β-hCG promotes epithelial ovarian cancer metastasis through ERK/MMP2 signaling pathway
Authors: Hao Gao
Weimin Wu
Guangxi Zhan
Xiaoqing Guo
Xiaofeng Li
Jing Yu
Na Liu
Yong Zhu
Shumin Peng
Kai Wang
Journal: Cell Cycle (2019)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: ERK1/2; Epithelial ovarian cancer; invasion and metastasis; proliferation; β-hCG.
Affiliations: Department of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China, Department of Obstetrics and Gynecology, Chongqing Health Center for Women and Children, Chongqing, China, Department of Pathology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China, Department of Obstetrics and Gynecology, The First Affiliated Hospital, Shihezi University School of Medicine, Xinjiang, China, Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China

Abstract:  Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy, with typically extensive intraperitoneal implantation leading to poor prognosis. Our previous study preliminarily demonstrated β-hCG can promote tumorigenesis in immortalized nontumorigenic ovarian epithelial cells. In this study, the roles and mechanisms of β-hCG in regulating EOC proliferation and metastasis were thoroughly explored. First, histologically, β-hCG was aberrantly overexpressed in human EOC metastatic tissues, and significantly correlated with FIGO stage, tumor size, differentiation, histologic grade and high grade serous ovarian carcinoma (HGSOC) (P &lt; 0.05). However, serologically, β-hCG expression showed no significant difference between EOC and nonmalignant ovarian patients. Second, β-hCG was confirmed to have no significant effects on EOC proliferation in vitro and in vivo, while β-hCG upregulation was proven to promote migration and invasion ability in ES-2 and OVCAR-3 cells in vitro (P &lt; 0.05), and β-hCG downregulation in SKOV3 cells had the opposite effect. Moreover, more invadopodia protrusions, mitochondria accumulations and cytoskeletal rearrangements were observed in β-hCG-overexpressing ES-2 cells, while β-hCG-depleted SKOV3 cells produced the opposite effect. Furthermore, β-hCG was confirmed to clearly facilitate intraperitoneal metastasis in nude mouse orthotopic ovarian xenograft models. Importantly, these effects of β-hCG were mediated by activation of the ERK/MMP2 signaling pathway, independently of luteinizing hormone/chorionic gonadotropin receptor (LHCGR) presence, and inhibition the pathway with the p-ERK1/2 inhibitor SCH772984 significantly impaired the tumor-promoting effects induced by β-hCG. Collectively, these data provide new insight into the roles and mechanisms of β-hCG in regulating EOC metastasis through ERK/MMP2 signaling pathway and may become a new target for therapeutic intervention. 

Retracted: No

PubPeer comments:
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