERK axis via decreasing VEGFR2 expression

“…Similar to sorafenib, lenvatinib is an orally multi‐targeted tyrosine kinase inhibitor that selectively inhibits vascular endothelial growth factor receptors (VEGFR), fibroblast growth factor receptors (FGFR), platelet‐derived growth factor receptor α (PDGFRα), KIT and RET 9,10 . It is highlighted that the resistance of targeted therapy still exists because of the primary resistance or adaptive resistance, which has hindered the treatment of advanced HCC 11,12 . Therefore, exploring the potential underlying mechanisms of lenvatinib resistance is necessary with clinical significance.…”

“…9,10 It is highlighted that the resistance of targeted therapy still exists because of the primary resistance or adaptive resistance, which has hindered the treatment of advanced HCC. 11,12 Therefore, exploring the potential underlying mechanisms of lenvatinib resistance is necessary with clinical significance.…”

MTDH Inhibits K48-Linked Degradation of TAK1 and Promotes Sorafenib Resistance in Hepatocellular Carcinoma

“…50 Based on this models, our previous studies had proved the crucial role of androgen receptor signals and several non-coding RNAs in sorafenib resistance, highlighting the epigenetic regulation of driver oncogenes in sorafenib resistance. [5,6,[51][52][53] However, therapy-induced tumour cell evolving is comprehensive and systematic in terms of cellular and molecular alteration. Thus, identifying other novel targets still remains an unmet medical need, requiring new insights into underlying molecular mechanisms that support hepato-carcinogenesis, HCC progression, and drug resistance based on genomic, transcriptomic, and epigenomic studies.…”