MiR-19b/20a/92a regulates the self-renewal and proliferation of gastric cancer stem cells

Abstract

Human gastric cancers contain a population of gastric cancer stem cells (GCSCs) that can undergo self-renewal and multipotent differentiation. GCSCs can be enriched by EpCAM+/CD44+ gastric cancer cells. However, the mechanisms underlying how GCSCs balance self-renewal and differentiation remain to be explored. Because miRNAs can regulate cancer cell fates, we compared tumorspheric cancer cells enriched for GCSCs with more differentiated cells in terms of miRNA expression. We found that the miR-17-92 cluster members miR-19b, miR-20a and miR-92a were gradually reduced during the differentiation of GCSCs. Herein, we speculated that miR-17-92 members might function as regulators to sustain the self-renewal ability of GCSCs. By down-regulating miR-19b, miR-20a and miR-92a in EpCAM+/CD44+ GCSCs, or over-expressing them in EpCAM-/CD44- non-GCSC populations, we found that miR-19b, miR-20a and miR-92a could sustain the self-renewal function of GCSCs. Furthermore, we found that miR-19b, miR-20a and miR-92a could also promote the proliferation of gastric cancer cells. Moreover, miR-17-92 targeted the E2F1 and HIPK1 proteins, which suppressed Wnt-β-catenin signaling. A real-time PCR analysis of miR-19b, miR-20a and miR-92a expression in 97 gastric cancer specimens suggested that miR-92a could be used as an independent prognostic factor in gastric cancer. This study indicated that several members of the miR-17-92 cluster,miR-19b, miR-20a and miR-92a, might play significant roles in the development of gastric cancer stem cells and that miR-92a has the potential to be used as a predictive prognostic marker in gastric cancer.