Knockdown of SNHG3 or BMI1 and overexpression of miR-139-5p could inhibit cell proliferation, migration, and invasion in HCC. miR-139-5p was a target of SNHG3 and BMI1 was a direct target mRNA of miR-139-5p.
The present study indicated that miR-139 exerts a tumor-suppressive effect during hepatocarcinogenesis via the suppression of expression of <i>TOP1</i>; therefore, miR-139 is a promising target for the treatment of HCC.
Our study indicates that miR-139-5p functions as a suppressor of HCC EMT and metastasis by targeting ZEB1 and ZEB2, and it may be a therapeutic target for metastatic HCC.
In conclusion, our study demonstrates that miR-139 downregulation is common in HCC and that overexpression of miR-139 expression inhibits cell proliferation and invasion, suggesting that miR-139 may provide a therapeutic strategy for the treatment of HCC patients.
MiR-139-5p (denoted thereafter as miR-139) has recently been reported to function as a tumor suppressor in several types of human cancer (hepatocellular carcinoma, colorectal cancer, breast cancer, and gastric cancer), but its function in non-small-cell lung cancer (NSCLC) and the mechanism of its suppression have not been studied in detail.
Pooled analyses showed that low miR-139 expression was related to worse overall survival (OS) [hazard ratio (HR) = 2.27; 95% confidence intervals (CI): 1.74-2.95; P < 0.001] in solid tumors, including hepatocellular carcinoma (HCC) and glioblastoma multiforme (GBM), consisting with the results of TCGA.
High miR-139-3p expression in HCC tissues was indicative of good patient prognosis. miR-139-3p target genes ISG20L2, RAD54B, KIAA0101, and PIGS were related to HCC prognosis.
The results revealed that the expression of miR-139-5p was noticeably lower in HCC compared with non-tumor liver tissues according to the pooled standard mean difference, which was -0.84 [95% confidence interval (CI): -1.36 to -0.32; P<0.001].
We found that overexpressing miR-139-5p restrained aerobic glycolysis, suppressing proliferation, migration, and invasion in HCC cells. miR-139-5p regulated hexokinase 1 (HK1) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) expression by directly targeting the transcription factor ETS1, which bound to the promoters of the HK1 and PFKFB3 genes. miR-139-5p-induced aerobic glycolysis, proliferation, migration, and invasion were reversed by ETS1 overexpression, while ETS1 silencing induced the expression of miR-139-5p via a post-transcriptional regulation mode involving Drosha. miR-139-5p expression was reduced in HCC compared to para-carcinoma tissue, which was confirmed in The Cancer Genome Atlas and GSE54751 HCC cohorts.
MiR-139 level was negatively associated with the stage of HCC, and HCC patients with higher miR-139 level had longer overall survival (OS) than these having lower miR-139 expression.
<i>SNHG6</i>, serpin family H member 1 (<i>SERPINH1</i>) and miR-139-5p expression levels in HCC tissues and cells were determined by quantitative real-time PCR (qRT-PCR).
In conclusion, for the first time, we identify 25 deregulated miRNAs that are associated with prognosis and prove that miR-139-5p functions as a tumor suppressor in HCC and its low expression predicts poor prognosis.