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

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

doi:10.18632/oncotarget.9895

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.

Highlights

Colorectal cancer remains the third leading cause of cancer death in the United States claiming approximately 50 000 lives yearly [1]
Through mechanistic studies in multiple colorectal cancer cell lines, we show that ERβ upregulates miR-205, and that miR-205 targets and represses prospero homebox 1 (PROX1) through direct interaction with its 3’UTR
Using 3ʹ-untranslated region (3ʹUTR)-luciferase-reporter assay we demonstrated that the activity of luciferase cloned with a PROX1 wild-type 3ʹUTR was significantly reduced by miR-205 expression, while its activity was unaffected in the clone with a mutation in the putative 3ʹUTR target site (Figure 3E)

Summary

Introduction

Colorectal cancer remains the third leading cause of cancer death in the United States claiming approximately 50 000 lives yearly [1]. ERβ has further been demonstrated to have a protective role against colorectal cancer in animal models [16,17,18,19,20]. While both ERs are activated by estrogen, their ligand-binding domains differ slightly and selective ER modulators (SERMs) has been designed to preferentially activate either ER. There is a potential for ERβ-selective agonists as a chemopreventive approach against colon cancer development. The underlying molecular mechanism for this protective effect and the function of ERβ in the colon is not understood

Methods

Results

Conclusion