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

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 (ER?) but the mechanism of action is not known. Here, we elucidate a molecular mechanism whereby ER? 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, ER? 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 ER? upregulates miR-205, and that miR-205 targets and represses PROX1 through direct interaction with its 3'UTR. Through the generation of intestine-specific ER? 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, ER? 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 ER?-selective agonists and/or miR-205-replacement therapy in order to improve preventive and therapeutic approaches against colon cancer.

SUBMITTER: Nguyen-Vu T 

PROVIDER: S-EPMC5173124 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature