MiR-200b/200c/429 subfamily negatively regulates Rho/ROCK signaling pathway to suppress hepatocellular carcinoma metastasis

Oncotarget. 2015 May 30;6(15):13658-70. doi: 10.18632/oncotarget.3700.

Abstract

MiR-200 family is an important regulator of epithelial-mesenchymal transition and has been implicated in human carcinogenesis. However, their expression and functions in human cancers remain controversial. In the work presented here, we showed that miR-200 family members were frequently down-regulated in hepatocellular carcinoma (HCC). Although all five members of miR-200 family inhibited ZEB1/2 expression in HCC cell lines, we showed that overexpression only of the miR-200b/200c/429 subfamily, but not the miR-200a/141 subfamily, resulted in impeded HCC cell migration. Further investigations led to the identification of RhoA and ROCK2 as specific down-stream targets of the miR-200b/200c/429 subfamily. We demonstrated that the miR-200b/200c/429 subfamily inhibited HCC cell migration through modulating Rho/ROCK mediated cell cytoskeletal reorganization and cell-substratum adhesion. Re-expression of miR-200b significantly suppressed lung metastasis of HCC cells in an orthotopic liver implantation model in vivo. In conclusion, our findings identified the miR-200b/200c/429 subfamily as metastasis suppressor microRNAs in human HCC and highlighted the functional discrepancy among miR-200 family members.

Keywords: Rho/ROCK signaling pathway; cancer metastasis; cytoskeletal reorganization; hepatocellular carcinoma; miR-200 family.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Cell Growth Processes / physiology
  • Cell Line, Tumor
  • Hep G2 Cells
  • Heterografts
  • Humans
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Middle Aged
  • Neoplasm Metastasis
  • Signal Transduction
  • rho-Associated Kinases / genetics
  • rho-Associated Kinases / metabolism*
  • rhoA GTP-Binding Protein / genetics
  • rhoA GTP-Binding Protein / metabolism*

Substances

  • MIRN200 microRNA, human
  • MIRN429 microRNA, human
  • MicroRNAs
  • RHOA protein, human
  • ROCK2 protein, human
  • rho-Associated Kinases
  • rhoA GTP-Binding Protein