Stromal miR-20a controls paracrine CXCL8 secretion in colitis and colon cancer

// Steven A. Signs 1 , Robert C. Fisher 1 , Uyen Tran 2 , Susmita Chakrabarti 3 , Samaneh K. Sarvestani 1 , Shao Xiang 1 , David Liska 1, 4 , Veronique Roche 1 , Wei Lai 1 , Haley R. Gittleman 5 , Oliver Wessely 2, * and Emina H. Huang 1, 4, * 1 Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA 2 Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA 3 Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA 4 Department of Colorectal Surgery, Cleveland Clinic, Cleveland, Ohio, USA 5 Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio USA * Co-corresponding authors Correspondence to: Emina H. Huang, email: huange2@ccf.org Keywords: fibroblasts; miR-20a; CXCL8; colitis; colon cancer Abbreviations: CAC: colitis-associated cancer; IBD: inflammatory bowel disease; UC: ulcerative colitis Received: November 30, 2017      Accepted: February 10, 2018      Published: February 14, 2018 ABSTRACT Inflammatory bowel disease (IBD) affects one million people in the US. Ulcerative colitis (UC) is a subtype of IBD that can lead to colitis-associated cancer (CAC). In UC, the rate of CAC is 3-5-fold greater than the rate of sporadic colorectal cancer (CRC). The pathogenesis of UC and CAC are due to aberrant interactions between host immune system and microenvironment, but precise mechanisms are still unknown. In colitis and CAC, microenvironmental fibroblasts exhibit an activated, inflammatory phenotype that contributes to tumorigenesis accompanied by excessive secretion of the chemokine CXCL8. However, mechanisms regulating CXCL8 secretion are unclear. Since it is known that miRNAs regulate chemokines such as CXCL8, we queried a microRNA library for mimics affecting CXCL8 secretion. Among the identified microRNAs, miR-20a/b was further investigated as its stromal expression levels inversely correlated with the amounts of CXCL8 secreted and predicted fibroblast tumor-promoting activity. Indeed, miR-20a directly bound to the 3′UTR of CXCL8 mRNA and regulated its expression by translational repression. In vivo co-inoculation studies with CRC stem cells demonstrated that fibroblasts characterized by high miR-20a expression had reduced tumor-promoting activities. These studies reveal that in stromal fibroblasts, miR-20a modulates CXCL8 function, therefore influencing tumor latency.