MELK Promotes Endometrial Carcinoma Progression via Activating mTOR Signaling Pathway

Abstract

Maternal embryonic leucine zipper kinase (MELK) is upregulated in a variety of human tumors, where it contributes to a malignant phenotype and correlates with a poor prognosis. Nonetheless, the biological function of MELK in endometrial carcinoma (EC) progression remains largely unknown. In this study, we investigated the mRNA and protein expression of MELK in EC by in silico and immunohistochemical (IHC) methods. We found that MELK expression was significantly higher in patients with EC, and that high expression of MELK was associated with serous EC, high histological grade, an advanced clinical stage, and shorter overall survival and disease-free survival. A MELK knockdown decreased the capacity for cell proliferation and migration in vitro and subcutaneous tumorigenesis in vivo. Chromatin immunoprecipitation and a luciferase reporter assay were performed to demonstrate that high expression of MELK may be caused by transcription factor E2F1. Moreover, we found that MELK directly interacts with MLST8 and then activates the mTORC1 and mTORC2 signaling pathway to promote EC progression. OTSSP167, an effective MELK inhibitor, suppressed the cell proliferation driven by MELK. Thus, we identified the crucial role of the E2F1-MELK-mTORC1/2 axis in the progression of EC, which may contain potential therapeutic targets of EC. Funding Statement: This work was supported by National Natural Science Foundation of China (Nos.81672565). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: All of the patients provided written informed consent, and all the experiments were approved by the Research Ethics Committee of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital and complied with the Declaration of Helsinki.