MELK promotes Endometrial carcinoma progression via activating mTOR signaling pathway

Qinyang Xu; Qiulin Ge; Yang Zhou; Bikang Yang; Qin Yang; Shuheng Jiang; Rongzhen Jiang; Zhihong Ai; Zhigang Zhang; Yincheng Teng

EBioMedicine (Jan 2020)

MELK promotes Endometrial carcinoma progression via activating mTOR signaling pathway

Qinyang Xu,
Qiulin Ge,
Yang Zhou,
Bikang Yang,
Qin Yang,
Shuheng Jiang,
Rongzhen Jiang,
Zhihong Ai,
Zhigang Zhang,
Yincheng Teng

Affiliations

Qinyang Xu: Department of Gynecology and Obstetrics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No.600 Yishan Road, Shanghai 200233, PR China
Qiulin Ge: Centre of assisted reproduction, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, PR China
Yang Zhou: Department of Gynecology and Obstetrics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No.600 Yishan Road, Shanghai 200233, PR China
Bikang Yang: Department of Gynecology and Obstetrics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No.600 Yishan Road, Shanghai 200233, PR China
Qin Yang: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, PR China
Shuheng Jiang: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, PR China
Rongzhen Jiang: Department of Gynecology and Obstetrics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No.600 Yishan Road, Shanghai 200233, PR China
Zhihong Ai: Department of Gynecology and Obstetrics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No.600 Yishan Road, Shanghai 200233, PR China
Zhigang Zhang: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, PR China; Corresponding authors at: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P.R. China.
Yincheng Teng: Department of Gynecology and Obstetrics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No.600 Yishan Road, Shanghai 200233, PR China; Corresponding authors at: Department of Gynecology and Obstetrics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No.600 Yishan Road, Shanghai 200233, P. R. China.

Journal volume & issue: Vol. 51

Abstract

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Background: Endometrial carcinoma (EC) is one of the most common gynecological malignancies among women. Maternal embryonic leucine Zipper Kinase (MELK) is upregulated in a variety of human tumors, where it contributes to malignant phenotype and correlates with a poor prognosis. However, the biological function of MELK in EC progression remains largely unknown. Methods: We explored the MELK expression in EC using TCGA and GEO databases and verified it using clinical samples by IHC methods. CCK-8 assay, colony formation assay, cell cycle assay, wound healing assay and subcutaneous xenograft mouse model were generated to estimate the functions of MELK and its inhibitor OTSSP167. qRT-PCR, western blotting, co-immunoprecipitation, chromatin immunoprecipitation and luciferase reporter assay were performed to uncover the underlying mechanism concerning MELK during the progression of EC. Findings: MELK was significantly elevated in patients with EC, and high expression of MELK was associated with serous EC, high histological grade, advanced clinical stage and reduced overall survival and disease-free survival. MELK knockdown decreased the ability of cell proliferation and migration in vitro and subcutaneous tumorigenesis in vivo. In addition, high expression of MELK could be regulated by transcription factor E2F1. Moreover, we found that MELK had a direct interaction with MLST8 and then activated mTORC1 and mTORC2 signaling pathway for EC progression. Furthermore, OTSSP167, an effective inhibitor, could inhibit cell proliferation driven by MELK in vivo and vitro assays. Interpretation: We have explored the crucial role of the E2F1/MELK/mTORC1/2 axis in the progression of EC, which could be served as potential therapeutic targets for treatment of EC. Funding: This research was supported by National Natural Science Foundation of China (No:81672565), the Natural Science Foundation of Shanghai (Grant NO:17ZR1421400 to Dr. Zhihong Ai) and the fundamental research funds for central universities (No: 22120180595). Keywords: Endometrial carcinoma, MELK, E2F1, mTOR, MLST8, OTSSP167

Published in EBioMedicine

ISSN: 2352-3964 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General)
Website: http://www.journals.elsevier.com/ebiomedicine/

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