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Identification and Validation of MSX1 as a Key Candidate for Progestin Resistance in Endometrial Cancer
Linlin Yang1,2,3, Yunxia Cui1,2,3, Ting Huang1,2,3
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.
Purpose:
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.
Insights
MSX1 is a promising therapeutic target for overcoming progestin resistance in endometrial cancer. Its knockdown inhibits tumor progression and enhances progesterone efficacy, offering new treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Progestin resistance is a major challenge in endometrial cancer conservative therapy.
- Understanding the molecular mechanisms of progestin resistance is crucial for developing effective treatments.
- Pivotal molecules driving progestin resistance remain largely unexplored.
Purpose of the Study:
- To identify key molecular players involved in progestin resistance in endometrial cancer.
- To explore the therapeutic potential of identified molecules in overcoming progestin resistance.
Main Methods:
- Analysis of differentially expressed genes (DEGs) from the GSE121367 dataset.
- Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA).
- Protein-protein interaction network construction and analysis.
- Tumor immune microenvironment exploration using TISIDB.
- Methylation and overall survival analysis using TCGA data.
- Validation of gene expression via qRT-PCR, Western blot, and IHC.
- In vitro assays to assess the role of MSX1 in progestin resistance.
Main Results:
- Identified 3,282 DEGs, enriched in cell adhesion pathways.
- Screened ten hub genes with low genomic alteration rates.
- MSX1 showed decreased methylation, high protein expression, and predicted better overall survival.
- MSX1 knockdown inhibited epithelial-mesenchymal transitions (EMT) and enhanced progesterone efficacy in vitro.
Conclusions:
- MSX1 is identified as a potential specific indicator and therapeutic target for progestin resistance in endometrial cancer.
- This finding offers novel insights into the biological mechanisms to overcome progestin resistance.
- MSX1 represents a promising target for future endometrial cancer therapies.
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