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Causal genetic regulation of DNA replication on immune microenvironment in colorectal tumorigenesis: Evidenced by an integrated approach of trans-omics and GWAS

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The Journal of Biomedical Research 2024年第1期38卷 37-50页

作者： Sumeng Wang Silu Chen Huiqin Li Shuai Ben Tingyu Zhao Rui Zheng Meilin Wang Dongying Gu Lingxiang Liu Department of Oncology the First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu 210029China Department of Environmental Genomics Jiangsu Key Laboratory of Cancer BiomarkersPrevention and TreatmentCollaborative Innovation Center for Cancer Personalized MedicineNanjing Medical UniversityNanjingJiangsu 211166China Department of Genetic Toxicology the Key Laboratory of Modern Toxicology of Ministry of EducationCenter for Global HealthSchool of Public HealthNanjing Medical UniversityNanjingJiangsu 211166China Department of Biostatistics Center for Global HealthSchool of Public HealthNanjing Medical UniversityNanjingJiangsu 211166China Department of Oncology Nanjing First HospitalNanjing Medical UniversityNanjingJiangsu 210006China.

The interplay between DNA replication stress and immune microenvironment alterations is known to play a crucial role in colorectal tumorigenesis,but a comprehensive understanding of their association with and relevant biomarkers involved in colorectal tumorigenesis is *** address this gap,we conducted a study aiming to investigate this association and identify relevant *** analyzed transcriptomic and proteomic profiles of 904 colorectal tumor tissues and 342 normal tissues to examine pathway enrichment,biological activity,and the immune ***,we evaluated genetic effects of single variants and genes on colorectal cancer susceptibility using data from genome-wide association studies(GWASs)involving both East Asian(7062 cases and 195745 controls)and European(24476 cases and 23073 controls)*** employed mediation analysis to infer the causal pathway,and applied multiplex immunofluorescence to visualize colocalized biomarkers in colorectal tumors and immune *** findings revealed that both DNA replication activity and the flap structure-specific endonuclease 1(FEN1)gene were significantly enriched in colorectal tumor tissues,compared with normal ***,a genetic variant rs4246215 G>T in FEN1 was associated with a decreased risk of colorectal cancer(odds ratio=0.94,95%confidence interval:0.90–0.97,P_(meta)=4.70×10^(-9)).Importantly,we identified basophils and eosinophils that both exhibited a significantly decreased infiltration in colorectal tumors,and were regulated by rs4246215 through causal pathways involving both FEN1 and DNA *** conclusion,this trans-omics incorporating GWAS data provides insights into a plausible pathway connecting DNA replication and immunity,expanding biological knowledge of colorectal tumorigenesis and therapeutic targets.

关键词： trans-omics DNA replication tumor immune microenvironment causal mediation colorectal tumorigenesis

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Oncogenic role of clusterin overexpression in multistage colorectal tumorigenesis and progression

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World Journal of Gastroenterology 2005年第21期11卷 3285-3289页

作者： DanXie JonathanS.T.Sham Wei-FenZeng Li-HongChe MengZhang Hui-XiWu Han-LiangLin Jian-MingWen SzeHangLau LiangHu Xin-YuanGuan DepartmentofPathology ZhongShanMedicalCollegeSunYat-SenUniversityGuangzhou510089GuangdongProvinceChina DepartmentofClinicalOncology TheUniversityofHongKongHongKongChina

AIM: To investigate the expression pattern of clusterin in colorectal adenoma-carcinoma-metastasis series,and to explore the potential role of clusterin in multistage colorectal tumorigenesis and progression. METHODS: A colorectal carcinoma (CRC)-tissue microarray (TMA), which contained 85 advanced CRCs including 43 cases of Dukes B,21 of Dukes C and 21 of Dukes D tumors, were used for assessing the expression of clusterin (clone 41D) and tumor cell apoptotic index (AI) by immunohist-ochemistry and TUNEL assay,*** the potential correlation of dusterin expression with the patient's clinical-pathological features were also examined. RESULTS: The positive staining of clusterin in different colorectal tissues was primarily a cytoplasmic pattern. Cytoplasmic overexpression of clusterin was detected in none of the normal colorectal mucosa, 17% of the adenomas, 46% of the primary CRCs, and 57% of the CRC metastatic lesions. In addition, a significant positive correlation between overexpression of clusterin and advanced clinical (Dukes) stage was observed (Ptumorigenesis and/or progression of CRCs. The anti-apoptotic function of cytoplasmic dusterin may be responsible, at least in part, for the development and biologically aggressive behavior of CRC.

关键词： Clusterin colorectal tumorigenesis

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