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

Trang Nguyen-Vu, Jun Wang, Fahmi Mesmar, Srijita Mukhopadhyay, Ashish Saxena, Catherine W. McCollum, Jan Åke Gustafsson, Maria Bondesson, Cecilia Williams

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)42159-42171
Number of pages13
JournalOncotarget
Volume7
Issue number27
DOIs
StatePublished - Jul 5 2016

Keywords

  • PROX1
  • colorectal cancer
  • estrogen receptor
  • metastasis
  • microRNA

ASJC Scopus subject areas

  • Oncology

Fingerprint

Dive into the research topics of 'Estrogen receptor beta reduces colon cancer metastasis through a novel miR-205 - PROX1 mechanism'. Together they form a unique fingerprint.

Cite this