MicroRNA-223 Is Commonly Repressed in Hepatocellular Carcinoma and Potentiates Expression of Stathmin1

Gastroenterology. 2008 Jul;135(1):257-69. doi: 10.1053/j.gastro.2008.04.003. Epub 2008 Apr 11.

Abstract

Background & aims: Recent studies have emphasized causative links between microRNA (miRNA) deregulations and cancer development. In hepatocellular carcinoma (HCC), information on differentially expressed miRNA remained largely undefined.

Methods: Array-based miRNA profiling was performed on HCC cells that were derived from chronic carriers of hepatitis B virus (HBV) and hepatitis C virus (HCV), and nonviral-associated patients. Specific microRNA (miR)-223 and miR-222 deregulations were verified in an independent series of tumors. The functional effect of miR-223 was examined further. An integrative analysis of messenger RNA (mRNA) array with in silico predictions defined potential downstream targets of miR-223. A luciferase reporter assay was conducted to confirm target association.

Results: Distinct up-regulations of miR-222, miR-221, and miR-31, and down-regulations of miR-223, miR-126, and miR-122a were identified. Further investigations suggested the highly deregulated miR-223 and miR-222 could unequivocally distinguish HCC from adjacent nontumoral liver, irrespective of viral associations (P <or= .0002). Re-expression of miR-223 in HBV, HCV, and non-HBV non-HCV-related HCC cell lines revealed a consistent inhibitory effect on cell viability (P < .01). Integrative analysis further implicated Stathmin 1 (STMN1) as a downstream target of miR-223. A strong inverse relationship between STMN1 mRNA and miR-223 expressions was shown (P = .006). A substantial reduction in STMN1 protein was further demonstrated upon restoration of miR-223 expression in HCC cell lines. We further showed that miR-223 readily could suppress the luciferase activity in reporter construct containing the STMN1 3' untranslated region (P = .02).

Conclusions: Our study revealed specific miRNA differential expressions in HCC and underscores the potential importance of miR-223 down-regulations in the development of HCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / virology
  • Down-Regulation
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Hepatitis B, Chronic / complications
  • Hepatitis C, Chronic / complications
  • Humans
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / virology
  • Luciferases / genetics
  • Male
  • MicroRNAs / genetics*
  • Middle Aged
  • Oligonucleotide Array Sequence Analysis
  • Stathmin / genetics*

Substances

  • MIRN222 microRNA, human
  • MIRN223 microRNA, human
  • MicroRNAs
  • STMN1 protein, human
  • Stathmin
  • Luciferases