MicroRNA targeting for the therapy of colitis-associated colon cancer.

Abstract

571 Background: Inflammatory Bowel Diseases (IBD) consist of ulcerative colitis (UC) and Crohn’s Disease (CD), which are characterized by activation of inflammatory responses. Patients with longstanding UC are at high risk of developing colorectal cancer. The identification of novel molecular targets with therapeutic potential for UC and UC-related dysplasia are of major importance. Methods: Using a high throughput functional suppressor screen of the human microRNAome, we identified microRNAs involved in the regulation nuclear factor kappa beta (NF-κB). We correlated microRNA expression levels with different clinicopathological parameters in 401 colonic specimens derived from patients with UC, CD, irritable bowel syndrome (IBS), sporadic colon cancer (CRC), colitis-associated cancer (CAC) and control subjects. Bioinformatic and molecular analyses were employed for the study of micoRNA-regulated signaling pathways. A microRNA specific chemical inhibitor was used to treat colonic biopsies ex vivo and murine CAC development in vivo. Results: The microRNA screen identified miR-214 as master regulator of NF-κB. MiR-214 levels are increased in colonic tissues from UC and CAC, but not from CD, IBS and CRC patients and positively correlate with UC disease activity and duration. STAT3 regulates miR-214 expression in colonocytes in vitro and STAT3 and miR-214 levels positively correlate in UC and CAC. MiR-214 regulates the expression of phosphatase and tensin homolog (PTEN) and PDZ and LIM domain 2 (PDLIM2) and both are decreased in colonic tissues of UC and CAC patients. MiR-214 is amplified through a feedback loop circuit and its overexpression increases the tumorigenic and invasive phenotype of colon cancer cells. A chemical miR-214 inhibitor perturbs this circuit in colonic biopsies from UC patients ex vivo while intracolonic delivery suppresses CAC growth in mice. Conclusions: Our findings demonstrate a gene controlling the inflammatory response specifically in UC and CAC. The miR-214 molecular circuit activity correlates with UC disease activity and duration. Activation of this circuit contributes to colitis-associated colon carcinogenesis, and its suppression has therapeutic potential for patients with UC-related dysplasia.