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（由申请人提供）结肠癌（CRC），包括结肠和招募癌症的生物标志物有用的有用的诊断和靶向偏好，对肿瘤相关。 saryltn（Neuac 2-6galnac 1-Ser/thr）通常出现在早期的阶段，并且预后不良和肿瘤转移。 T合酶，正常核1-o-glycans Biosynsisis所需的，因为它的折叠不正确，因为它是由特异性分子伴侣COSMC表达的，这是由X连接的（XQ24）编码的。线，在COSMC中获得的突变，其中包括编码区域中的点突变，杂合子丧失和与T-synthase活性丧失和TN/STN的表达相关的IS启动子C的高甲基化。（gi）小鼠中COSMC的上皮细胞特异性损失在小型和大型的情况下表达tn/stn抗原。 T合酶和/或C3GNT将在人类原发性结肠肿瘤中进行4个特定目标。 S）通过ID诱导COSMC的改变，并分析其他与糖基因的基因4：开发的单克隆抗体，以高特异性和对TN或STN触觉的亲和力分析转录水平。 CRC的GNOSIS和治疗将定义CRC中TN和STN表达的分子基础及其作为人类结肠癌的新型聚糖生物标志物的潜力。