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.
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].
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).
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.
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.
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.
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.
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.