Functional analysis of microRNAs in human hepatocellular cancer stem cells.
Bottom Line: 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.In conclusion, alterations of IL-6- and Twist-regulated microRNA expression in HSCs play a part in tumour spreading and responsiveness to chemotherapy.
Affiliation: Department of Medicine and Scott & White Digestive Disease Research Center, Texas A&M Health Science Center College of Medicine and Scott & White Hospital, Temple, TX 76504, USA.Show MeSH
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Mentions: We then compared miRNA expression between HCC CSCs and HepG2/N-LSCs. The pattern of miRNA expression in HCC CSCs was markedly different from that of either normal human liver stem cells or the HepG2 HCC cells (Fig. 3A). The expression of a group of miRNA was differentially increased in HSC cells. These include the human let-7 and miR-181 family members, all of which were expressed >4.0-fold in HSC-SR and HSC-DF CSCs compared with HepG2 HCC cells as well as normal liver stem cells (Fig. 3B). Aberrant expressions of let-7a, let-7b and miR-181a were verified by Northern blot (Fig. 3A) as well as real-time PCR analysis (Fig. 3B). Furthermore, silencing IL-6 and Twist in HSCs significantly reduced let-7a and miR-181a expression respectfully, but not vice versa (Fig. S2), implicated the specific link between IL-6 and let-7, as well as Twist and miR-181 in tumour stem cell behaviour.
Affiliation: Department of Medicine and Scott & White Digestive Disease Research Center, Texas A&M Health Science Center College of Medicine and Scott & White Hospital, Temple, TX 76504, USA.