Functional analysis of microRNAs in human hepatocellular cancer stem cells

Fanyin Meng, Shannon S. Glaser, Heather Francis, Sharon Demorrow, Yuyan Han, Jenna D. Passarini, Allison Stokes, John P. Cleary, Xiuping Liu, Julie Venter, Preetham Kumar, Sally Priester, Levi Hubble, Dustin Staloch, Jay Sharma, Chang Gong Liu, Gianfranco Alpini

Research output: Contribution to journalArticlepeer-review

115 Scopus citations

Abstract

MicroRNAs are endogenous small non-coding RNAs that regulate gene expression and cancer development. A rare population of hepatocellular cancer stem cells (HSCs) holds the extensive proliferative and self-renewal potential necessary to form a liver tumour. We postulated that specific transcriptional factors might regulate the expression of microRNAs and subsequently modulate the expression of gene products involved in phenotypic characteristics of HSCs. We evaluated the expression of microRNA in human HSCs by microarray profiling, and defined the target genes and functional effects of two groups of microRNA regulated by IL-6 and transcriptional factor Twist. A subset of highly chemoresistant and invasive HSCs was screened with aberrant expressions of cytokine IL-6 and Twist. We demonstrated that conserved let-7 and miR-181 family members were up-regulated in HSCs by global microarray-based microRNA profiling followed by validation with real-time polymerase chain reaction. Importantly, inhibition of let-7 increases the chemosensitivity of HSCs to sorafenib and doxorubicin whereas silencing of miR-181 led to a reduction in HSCs motility and invasion. Knocking down IL-6 and Twist in HSCs significantly reduced let-7 and miR-181 expression and subsequently inhibited chemoresistance and cell invasion. We showed that let-7 directly targets SOCS-1 and caspase-3, whereas miR-181 directly targets RASSF1A, TIMP3 as well as nemo-like kinase (NLK). In conclusion, alterations of IL-6- and Twist-regulated microRNA expression in HSCs play a part in tumour spreading and responsiveness to chemotherapy. Our results define a novel regulatory mechanism of let-7/miR-181s suggesting that let-7 and miR-181 may be molecular targets for eradication of hepatocellular malignancies.

Original languageEnglish (US)
Pages (from-to)160-173
Number of pages14
JournalJournal of Cellular and Molecular Medicine
Volume16
Issue number1
DOIs
StatePublished - Jan 2012
Externally publishedYes

Keywords

  • Chemotherapy
  • Human hepatocellular cancer stem cells (HSCs)
  • Interleukin-6 (IL-6)
  • Invasion
  • MicroRNAs (miRNAs)
  • Twist

ASJC Scopus subject areas

  • Molecular Medicine
  • Cell Biology

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