Abstract A53: Tumor suppressor microRNA miR-34 inhibits human pancreatic and gastric cancer stem cells

Abstract

Abstract MicroRNAs (miRNAs) have been implicated in cancer initiation and progression via their ability to affect expression of genes and proteins that regulate cell proliferation and/or cell death. Transcription of the three miRNA miR-34 family members was recently found to be directly regulated by p53. Among the target proteins regulated by miR-34 are Notch and Bcl-2, suggesting the possibility of a role for miR-34 in the maintenance and survival of cancer stem cells. We examined the roles of miR-34 in p53-mutant human pancreatic and gastric cancer cell lines and the potential link to cancer stem cells. Restoration of miR-34 expression in the cancer cells by miR-34 mimics or lentiviral miR-34 downregulated Bcl-2 and Notch1/2. miR-34 restoration significantly inhibited clonogenic cell growth and invasion, induced apoptosis and G1 and G2/M arrest in cell cycle, and sensitized the cancer cells to chemotherapy and radiation. We identified that CD44+/CD133+ cancer cells are enriched with tumorsphere-forming and tumor-initiating cells or cancer stem/progenitor cells with high levels of Notch/Bcl-2 and loss of miR-34. More significantly, miR-34 restoration led to a significant reduction of the tumor-initiating cell population, accompanied by significant inhibition of tumorsphere growth in vitro and tumor formation in vivo. Our results demonstrate that miR-34 may restore, at least in part, the tumor suppressing function of the p53 in p53-deficient human pancreatic and gastric cancer cells. Our data support that miR-34 may be involved in cancer stem cell self-renewal, potentially via the direct modulation of downstream targets Bcl-2 and Notch, implying that miR-34 may play an important role in cancer stem cell self-renewal and/or cell fate determination. Currently, we are exploring the nanoparticle-targeted delivery of miR-34 to cancer stem cells as a novel molecular therapy for human pancreatic/gastric cancer, based on our patented nanobiotechnology which has been approved by FDA for clinical trials. Taken together, our results demonstrate that restoration of miR-34 may hold significant promise as a novel molecular therapy for human pancreatic/gastric cancer with loss of p53-miR34, potentially via inhibiting cancer stem cells. The project is funded by NIH grants CA121830, CA128220 and CA134655 (to L. Xu.). Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A53.