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: HCCs are commonly resistant to treatment because the malignant cells survive chemotherapy . To explore the possible role of CSC cells in the development of chemoresistance, cultured HSC-SR, HSC-DF, HepG2 and N-LSC cells were treated with sorafenib and doxorubicin and the IC50 was analysed by MTS assay. Doxorubicin has been considered to be the most effective single agent and the multi-kinase inhibitor sorafenib has recently been approved for the therapy of advanced HCC . Sorafenib acts by inhibition of the RAF/MEK/ERK pathway and down-regulation of MCL-1, leading to a disruption of survival signals in HCC cells [22, 23]. As shown in Figure 4A–D, IC50s of HSCs in two chemotherapeutic reagents tested are significantly higher than HepG2 HCC cells as well as normal liver stem cells, suggesting that HCC stem cells have greater chemoresistance in vitro. In addition, HSC xenograft tumours in nude mice are more resistant to doxorubicin treatment than the control HCC xenografts (Fig. 4E). Enhanced CD133 and let-7a expressions are observed in doxorubicin-treated HSC xenograft tumours when compare to controls (Fig. 4F and G), further implicated a functional link between CD133/let-7a and tumour stem cell phenotypes.
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.