miR-139-5p inhibits aerobic glycolysis, cell proliferation, migration, and invasion in hepatocellular carcinoma via a reciprocal regulatory interaction with ETS1

Abstract

Cancer cells have metabolic features that allow them to preferentially metabolize glucose through aerobic glycolysis, providing them with a progression advantage. However, microRNA (miRNA) regulation of aerobic glycolysis in cancer cells has not been extensively investigated. We addressed this in the present study by examining the regulation of miR-139-5p on aerobic glycolysis of hepatocellular carcinoma (HCC) using clinical specimens, HCC cells, and a mouse xenograft model. 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. Notably, the lower expression of mir-139 was correlated with worse prognosis. These outcomes indicate that reciprocal regulatory interactions between miR-139-5p and ETS1 modulate aerobic glycolysis, proliferation, and metastasis in HCC cells, suggesting new targets for HCC treatment.

MicroRNA‐139 is a predictor of prostate cancer recurrence and inhibits growth and migration of prostate cancer cells through cell cycle arrest and targeting IGF1R and AXL

“…Previous studies have shown that miR‐139‐5p decreases cancer cell growth in many different types of cancers . Similarly, our data show decreased proliferation and migration in PC3 and Du145 PCa cell lines overexpressing miR‐139 compared with control cells (Figures and ).…”

“…AXL also activates the PI3K/AKT cascade . AKT activation leads to cyclin D1 upregulation through inhibition of GSK3β . Cyclin D1 then stimulates cell cycle entry and proliferation .…”

Upregulation of 6‐phosphofructo‐2‐kinase (PFKFB3) by hyperactivated mammalian target of rapamycin complex 1 is critical for tumor growth in tuberous sclerosis complex

“…Among all PFKFBs, PFKFB3 exerts a central role in controlling glycolysis flux and has aroused a great deal of attention in recent years . In addition to activation of mTORC1, inactivated mutation of Pten or the aberrant activation of Ras and PI3K have been shown that take part in the regulation of glycolysis and tumorigenesis through modification of PFKFB3 expression . However, the detailed transcriptional regulation mechanisms of PFKFB3 expression are far from fully understood.…”

“…Zhu et al demonstrated that the transcription factor PU.1 upregulates PFKFB3 which is responsible for the chemoresistance in chronic myeloid leukemia . The transcription factor ETS1 has been shown to promoted glycolysis through directly binding to the promoter of PFKFB3 and enhanced its transcription in hepatocellular carcinoma . In addition, transcription factors KLF2 and STAT5 also participate in the tumorigenesis through regulating PFKFB3 expression in different cancer cell content.…”

Epigenomic profiling of DNA methylation for hepatocellular carcinoma diagnosis and prognosis prediction

“…In addition, besides CpG islands, there were also some DMRs located within noncoding regions, which harbor microRNA, lncRNA, cirRNA, and so forth, implicating that DNA hypermethylation may interact with noncoding RNA to regulate gene expression. In HCC, it had been reported that DNA hypermethylation can mediate epigenetic silencing of some tumor‐suppressive miRNAs, such as miR‐9, miR‐124, miR‐129, miR‐139, miR‐200b, and miR‐203 …”