Estrogen receptor beta reduces colon cancer metastasis through a novel miR-205 - PROX1 mechanism

• Published in: Oncotarget 2016-07, Vol.7 (27), p.42159-42171
• Main Authors: Nguyen-Vu, Trang, Wang, Jun, Mesmar, Fahmi, Mukhopadhyay, Srijita, Saxena, Ashish, McCollum, Catherine W, Gustafsson, Jan-Åke, Bondesson, Maria, Williams, Cecilia
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions; Adenocarcinoma - metabolism; Animals; Cell Adhesion; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms - metabolism; colorectal cancer; estrogen receptor; Estrogen Receptor beta - metabolism; Female; Gene Expression Regulation, Neoplastic; Gene Silencing; Homeodomain Proteins - metabolism; Humans; Intestinal Mucosa - metabolism; Male; Medicin och hälsovetenskap; metastasis; Mice; Mice, Knockout; microRNA; MicroRNAs - metabolism; Neoplasm Invasiveness; Neoplasm Metastasis; PROX1; Research Paper; Transcription Factors - metabolism; Tumor Suppressor Proteins - metabolism
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.9895

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.