MicroRNA‑361‑5p induces hepatocellular carcinoma cell apoptosis and enhances drug sensitivity by targeting MAP3K9

Abstract

MicroRNAs (miRs) participate in the development of several cancers. miR-361-5p suppresses the proliferation of hepatocellular carcinoma (HCC) cells. However, its function and potential underlying mechanism of action in the chemoresistance of HCC remains unknown. Therefore, cisplatin (DDP)-resistant HCC cells were used to study the role and potential mechanism of action of miR-361-5p in HCC resistance to chemotherapy. TargetScan software and dual-luciferase reporter assays were used to determine whether MAPK kinase kinase 9 (MAP3K9) is a target gene of miR-361-5p. Subsequently, reverse transcription-quantitative PCR and western blot analyses demonstrated that miR-361-5p mimic decreased MAP3K9 expression levels in Huh7 cells and this change was reversed by transfection with the MAP3K9-plasmid. In addition, compared with THLE-2 cells, miR-361-5p was downregulated, while MAP3K9 was upregulated in Huh7 cells. MAP3K9 also reversed the miR-361-5p-induced HCC cell apoptosis. A DDP-resistant cell line, Huh7/DDP, was established and MTT analysis revealed that the IC 50 value of DDP treatment in Huh7/DDP cells was higher compared with that in Huh7 cells. miR-361-5p expression was lower in Huh7/DDP cells compared with that in Huh7 cells. Similarly, miR-361-5p downregulated the expression levels of MAP3K9 in Huh7/DDP cells. Furthermore, MAP3K9 reversed miR-361-5p-induced sensitivity of Huh7/DDP cells to DDP and miR-361-5p induced Huh7/DDP cell apoptosis. Therefore, the findings of the present study demonstrated that the miR-361-5p/MAP3K9 axis may serve as a new potential biomarker and therapeutic target for DDP-resistant HCC.

MAP3K Family Review and Correlations with Patient Survival Outcomes in Various Cancer Types

“…MAP3K9, also known as mixed lineage kinase I (MLK1), belongs to the MLK family, which are upstream activators of MEK/ERK and JNK pathways [88]. While the role of MAP3K9 in cancer is not well-defined, previous studies reported that targeting MAP3K9 using microRNA suppressed tumor progression in pancreatic cancer, pharyngolaryngeal cancer, HCC, and esophagus squamous cell carcinoma, suggesting its involvement in cancer pathogenesis [89][90][91]. In lung cancer cells, gain-of-function mutation MAP3K9 leads to the increased activation of downstream ERK pathway, which potentially promotes tumor proliferation [92].…”

Epigenetic Changes Affecting the Development of Hepatocellular Carcinoma

“…Additionally, when miR-369 expression was restored, proliferation and metastasis of HCC cells in vitro and in vivo were inhibited. Numerous other miRNAs were related to HCC cells proliferation, apoptosis, as well as chemoresistance: miR-3174 by targeting FOXO1, miR-383 by targeting IL-17 via STAT3 signaling pathway, and miR-361-5p by targeting CXCR6, VEGFA, or MAP3K9 [30][31][32]58,59]. Another important property of miRNA molecules is their effect on cancer stem cells.…”