Estrogen receptor beta reduces colon cancer metastasis through a novel miR-205 - PROX1 mechanism
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Trang Nguyen-Vu1,*, Jun Wang1,*, Fahmi Mesmar1, Srijita Mukhopadhyay1, Ashish Saxena1, Catherine W. McCollum1, Jan-Åke Gustafsson1,2, Maria Bondesson1,3, Cecilia Williams1,2,4
1Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA
2Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden
3Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, USA
4Science for Life Laboratory, School of Biotechnology, KTH The Royal Institute of Technology, Solna, Sweden
*These authors have contributed equally to this work
Cecilia Williams, email: Cecilia.firstname.lastname@example.org
Keywords: colorectal cancer, PROX1, estrogen receptor, microRNA, metastasis
Received: October 05, 2015 Accepted: May 25, 2016 Published: June 07, 2016
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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