miR-17-5p Promotes migration of human hepatocellular carcinoma cells through the p38 mitogen-activated protein kinase-heat shock protein 27 pathway.
miR-17-5p is overexpressed in hepatocellular carcinoma (HCC), but the specific regulatory mechanisms of miR-17-5p in HCC remain unknown. We investigated the molecular basis of miR-17-5p as an oncogene in human HCC cell lines. Our in vivo and in vitro data indicate that miR-17-5p up-regulates the migration and proliferation of HCC cells. Interestingly, proteomic and western blotting assays revealed that miR-17-5p significantly activates the p38 mitogen-activated protein kinase MAPK pathway and increases the phosphorylation of heat shock protein 27 (HSP27). Our results also suggest that E2F1-dependent down-regulation of Wip1 regulates miR-17-5p-p38-HSP27 signaling. Furthermore, suppression of HSP27 expression by small interfering RNA or the p38 MAPK pathway-specific inhibitor SB203580 decreases the migration of HCC cells overexpressing miR-17-5p but does not reduce their proliferation. Finally, we show that miR-17-5p expression correlates well with HSP27 status in primary human HCC tissues with metastasis.


CONCLUSIONS
Our findings suggest that the p38 MAPK pathway plays a crucial role in miR-17-5p-induced phosphorylation of HSP27 and, as a consequence, phosphorylated HSP27 enhances the migration of HCC cells. Our data highlight an important role of miR-17-5p in the proliferation and migration of HCC cells and support the potential application of miR-17-5p in HCC therapy.
Yang
Fu
F
Department of Medical Genetics, Second Military Medical University, Shanghai, PR China.
Yin
Yixuan
Y
Wang
Fang
F
Wang
Yuqi
Y
Zhang
Ling
L
Tang
Ying
Y
Sun
Shuhan
S
D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D050687:E2F1 Transcription Factor / Q000502:physiology; D055551:HSP27 Heat-Shock Proteins / Q000096:biosynthesis / Q000502:physiology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000494:pharmacology*; D010749:Phosphoprotein Phosphatases / Q000502:physiology; D000071636:Protein Phosphatase 2C; D011725:Pyridines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D055551:HSP27 Heat-Shock Proteins; D007093:Imidazoles; C524941:MIRN17 microRNA, human; D035683:MicroRNAs; D011725:Pyridines; D034741:RNA, Small Interfering; D048051:p38 Mitogen-Activated Protein Kinases; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C; C093642:SB 203580