miR-149 represses metastasis of hepatocellular carcinoma by targeting actin-regulatory proteins PPM1F

Oncotarget. 2015 Nov 10;6(35):37808-23. doi: 10.18632/oncotarget.5676.


microRNAs have been implicated in hepatocellular carcinoma (HCC) metastasis, which is predominant cause of high mortality in these patients. Although an increasing body of evidence indicates that miR-149 plays an important role in the growth and metastasis of multiple types of cancers, its role in the progression of HCC remains unknown. Here, we demonstrated that miR-149 was significantly down-regulated in HCC, which was correlated with distant metastasis and TNM stage with statistical significance. A survival analysis showed that decreased miR-149 expression was correlated with a poor prognosis of HCC as well. We found that over-expression of miR-149 suppressed migration and invasion of HCC cells in vitro. In addition, we identified PPM1F (protein phosphatase, Mg(2+)/Mn(2+)-dependent, 1F) as a direct target of miR-149 whose expression was negatively correlated with the expression of miR-149 in HCC tissues. The re-expression of PPM1F rescued the miR-149-mediated inhibition of cell migration and invasion. miR-149 regulated formation of stress fibers to inhibit migration, and re-expression of PPM1F reverted the miR-149-mediated loss of stress fibers. Moreover, we demonstrated that over-expression of miR-149 reduced pMLC2, a downstream effector of PPM1F, in MHCC-97H cells. In vivo studies confirm inhibition of HCC metastasis by miR-149. Taken together, our findings indicates that miR-149 is a potential prognostic biomarker of HCC and that the miR-149/PPM1F regulatory axis represents a novel therapeutic target for HCC treatment.

Keywords: PPM1F; hepatocellular carcinoma; metastasis; miR-149; microRNA.

MeSH terms

  • Animals
  • Apoptosis
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Blotting, Western
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / mortality
  • Carcinoma, Hepatocellular / prevention & control*
  • Carcinoma, Hepatocellular / secondary
  • Cell Movement
  • Cell Proliferation
  • Female
  • Fluorescent Antibody Technique
  • Follow-Up Studies
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Immunoenzyme Techniques
  • In Situ Hybridization, Fluorescence
  • Liver Neoplasms / genetics
  • Liver Neoplasms / mortality
  • Liver Neoplasms / pathology
  • Liver Neoplasms / prevention & control*
  • Lymphatic Metastasis
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / genetics*
  • Middle Aged
  • Neoplasm Grading
  • Neoplasm Invasiveness
  • Neoplasm Staging
  • Phosphoprotein Phosphatases / antagonists & inhibitors*
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / metabolism
  • Prognosis
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Survival Rate
  • Tumor Cells, Cultured
  • Wound Healing
  • Xenograft Model Antitumor Assays


  • Biomarkers, Tumor
  • MIRN149 microRNA, human
  • MicroRNAs
  • RNA, Messenger
  • PPM1F protein, human
  • Phosphoprotein Phosphatases