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MAD2L1 Functions As a Novel Diagnostic and Predictive Biomarker in Cholangiocarcinoma
1Departments of General Surgery, The Affiliated Changzhou No. 2 People's Hospital, Nanjing Medical University, Changzhou, China.
Abstract:
Most cholangiocarcinoma (CCA) patients are diagnosed at an advanced stage of disease, and the postoperational recurrence rates are high in those undergoing resection. The lack of satisfying biomarkers for early diagnoses and effective targeting of driver pathways is the leading reason for therapeutic failures. The goal of this study was to find a biomarker for making improved diagnoses with enhanced prognostic capabilities for CCA. Our study used bioinformatic analyses of microarray data from the Gene Expression Omnibus (GEO) database and investigated mitotic arrest deficient 2-like protein 1 (MAD2L1) expression in tumor and adjacent non-neoplastic biliary ducts through immunocytochemistry in 42 surgically removed primary CCAs from a single institute. In vitro and in vivo models were used to explore the function of MAD2L1. In total, 297 high probability differentially expressed genes (DEGs) were obtained from overlapping the DEGs from the three individual data sets. Through enrichment assays and protein-protein interaction networks analyses, seven hub genes were identified. MAD2L1 was picked up as a novel biomarker based on hierarchical cluster analyses and Kaplan-Meier survival analyses. MAD2L1 was expressed in cancer tissues but not in the surrounding normal tissue, with 31 (73.81%) of 42 CCAs MAD2L1 positive by immunohistochemistry (IHC). MAD2L1 expression levels were significantly correlated with tumor size, pathological grade, and clinical stage. A Kaplan-Meier survival analysis demonstrated an inverse correlation with MAD2L1 expression. Real-time polymerase chain reaction and immunoblotting results further confirmed the results of IHC and bioinformatic analyses. In vitro and in vivo models demonstrated decreasing MAD2L1 could significantly suppress tumor growth, whereas increasing MAD2L1 could promote tumor growth. MAD2L1 could be used as a biomarker to predict prognosis and potential therapeutic target in CCA. Clinical Trial Registration Number: [2020]KY157-01.
Insights
Mitotic arrest deficient 2-like protein 1 (MAD2L1) shows promise as a biomarker for cholangiocarcinoma (CCA) diagnosis and prognosis. Lower MAD2L1 levels correlate with better outcomes, suggesting it as a therapeutic target for CCA.
Area of Science:
- Oncology
- Molecular Biology
- Biomarker Discovery
Background:
- Cholangiocarcinoma (CCA) often presents at advanced stages with high recurrence rates post-surgery.
- Current diagnostic biomarkers and targeted therapies for CCA are insufficient, leading to therapeutic failures.
- There is a critical need for improved diagnostic and prognostic biomarkers in CCA.
Purpose of the Study:
- To identify a novel biomarker for enhanced diagnosis and prognosis of cholangiocarcinoma (CCA).
- To investigate the expression and functional role of mitotic arrest deficient 2-like protein 1 (MAD2L1) in CCA.
Main Methods:
- Bioinformatic analysis of Gene Expression Omnibus (GEO) microarray data.
- Immunohistochemistry (IHC) to assess MAD2L1 expression in 42 primary CCA tissues.
- In vitro and in vivo models to explore MAD2L1's functional impact on tumor growth.
Main Results:
- MAD2L1 was identified as a significant hub gene and potential biomarker through bioinformatic and survival analyses.
- MAD2L1 was overexpressed in CCA tissues compared to normal ducts (73.81% positive by IHC) and correlated with tumor progression.
- Functional studies confirmed that reduced MAD2L1 suppresses, while increased MAD2L1 promotes, CCA tumor growth.
Conclusions:
- MAD2L1 serves as a promising biomarker for predicting prognosis in cholangiocarcinoma (CCA).
- MAD2L1 represents a potential therapeutic target for developing novel treatments for CCA.
- Clinical Trial Registration Number: [2020]KY157-01.
