Estrogen receptor beta reduces colon cancer metastasis through a novel miR-205-PROX1 mechanism
2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 27, 42159-42171 p.Article in journal (Refereed) Published
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 beta) but the mechanism of action is not known. Here, we elucidate a molecular mechanism whereby ER beta 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 beta 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 beta 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 beta 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 beta 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 beta-selective agonists and/or miR-205-replacement therapy in order to improve preventive and therapeutic approaches against colon cancer.
Place, publisher, year, edition, pages
IMPACT JOURNALS LLC , 2016. Vol. 7, no 27, 42159-42171 p.
colorectal cancer, PROX1, estrogen receptor, microRNA, metastasis
Cancer and Oncology
IdentifiersURN: urn:nbn:se:kth:diva-193837DOI: 10.18632/oncotarget.9895ISI: 000380942600094OAI: oai:DiVA.org:kth-193837DiVA: diva2:1034534
FunderVINNOVA, 291795Swedish Cancer SocietyStockholm County Council
QC 201610122016-10-122016-10-112016-10-12Bibliographically approved