Epigenetic down regulation of G protein-coupled estrogen receptor (GPER) functions as a tumor suppressor in colorectal cancer

Molecular Cancer

卷:16

Jun Du¹  Guanmin Jiang¹  Qiao Liu²  Xiangling Yang²  Hongbin Huang³  Hongsheng Wang³  Yan Zhou⁴  Huanliang Liu⁵  Zhuojia Chen⁵ 

[1] Collaborative Innovation Center for Cancer Medicine;

[2] Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University;

[3] Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Institute of Human Virology, Key Laboratory of Tropical Disease Control (Ministry of Education), Sun Yat-sen University;

[4] Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University;

[5] Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China;

关键词: GPER;    G-1;    CRC;    NF-κB;    ROS;   

DOI  :  10.1186/s12943-017-0654-3

来源: DOAJ

【 摘 要 】

Abstract Background Estrogenic signals are suggested to have protection roles in the development of colorectal cancer (CRC). The G protein-coupled estrogen receptor (GPER) has been reported to mediate non-genomic effects of estrogen in hormone related cancers except CRC. Its expression and functions in CRC were investigated. Methods The expression of GPER and its associations with clinicopathological features were examined. The mechanisms were further investigated using cells, mouse xenograft models, and clinical human samples. Results GPER was significantly (p < 0.01) down regulated in CRC tissues compared with their matched adjacent normal tissues in our two cohorts and three independent investigations from Oncomine database. Patients whose tumors expressing less (n = 36) GPER showed significant (p < 0.01) poorer survival rate as compared with those with greater levels of GPER (n = 54). Promoter methylation and histone H3 deacetylation were involved in the down regulation of GPER in CRC cell lines and clinical tissues. Activation of GPER by its specific agonist G-1 inhibited proliferation, induced cell cycle arrest, mitochondrial-related apoptosis and endoplasmic reticulum (ER) stress of CRC cells. The upregulation of reactive oxygen species (ROS) induced sustained ERK1/2 activation participated in G-1 induced cell growth arrest. Further, G-1 can inhibit the phosphorylation, nuclear localization, and transcriptional activities of NF-κB via both canonical IKKα/ IκBα pathways and phosphorylation of GSK-3β. Xenograft model based on HCT-116 cells confirmed that G-1 can suppress the in vivo progression of CRC. Conclusions Epigenetic down regulation of GPER acts as a tumor suppressor in colorectal cancer and its specific activation might be a potential approach for CRC treatment.

【 授权许可】

Unknown