Our study demonstrated that MDH2, stimulated by estrogen, was involved in the development of PTEN-regulated endometrial carcinoma through GPR30-related pathway.
In addition, the results suggest that miR-424 up-regulation inactivated the PI3K/AKT signaling, which was mediated by G-protein-coupled estrogen receptor-1 (GPER) in endometrial cancer.
E2 stimulated cell proliferation and induced GPR30 expression and PI3K/Akt pathway activation in endometrial cancer cells, Ishikawa cells, and HEC-1A cells, whereas the expression of ERs remained unchangeable.
We evaluated the expression of Gankyrin in endometrial tissues and further explored its roles in estrogen-driven and GPR30-mediated endometrial cancer cell proliferation.
These results support that GPER status adds clinically relevant information to ERα status in endometrial carcinoma and suggest a potential for new inhibitors in the treatment of metastatic endometrial cancers with ERα expression and GPER loss.
We propose that this novel GPR30/SF-1 pathway increases local concentrations of estrogen, and together with classic ER signaling, mediate the proliferative effects of synthetic estrogens such as tamoxifen, in promoting endometriosis and endometrial cancers.
GPR30 represents an alternative estrogen-responsive receptor that is overexpressed in tumors where estrogen and progesterone receptors are downregulated, and in high-risk endometrial cancer patients with lower survival rates.
Transfecting a GPR30 antisense expression vector in both endometrial cancer cell lines, OHT was no longer able to induce growth effects, whereas the proliferative response to E2 was completely abrogated only in HEC1A cells.