期刊
FRONTIERS IN ONCOLOGY
卷 11, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fonc.2021.638171
关键词
G protein-coupled estrogen receptor; cell viability; hepatocellular carcinoma; ERK signaling; therapeutic target
类别
资金
- National Natural Science Foundation of China [81702641]
- Natural Science Foundation of Jiangxi Province [2018ACB21042, 20171BAB215046, 20192BAB205069]
GPER has shown significant potential as a therapeutic target for hepatocellular carcinoma (HCC) treatment, with GPER-positive patients showing associations with specific clinical characteristics and improved prognosis. Activation of the GPER/ERK axis inhibits tumor growth in HCC by blocking cell cycle progression and promoting apoptosis, suggesting a novel tumor-suppressive mechanism for HCC therapy. High expression of GPER and phosphorylated-ERK may serve as a predictive biomarker for HCC prognosis.
Hepatocellular carcinoma (HCC) is an aggressive malignancy with a poor prognosis. Effective biomarkers and specific therapeutic targets for HCC are therefore urgently needed. G protein-coupled estrogen receptor (GPER) plays a crucial role in numerous cancer types; however, its functions in HCC require further exploration. In the present study, we found a remarkable difference in GPER staining between tumor tissue (100/141, 70.9%) and matched non-tumor tissue (27/30, 90.0%). Compared with the GPER-negative patients, the GPER-positive patients with HCC were closely associated with female sex, negative hepatitis B surface antigen, small tumor size, low serum alpha fetoprotein level, and longer overall survival. Treatment with GPER-specific agonist G1 led to the sustained and transient activation of the EGFR/ERK and EGFR/AKT signaling pathways, respectively, in the HCC cell lines HCCLM3 and SMMC-7721, which express high levels of GPER. Interestingly, G1-induced EGFR/ERK signaling, rather than EGFR/AKT signaling mediated by GPER, was involved in decreasing cell viability by blocking cell cycle progression, thereby promoting apoptosis and inhibiting cell growth. Clinical analysis indicated that simultaneous high expression of GPER and phosphorylated-ERK (p-ERK) predicted improved prognosis for HCC. Finally, the activation of GPER/ERK signaling remarkably suppressed tumor growth in an HCC xenograft model, and this result was consistent with the in vitro data. Our findings suggest that specific activation of the GPER/ERK axis may serve as a novel tumor-suppressive mechanism and that this axis could be a therapeutic target for HCC.
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