ANXA1 inhibits miRNA-196a in a negative feedback loop through NF-kB and c-Myc to reduce breast cancer proliferation

// Yi Yuan 1 , Durkeshwari Anbalagan 1 , Lay Hoon Lee 1 , Ramar Perumal Samy 1 , Muthu K. Shanmugam 2 , Alan Prem Kumar 2,3,4,5,6 , Gautam Sethi 2 , Peter E. Lobie 2,3 and Lina H.K. Lim 1,7 1 Department of Physiology, Yong Loo Lin School of Medicine, National University Health System (NUHS), National University of Singapore (NUS), Singapore 2 Department of Pharmacology, Yong Loo Lin School of Medicine, NUHS, National University of Singapore, Singapore 3 Cancer Science Institute of Singapore, National University of Singapore, Singapore 4 School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth WA, Australia 5 National University Cancer Institute, NUHS, Singapore 6 Department of Biological Sciences, University of North Texas, Denton, Texas, United States of America 7 NUS Immunology Program, Life Sciences Institute, NUS, Singapore Correspondence to: Lina H. K. Lim, email: // Keywords : microRNAs, breast cancer, annexin 1, pri-miR-196a, c-myc, Immunology and Microbiology Section, Immune response, Immunity Received : January 13, 2016 Accepted : March 31, 2016 Published : April 20, 2016 Abstract MiRNAs are endogenous ~22 nt RNAs which play critical regulatory roles in a wide range of biological and pathological processes, which can act as oncogenes or tumor suppressor genes depending on their target genes. We have recently shown that ANXA1 inhibits the expression of miRNAs including miR196a. Here, we show that miR196a was highly expressed in ER+ MCF-7 breast cancer cells when compared to normal mammary gland cells, with expression levels negatively correlating to ANXA1. ANXA1 inhibits the biogenesis of oncogenic miR-196a by suppressing primary-miR196a indirectly through the stimulation of c-myc and NFkB expression and activity in breast cancer cells. In a negative feedback loop, miR-196a directly inhibits ANXA1 and enhances breast cancer cell proliferation in vitro. Finally, miR196a promotes breast tumor growth in vivo . This study reports a novel regulatory circuit between ANXA1, NF-kB, c-myc and miR-196a which regulates breast cancer cell proliferation and tumor growth.