The Tumor Antigens Tn and SialylTn in Human Colorectal Carcinoma

人结直肠癌中的肿瘤抗原 Tn 和唾液酸 Tn

基本信息

批准号：
9070397
负责人：
RICHARD D CUMMINGS
金额：
$ 37.11万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-23 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9070397
关键词：
Affinity Animal Organ Antibodies Antigens Area Biological Markers Cancer Etiology Carbohydrates Carcinoma Cell surface Cessation of life Code Colon Colon Carcinoma Colonic Neoplasms Detection Development Diagnosis Disease Early Diagnosis Embryo Endoplasmic Reticulum Enzymes Epithelial Cells Exhibits Exons Future Gastrointestinal tract structure Gene Deletion Gene Expression Genes Genetic Glycopeptides Glycoproteins Golgi Apparatus Human Hypermethylation Immunohistochemistry Knockout Mice Large Intestine Large Intestine Carcinoma Lectin Link Loss of Heterozygosity Malignant Epithelial Cell Membrane Glycoproteins Methods Molecular Molecular Chaperones Monoclonal Antibodies Mucins Mus Mutation N-Acetylglucosaminyltransferases N-acetylglucopyranosylamine Neoplasm Metastasis Normal Cell O-Glycans Biosynthesis Pathway Patients Point Mutation Polysaccharides Predisposition Proteins Rectal Cancer Sampling Serum Small Intestines Specificity Staging Structure Surface Technology Time Tn antigen Transcript Tumor Antigens Tumor Cell Line Tumor-Associated Carbohydrate Antigens Western World Xq24 animal tissue base carcinogenesis colon carcinogenesis colon tumorigenesis glycosylation glycosyltransferase intestinal epithelium loss of function neoplastic cell novel novel marker outcome forecast prevent promoter targeted treatment therapeutic target tumor

项目摘要

DESCRIPTION (provided by applicant) Colorectal carcinoma (CRC), including colon and rectal cancer, is a leading cause of cancer deaths in the Western world but reliable biomarkers useful for early diagnosis and targeted therapy of this disease are lacking. The tumor-associated carbohydrate antigens (TACAs) termed Tn (GalNAc�1-Ser/Thr) and sialylTn (STn) (NeuAc�2-6GalNAc�1-Ser/Thr) often appear at an early stage of colon carcinogenesis, and are associated with poor prognosis and tumor metastasis. However, the genetic basis for Tn/STn antigen expression is unclear. We recently found that expression of the Tn/STn antigens can arise from loss-of-function of T-synthase, required for normal core 1 O-glycans biosynthesis, due to its incorrect folding as a result of compromised expression of its specific molecular chaperone Cosmc, which is encoded by an X-linked (Xq24) gene. We showed that in human tumors and tumor cell lines, acquired mutations in Cosmc, which include point mutations in the coding region, deletion of the gene, loss-of-heterozygosity, and hypermethylation of its promoter, can result in a dysfunctional Cosmc associated with loss of T-synthase activity and expression of Tn/STn. Our preliminary studies now show that gastrointestinal (GI) tract epithelial cell-specific loss of Cosmc in mice causes Tn/STn antigen expression in the small and large intestine. We hypothesize that Tn and STn tumor antigens in CRC are novel glycan biomarkers for human colon cancer and arise from alterations in Cosmc or altered expression of T-synthase and/or C3GnT. We will explore this hypothesis in 4 specific aims. Aim 1: define the expression of Tn/STn and other TACAs in human primary colon tumors; Aim 2: compare glycan and glycopeptide profiles of colorectal carcinoma cells to normal cells; Aim 3: define the molecular mechanism(s) for Tn/STn expression in human primary colon tumors by identifying the alterations in Cosmc, as well as analyze transcript levels for other glycomics-relevant genes; and Aim 4: develop well- defined monoclonal antibodies that exhibit both high specificity and affinity to Tn or STn antigens, which could be used in both diagnosis and treatment of CRC. This project will define the molecular basis for Tn and STn expression in CRC and their potential as novel glycan biomarkers for human colon cancer.

描述（由适用）描述（包括结肠癌和直肠癌）包括结肠直肠癌（CRC）是西方世界癌症死亡的主要原因，但可靠的生物标志物可用于早期诊断和对该疾病的靶向治疗有用。称为TN的肿瘤相关的碳水化合物抗原（TACAS）（galnac≥1-Ser/Thr）和siAllyltn（STN）（Neuac≥2-6GalNAC≥1-Ser/Thr）通常出现在结肠癌的早期阶段，并且与不良的预后症和肿瘤转移相关。但是，TN/STN抗原的遗传基础尚不清楚。我们最近发现，TN/STN抗原的表达可能是由于其特异性分子伴侣COSMC的表达不正确的折叠，因此TN/STN抗原的表达是TN/STN抗原的表达，TN/STN抗原的表达是正常核心1 O-Glycans Biosynthess所必需的，该折叠的折叠不正确，该cosmc被X-linked（XQ24）Gene编码。我们表明，在人类肿瘤和肿瘤细胞系中，在COSMC中获得的突变，其中包括编码区域中的点突变，基因缺失，杂合性丧失以及其启动子的过度甲基化，可能会导致与T-Synthase活性和TN/STN的表达相关的功能障碍COSMC。我们的初步研究现在表明，小鼠胃肠道（GI）上皮细胞特异性损失会导致小肠和大肠中TN/STN抗原表达。我们假设CRC中的TN和STN肿瘤抗原是人类结肠癌的新型聚糖生物标志物，是由COSMC的改变或T合酶和/或C3GNT的改变而产生的。我们将以4个特定目标探讨这一假设。 AIM 1：定义人类原发性结肠肿瘤中TN/STN和其他TACA的表达；目标2：比较结直肠癌细胞的糖和糖肽谱与正常细胞； AIM 3：通过鉴定COSMC的改变，并分析其他与Glycos相关的基因的转录水平，定义了人原发性结肠肿瘤中TN/STN表达的分子机制；目标4：开发明确定义的单克隆抗体，这些抗体既具有较高的特异性和对TN或STN抗原的亲和力，又可以用于CRC的诊断和治疗。项目将定义CRC中TN和STN表达的分子基础，并将其作为人类结肠癌的新型聚糖生物标志物的潜力。