Oestrogens regulate proliferation in colorectal cancer via GPER and the hippo signalling pathway

[摘要] The concentration of circulating oestrogens is associated with the incidence and outcomes of colorectal cancer (CRC). Both the physiological and pathological effects of oestrogens are mediated by oestrogen receptors. This project aims to investigate the potential role of G protein-coupled oestrogen receptor 1 (GPER) as an oestrogen-induced mediator in CRC proliferation. To achieve this, colorectal adenoma and carcinoma cell lines were examined for protein expression of oestrogen receptors. Immunoblotting did not report ERa and ERb expression, although GPER was detected. Following this, the GPER-associated gene connective tissue growth factor (CTGF) expression was measured after I7β-estradiol (E2) and GPER agonist (G1) treatment. qRT-PCR results showed no significant increase in CTGF expression levels, 24 and 48 hours after treatment. In addition, GPER interaction with the Hippo pathway in CRC was examined by treating cells with E2 and G1 for 0, 15, 30 minutes, 1, and 2 hours. Alterations in P-Y API expression were unclear after treatment in the cell lines examined. However, addition of GPER antagonist, G15, resulted in significant inhibition in YAP1 phosphorylation in HCT116 cells, 15 and 30 minutes of treatment. Consequently, our data supports that oestrogens and G1 treatment leads to increase in YAP phosphorylation and nucleus-cytoplasmic shuttling via GPER stimulation. YAP1 knock-down studies and pharmacological inhibition followed by proliferation assays established that this early metabolic effect translates into increased cellular proliferation. Collectively, our data propose a novel oestrogen-driven pro-proliferative pathway via GPER through Hippo pathway's key downstream effector, YAP1, in CRC. Further studies are required to 'reveal the detailed signalling cascade by which GPER mediates the increased YAP1 phosphorylation.

[发布机构] University:University of Birmingham;Department:Institute of Metabolism and Systems Research

[关键词] R Medicine;RC Internal medicine;RC0254 Neoplasms. Tumors. Oncology (including Cancer)