OncoTargets and Therapy (Nov 2020)
Identification and Validation of MSX1 as a Key Candidate for Progestin Resistance in Endometrial Cancer
Abstract
Linlin Yang,1– 3 Yunxia Cui,1– 3 Ting Huang,1– 3 Xiao Sun,1– 3 Yudong Wang1– 3 1Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2Shanghai Municipal Key Clinical Specialty, Shanghai, People’s Republic of China; 3Shanghai Key Laboratory of Embryo Original Disease, Shanghai, People’s Republic of ChinaCorrespondence: Yudong Wang; Xiao Sun Department of Gynecologic OncologyThe International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, 1961 Huashan Road, Shanghai 200060, People’s Republic of ChinaEmail [email protected]; [email protected]: Progestin resistance is a critical obstacle for endometrial conservative therapy. Therefore, studies to acquire a more comprehensive understanding of the mechanisms are urgent. However, the pivotal molecules are still unexplored.Materials and Methods: We downloaded GSE121367 from the GEO database. The “limma” R language package was applied to identify differentially expressed genes (DEGs). We conducted Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA). Protein–protein interaction was constructed by STRING and visualized in Cytoscape. The tumor immune microenvironment was explored by the TISIDB database. Methylation validation and overall survival analysis were conducted by the TCGA database. In addition, the upstream modulators of hub genes were predicted by miRTarBase and Network Analyst databases. The expression levels of candidate genes were validated by quantitative real-time PCR (qRT-PCR), Western blot, and immunohistochemical assay (IHC). Cell growth, clone formation, migration, invasion, and wound healing assays were studied to explore the role of MSX1 in progestin resistance in vitro.Results: A total of 3,282 DEGs were identified and they were mostly enriched in the cell adhesion pathway. We screened out ten hub genes whose genomic alteration rates were low based on the current endometrial carcinoma sample sets. Has-miR-335-5p, has-miR-124-3p, MAZ, and TFDP1 were the most prominent upstream regulators. The methylation status of CDH1, JAG1, EPCAM, and MSX1 was decreased, corresponding to their high protein expression, which also predicted better overall survival. The homeobox protein of MSX1 showed significant tissue specificity and better prognostic value and its knockdown inhibited epithelial–mesenchymal transitions (EMT) and enhanced progesterone efficacy.Conclusion: Our study identified that the gene of MSX1 promised to be the specific indicator and therapeutic target for progestin resistance. This would shed new light on the underlying biological mechanism to overcome progestin resistance of endometrial cancer.Keywords: bioinformatic analysis, in vitro experiments, progestin resistance, MSX1, endometrial carcinoma
