Abstract
BackgroundAutocrine motility factor (AMF) is a critical factor regulating aggressiveness of endometrial cancer (EC). Multiple pieces of evidence indicate that it is through G protein coupled estrogen receptor (GPER) signaling pathway that some growth factors promoted the migration and proliferation of tumor cells. The aim of this study is to explore the role of GPER-1 in AMF mediated regulatory mechanisms of EC recurrence and progression.MethodsReal-Time Cell Analysis (RTCA) assays were performed to assess whether AMF depends on Autocrine motility factor recepter (AMFR) signaling in EC cells. A genome-wide expression microarray and Yeast Two-Hybrid assay were used to detect AMF and GPER-1 interaction in the context of AMFR depletion, and co-immunoprecipitation and immunofluorescence experiments were performed to confirm the physical interaction. Isobaric Tags for Relative and Absolute Quantification (iTRAQ) analysis was used for the identification of the target pathway activated by AMF-GPER-1 interaction. Cohorts of mice harboring xenografts derived from modified SPEC2 cell lines were treated with or without exogenous AMF to validate the results of previous experiments. Immunohistochemistry was performed to assess AMF and GPER-1 expression in endometrial cancer specimens and normal endometrium.ResultsOur data showed that GPER-1 binds to AMF and the formed complex translocates from the plasma membrane to the cytoplasm. Mechanistic investigations demonstrated that interaction between AMF and GPER-1 triggers phosphoinositide-3-kinase signaling and promotes EC cell growth. More importantly, through animal experiments and human tissue experiments, we found that AMF contributes to GPER-1-mediated EC progression, which is consistent with the above observations.ConclusionsOur work not only delineated the regulatory mechanisms of endometrial cancer progression by AMF-GPER-1-AKT signaling cascade but also laid the foundation of targeting this pathway for treating endometrial cancer.
Highlights
Autocrine motility factor (AMF) is a critical factor regulating aggressiveness of endometrial cancer (EC)
Autocrine motility factor recepter (AMFR) is well known as a conventional receptor of AMF, which is a protein secreted by tumor cell stimulating tumor motility
We showed that autocrine motility factor (AMF) binds G protein-coupled estrogen receptor 1 (GPER-1) and translocates from the plasma membrane to the cytoplasm
Summary
Autocrine motility factor (AMF) is a critical factor regulating aggressiveness of endometrial cancer (EC). Endometrial cancer (EC) is the most common malignancy of the female reproductive system, with a 3% risk of occurrence. Most patients with EC are diagnosed early, the median survival time is only 8–12 months, indicating the poor efficacy of treatment in improving survival [2]. In recent years, targeted therapy has attracted increasing attention due to its high specificity, absence of surgical injury and ability to avoid the general toxicity of radiotherapy and chemotherapy [3]. Targeted therapy for the treatment of EC has failed to achieve satisfactory efficacy with an objective response rate < 10%, suggesting that the molecular mechanisms that promote EC progression are still unclear [4]
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