The miR-20/c-Myc/E2F Regulatory Axis is Critical for the Tumor Promoting Activity of Inflammatory Fibroblasts in Colitis-Associated Cancer

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SUMMARY Inflammation is a risk factor for several types of cancer. For example, in ulcerative colitis (UC), a disease of chronic inflammation of the colon, the risk of developing colitis-associated cancer of the colon (CAC) is 3 to 5- fold higher than the risk in the general population of developing sporadic colorectal cancer (CRC). Worse, there are no curative CAC-preventing or CAC-reversing options for UC patients, and the pathogenesis of CAC is unclear. The precise oncogenic triggers in this complex milieu remain mysterious and are therefore difficult to target. Given this situation, our long-term goal is to understand the pathogenesis of colitis and CAC such that development of preventive interventions becomes more feasible. We recently reported that colitis-associated fibroblasts and cancer-associated fibroblasts from UC patients secrete elevated levels of CXCL8 (an inflammatory mediator), that CXCL8 levels are negatively regulated by a miRNA, miR-20a, and that miR-20a is, at least in part, responsible for the modulation of CXCL8 secretion in interstitial fibroblasts. miR-20a is known to be modulated by c-Myc via interaction with the E2F family of transcription factors. However, in contrast to the colon epithelia our data indicate that low miR-20a and low c-Myc levels in colitic fibroblasts increase tumorigenicity. To resolve this conundrum, the overall objective of this application, is to determine the contribution of fibroblast miR-20, a member of the miR-17 family, to the pathogenesis of CAC. Our central hypothesis is that downregulation of the miR-20a/c-Myc/E2F axis is critical for the tumor-promoting activity of colon interstitial fibroblasts. To test these relationships, we will pursue three Aims: 1) To define the contribution of miR-20 in the colitic stromal fibroblasts to tumorigenesis, 2) To delineate the roles of fibroblast c-Myc and E2F7/8 on miR-20 and tumor-promotion, and 3) To identify the stromal fibroblast populations associated with disease progression and to determine their use as prognostic tools. The approach is innovative as it uses exclusively human tissue isolates, focuses on mechanistic investigation of the miR-20a, c-Myc, and E2F7/8 relationships, and reconciles fibroblast subpopulations at the single cell level for their contributions to the pathogenesis of CAC. The research is significant as it provides a molecular basis for the tumor-promoting activity of the stroma, which will benefit the one million US colitis patients at risk for CAC. In addition, our findings will be applicable for any chronic inflammatory process for which the stroma provides additional avenues for intervention.