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Systematic Cancer-Testis Expression Analysis Identifies CDCA5 As a Potential Therapeutic Target in Esophageal Squamous Cell Carcinoma
48 Pages Posted: 1 Mar 2019
More...Abstract
Background: Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies with poor prognosis. Recently, the discovery of the immunogenic proteins, cancer-testis antigens, have been vigorously pursued as targets for therapeutic cancer vaccines.
Methods: A systematic screening strategy was adopted to screen cancer-testis genes (CTGs) in ESCC by integrating multiple public databases and RNA expression microarray data from 119 ESCC subjects. For our identified novel CTG, independent cohort with 118 ESCC patients were recruited to validate the protein level by immunohistochemistry. Furthermore, functional assays were used to determine the underlying mechanisms in vitro and in vivo.
Findings: 21 genes were recognized as CTGs, in particular, CDCA5 was aberrantly upregulated in 99.16% (118/119) of ESCC specimens and higher CDCA5 mRNA expression showed significant association with poor ESCC prognosis (HR = 1.85, 95%CI: 1.14-3.01, P = 0.013). Subsequently, immunohistochemical staining further confirmed that positive CDCA5 protein expression was associated with advanced TNM stage and shorter overall survival rate (45.59% vs 28.00% for CDCA5-/+ subjects, P = 1.86×10-3). Mechanistic exploration revealed that the activation of CDCA5 is associated with gain of H3K27ac. Silencing of CDCA5 significantly suppressed proliferation, invasion, migration and apoptosis resistance in ESCC cells. What's more, mouse xenograft assay showed that repressed CDCA5 inhibited tumor formation in vivo (P<0.01). Further investigations indicated that CDCA5 knockdown led to arrest in G2/M phase and expression changes of factors with functions in the cell cycle.
Interpretation: CDCA5 contributed to ESCC progression and might serve as an attractive target for ESCC immunotherapy.
Funding Statement: This work was supported by the Natural Science Foundation of Jiangsu Province (No. BK20181083 and BK20181496), Jiangsu Top Expert Program in Six Professions (No. WSW-007), Major Program of Science and Technology Foundation of Jiangsu Province (No. BE2016790 and BE2018746), Jiangsu Medical Young Talent Project (No. QNRC2016566), the Program of Jiangsu Medical Innovation Team (No. CXTDA2017006) and Jiangsu Province 333 Talents Project (No. BRA2017545).
Declaration of Interests: The authors declare no competing financial interest.
Ethics Approval Statement: This study was approved by the medical ethics committees of the First Affiliated Hospital of Nanjing Medical University.
Keywords: Esophageal Squamous Cell Cancer; Cancer-testis Gene; CDCA5; Immunotherapy; Biomarker
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