Estrogen receptor   expression induces changes in the microRNA pool in human colon cancer cells

Abstract

There is epidemiological, animal and in vitro evidence that estrogen receptor β (ERβ) can mediate protective effects against colon cancer, but the mechanism is not completely understood. Previous research has indicated critical pathways whereby ERβ acts in an antitumorigenic fashion. In this study, we investigate ERβ's impact on the microRNA (miRNA) pool in colon cancer cells using large-scale genomic approaches, bioinformatics and focused functional studies. We detect and confirm 27 miRNAs to be significantly changed following ERβ expression in SW480 colon cancer cells. Among these, the oncogenic miR-17-92 cluster and miR-200a/b are strongly downregulated. Using target prediction and anticorrelation to gene expression data followed by focused mechanistic studies, we demonstrate that repression of miR-17 is a secondary event following ERβ's downregulatory effect on MYC. We show that re-introduction of miR-17 can reverse the antiproliferative effects of ERβ. The repression of miR-17 also influences cell death upon DNA damage and mediates regulation of NCOA3 (SRC-3) and CLU in colon cancer cells. We further determine that the downregulation of miR-200a/b mediates increased ZEB1 while decreasing E-cadherin levels in ERβ-expressing colon cancer cells. Changes in these genes correspond to significant alterations in morphology and migration. Our work contributes novel data of ERβ and miRNA in the colon. Elucidating the mechanism of ERβ and biomarkers of its activity has significant potential to impact colon cancer prevention and treatment.

Estrogen suppresses hepatocellular carcinoma cells through ERβ-mediated upregulation of the NLRP3 inflammasome

“…In support of our study showing the tumor suppressor role of ERβ, there are emerging evidences showing that ERβ has an anti-oncogenic role in the development and progression of some tumor types, including ovarian cancer, renal cell carcinoma, prostate cancer, and colon cancers. [23][24][25][26][27][28][29] Our study and these previous reports altogether indicated a protective role of ERβ in the development and progression of cancer.…”

Estrogen receptor beta as target for colorectal cancer prevention

“…Additionally, non-genomic effects via phosphorylation and regulation of enzymes that impact cell physiology, such as kinases and phosphatases, and activity through the membrane-bound G protein-coupled estrogen receptor 1 (GPR30/GPER1), have been described [36]. While ERα protein is not detected in the colonic epithelium or in CRC (http://www.proteinatlas.org/ENSG00000091831-ESR1/tissue/colon), ERβ has been confirmed as the predominant form of ER in a number of studies [37–45]. …”

Insight into the mechanisms of action of estrogen receptor β in the breast, prostate, colon, and CNS

“…From the phenotype of ERb K/K mice, ERb in the colon appears to decrease proliferation and increase apoptosis, suggesting a tumor suppressive and tumor preventive effect (Wada-Hiraike et al 2006). ERb has also been shown to change the micro RNA pool in human colorectal cancer cells (Edvardsson et al 2013) and to regulate miR-135b and mismatch repair gene expressions in colorectal cells (He et al 2012).…”