GPER mediates differential effects of estrogen on colon cancer cell proliferation and migration under normoxic and hypoxic conditions
| Autor: | Anke Nijhuis, Viviana Bustos, Áine M. Nolan, Alexandra Parker, Harry Harvey, Richard Poulsom, Andrew Silver, Brian J. Harvey, Warren Thomas, Jean McBryan |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty medicine.drug_class Colorectal cancer Estrogen receptor colorectal cancer 03 medical and health sciences 0302 clinical medicine Internal medicine estrogen medicine hypoxia business.industry Cell migration Hypoxia (medical) GPER medicine.disease VEGF Molecular medicine 3. Good health Vascular endothelial growth factor A 030104 developmental biology Endocrinology Oncology Estrogen 030220 oncology & carcinogenesis Cancer research medicine.symptom business Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Viviana Bustos 1 , Aine M. Nolan 1 , Anke Nijhuis 2 , Harry Harvey 1 , Alexandra Parker 2 , Richard Poulsom 2 , Jean McBryan 1 , Warren Thomas 1 , Andrew Silver 2 and Brian J. Harvey 1 1 Department of Molecular Medicine, Education and Research Centre, Beaumont Hospital, Royal College of Surgeons in Ireland, Dublin, Ireland 2 Centre for Digestive Diseases, National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, UK Correspondence to: Brian J. Harvey, email: brianharvey@rcsi.ie Keywords: estrogen, GPER, VEGF, hypoxia, colorectal cancer Received: March 29, 2017 Accepted: July 26, 2017 Published: September 06, 2017 ABSTRACT The estrogen receptor ERβ is the predominant ER subtype expressed in normal well-differentiated colonic epithelium. However, ERβ expression is lost under the hypoxic microenvironment as colorectal cancer (CRC) malignancy progresses. This raises questions about the role of signalling through other estrogen receptors such as ERα or G-protein coupled estrogen receptor (GPER, GPR30) by the estrogen 17β-estradiol (E2) under hypoxic conditions after ERβ is lost in CRC progression. We tested the hypothesis that E2 or hypoxia can act via GPER to contribute to the altered phenotype of CRC cells. GPER expression was found to be up-regulated by hypoxia and E2 in a panel of CRC cell lines. The E2-modulated gene, Ataxia telangiectasia mutated ( ATM ), was repressed in hypoxia via GPER signalling. E2 treatment enhanced hypoxia-induced expression of HIF1-α and VEGFA, but repressed HIF1-α and VEGFA expression under normoxic conditions. The expression and repression of VEGFA by E2 were mediated by a GPER-dependent mechanism. E2 treatment potentiated hypoxia-induced CRC cell migration and proliferation, whereas in normoxia, cell migration and proliferation were suppressed by E2 treatment. The effects of E2 on these cellular responses in normoxia and hypoxia were mediated by GPER. In a cohort of 566 CRC patient tumor samples, GPER expression significantly associated with poor survival in CRC Stages 3-4 females but not in the stage-matched male population. Our findings support a potentially pro-tumorigenic role for E2 in ERβ-negative CRC under hypoxic conditions transduced via GPER and suggest a novel route of therapeutic intervention through GPER antagonism. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|