// Trang Nguyen-Vu 1, * , Jun Wang 1, * , Fahmi Mesmar 1 , Srijita Mukhopadhyay 1 , Ashish Saxena 1 , Catherine W. McCollum 1 , Jan-Åke Gustafsson 1, 2 , Maria Bondesson 1, 3 , Cecilia Williams 1, 2, 4 1 Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA 2 Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden 3 Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, USA 4 Science for Life Laboratory, School of Biotechnology, KTH The Royal Institute of Technology, Solna, Sweden * These authors have contributed equally to this work Correspondence to: Cecilia Williams, email: Cecilia.williams@scilifelab.se Keywords: colorectal cancer, PROX1, estrogen receptor, microRNA, metastasis Received: October 05, 2015 Accepted: May 25, 2016 Published: June 07, 2016 ABSTRACT Colon cancer is a common cause of cancer death in the Western world. Accumulating evidence supports a protective role of estrogen via estrogen receptor beta (ERβ) but the mechanism of action is not known. Here, we elucidate a molecular mechanism whereby ERβ represses the oncogenic prospero homebox 1 (PROX1) through the upregulation of miR-205. We show that PROX1 is a potential target of miR-205 and that in clinical specimens from The Cancer Genome Atlas data, ERβ and miR-205 are decreased in colorectal cancer tissue compared to non-tumorous colon, while PROX1 levels are increased. Through mechanistic studies in multiple colorectal cancer cell lines, we show that ERβ upregulates miR-205, and that miR-205 targets and represses PROX1 through direct interaction with its 3’UTR. Through the generation of intestine-specific ERβ knockout mice, we establish that this pathway is correspondingly regulated in normal intestinal epithelial cells in vivo . Functionally, we demonstrate that miR-205 decreases cell proliferation and decreases migratory and invasive potential of colon cancer cells, leading to a reduction of micrometastasis in vivo . In conclusion, ERβ in both normal and cancerous colon epithelial cells upregulates miRNA-205, which subsequently reduces PROX1 through direct interaction with its 3’UTR. This results in reduced proliferative and metastatic potential of the cells. Our study proposes a novel pathway that may be exploited using ERβ-selective agonists and/or miR-205-replacement therapy in order to improve preventive and therapeutic approaches against colon cancer.
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Nguyen-Vu et al. (2016) studied this question.