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1. Systematic cancer-testis gene expression analysis identified CDCA5 as a potential therapeutic target in esophageal squamous cell carcinomaResearch in context

Author

Jing Xu, Chengxiang Zhu, Yue Yu, Weibing Wu, Jing Cao, Zhihua Li, Juncheng Dai, Cheng Wang, Yu Tang, Quan Zhu, Jun Wang, Wei Wen, Lei Xue, Fuxi Zhen, Jinyuan Liu, Chenjun Huang, Fei Zhao, Yue Zhou, Zhicheng He, Xianglong Pan, Haixing Wei, Yining Zhu, Yaozhou He, Jun Que, Jinghua Luo, Liang Chen, and Wei Wang

Subjects
Medicine, Medicine (General), R5-920
Abstract

Background: Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies with poor prognosis. Cancer-testis genes (CTGs) have been vigorously pursued as targets for cancer immunotherapy, but the expressive patterns and functional roles of CTGs remain unclear in ESCC. Methods: A systematic screening strategy was adopted to screen CTGs in ESCC by integrating multiple public databases and RNA expression microarray data from 119 ESCC subjects. For the newly identified ESCC prognosis-associated CTGs, an independent cohort of 118 patients with ESCC was recruited to validate the relationship via immunohistochemistry. Furthermore, functional assays were performed to determine the underlying mechanisms. Findings: 21 genes were recognized as CTGs, in particular, CDCA5 was aberrantly upregulated in ESCC tissues and significantly associated with poor prognosis (HR = 1.85, 95%CI: 1.14–3.01, P = .013). Immunohistochemical staining confirmed that positive CDCA5 expression was associated with advanced TNM staging and a shorter overall survival rate (45.59% vs 28.00% for CDCA5−/+ subjects, P = 1.86 × 10−3). H3K27 acetylation in CDCA5 promoter might lead to the activation of CDCA5 during ESCC tumorigenesis. Functionally, in vitro assay of gain- and loss-of-function of CDCA5 suggested that CDCA5 could promote ESCC cells proliferation, invasion, migration, apoptosis resistance and reduce chemosensitivity to cisplatin. Moreover, in vivo assay showed that silenced CDCA5 could inhibit tumor growth. Mechanistically, CDCA5 knockdown led to an arrest in G2/M phase and changes in the expression of factors that played fundamental roles in the cell cycle pathway. Interpretation: CDCA5 contributed to ESCC progression and might serve as an attractive target for ESCC immunotherapy. Fund: 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-003 and 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), Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX18_1487) and Jiangsu Province 333 Talents Project (No. BRA2017545). Keywords: Esophageal squamous cell cancer, Cancer-testis gene, CDCA5, Immunotherapy, Biomarker

Published
2019
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2. Systematic cancer-testis gene expression analysis identified CDCA5 as a potential therapeutic target in esophageal squamous cell carcinoma

Author

Lei Xue, Cheng Wang, Jing Cao, Yu Tang, Fei Zhao, Yaozhou He, Jinyuan Liu, Haixing Wei, Wei Wen, Weibing Wu, Chenjun Huang, Yining Zhu, Liang Chen, Zhihua Li, Chengxiang Zhu, Xianglong Pan, Jun Wang, Jun Que, Quan Zhu, Zhicheng He, Jinghua Luo, Jing Xu, Juncheng Dai, Fuxi Zhen, Wei Wang, Yue Yu, and Yue Zhou

Subjects
Adult, Male, 0301 basic medicine, Research paper, medicine.medical_treatment, Esophageal squamous cell cancer, Cell Cycle Proteins, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, Mice, 03 medical and health sciences, Antineoplastic Agents, Immunological, 0302 clinical medicine, CDCA5, Cancer immunotherapy, Cell Line, Tumor, medicine, Animals, Humans, Adaptor Proteins, Signal Transducing, Aged, Neoplasm Staging, Gene knockdown, business.industry, Microarray analysis techniques, Gene Expression Profiling, Biomarker, General Medicine, Immunotherapy, Middle Aged, Cell cycle, Prognosis, Immunohistochemistry, digestive system diseases, Gene Expression Regulation, Neoplastic, 030104 developmental biology, Cancer-testis gene, 030220 oncology & carcinogenesis, Cancer research, Biomarker (medicine), Female, Esophageal Squamous Cell Carcinoma, Transcriptome, Carcinogenesis, business
Abstract

Background Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies with poor prognosis. Cancer-testis genes (CTGs) have been vigorously pursued as targets for cancer immunotherapy, but the expressive patterns and functional roles of CTGs remain unclear in ESCC. Methods A systematic screening strategy was adopted to screen CTGs in ESCC by integrating multiple public databases and RNA expression microarray data from 119 ESCC subjects. For the newly identified ESCC prognosis-associated CTGs, an independent cohort of 118 patients with ESCC was recruited to validate the relationship via immunohistochemistry. Furthermore, functional assays were performed to determine the underlying mechanisms. Findings 21 genes were recognized as CTGs, in particular, CDCA5 was aberrantly upregulated in ESCC tissues and significantly associated with poor prognosis (HR = 1.85, 95%CI: 1.14–3.01, P = .013). Immunohistochemical staining confirmed that positive CDCA5 expression was associated with advanced TNM staging and a shorter overall survival rate (45.59% vs 28.00% for CDCA5−/+ subjects, P = 1.86 × 10−3). H3K27 acetylation in CDCA5 promoter might lead to the activation of CDCA5 during ESCC tumorigenesis. Functionally, in vitro assay of gain- and loss-of-function of CDCA5 suggested that CDCA5 could promote ESCC cells proliferation, invasion, migration, apoptosis resistance and reduce chemosensitivity to cisplatin. Moreover, in vivo assay showed that silenced CDCA5 could inhibit tumor growth. Mechanistically, CDCA5 knockdown led to an arrest in G2/M phase and changes in the expression of factors that played fundamental roles in the cell cycle pathway. Interpretation CDCA5 contributed to ESCC progression and might serve as an attractive target for ESCC immunotherapy. Fund 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-003 and 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), Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX18_1487) and Jiangsu Province 333 Talents Project (No. BRA2017545).

Published
2019

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