Abstract

Characterization of microRNA-17-92 cluster in human gallbladder cancer stem cells

Fanyin Meng, Assistant Professor, Baylor-Scott & White Healthcare

microRNAs (miRNAs) are small endogenous molecules that can inhibit the translation of mRNAs. Our aim was to characterize the functional roles of the miR-17-92 cluster in human gall bladder cancer stem cells. We identified miR-17-92 which is differentially expressed in doxorubicin-enriched cell fractions in a mouse xenograft tumor model of gall bladder cancer. Members of the miR-17 family were notably more abundant in GB-CSCs compared with their parental gall bladder cancer cells (GBCs) and Mz-ChA-1 cells. Expression of miR-17 family microRNAs was substantially reduced concomitant with GBCs differentiation and loss of self-renewal. Mz-ChA-1 cells expressing increased levels of the miR-17-92 construct displayed a higher transformed cell growth, more stringent block of differentiation, and enhanced proliferation associated with reduced expression of PTEN, a tumor suppressor gene previously implicated as a direct target of miR-17-92 microRNAs. Knockdown of PTEN in Mz-ChA-1 cells phenocopied the overexpression of the miR-17-92 polycistron. Expression of c-myc, a crucial upstream regulator of the miR-17-92 polycistron, correlated with miR-17-92 levels, enhanced self-renewal, and GB-CSC potential. Our results define a novel regulatory mechanism of specific microRNA group and suggesting that miR-17-92 cluster may be the molecular targets for eradication of human gall bladder cancer.