Trefoil Factors in GI Cancer Biology

胃肠道癌症生物学中的三叶因子

• 批准号: 7877987
• 负责人: STEVEN H. ITZKOWITZ
• 金额: $ 27.12万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7877987
• 关键词: Apoptosis; Attention; Biological Assay; Biological Process; Cancer Biology; Carcinoma; Cell physiology; Cell surface; Colon Carcinoma; Cysteine; Diagnostic Neoplasm Staging; Disulfide Linkage; Ectopic Expression; Elements; Epithelial; Epithelial Cells; Family; Gastric Adenoma; Gastroenterology; Gene Mutation; Goals; Growth; Healed; Homeostasis; Human; In Vitro; Knockout Mice; Loss of Heterozygosity; Malignant Neoplasms; Measurable; Mediating; Methylation; Molecular; Mutation; Pathway interactions; Peptides; Phenotype; Play; Property; Protein Family; Proteins; Rattus; Reporting; Role; Sequence Homologs; Signal Pathway; Signal Transduction; Site; Stomach; Structure; TFF1 gene; Time; Tissues; Trefoil Motif; Tumor Promoters; Tumor Suppressor Proteins; Tumor stage; Work; cancer cell; cell motility; gain of function; gastrointestinal; healing; in vivo; insight; interest; malignant phenotype; malignant stomach neoplasm; mutant; novel; outcome forecast; prevent; receptor; spasmolytic polypeptide; treatment strategy; trefoil factor; tumor

DESCRIPTION (provided by applicant): The trefoil factor family consists of 3 proteins: pS2/TFF1, spasmolytic polypeptide (SP/TFF2) and intestinal trefoil factor (ITF/TFF3), which play an essential role in the homeostasis of gastrointestinal (Gl) epithelial cell surfaces. The 3 TFFs share many structural and functional similarities. Functionally, each has been shown to promote epithelial healing by enhancing cell migration while preventing apoptosis. Structurally, these small proteins share an absolutely conserved motif (the "trefoil domain") that forms a three-loop structure by virtue of disulphide linkages between the six cysteine residues. Despite considerable structural homology, TFF1 and TFF3 appear to play different roles in cancer cells. TFF1 has tumor suppressor activity in the stomach: TFF1 knockout mice develop gastric adenomas and carcinomas, and in human gastric cancer, TFF1 loss occurs by gene mutations, loss of heterozygosity, and methylation silencing. We recently demonstrated that gastric cancer-associated mutations of TFF1 lose their tumor suppressor function and actually enhance cancer cell invasion by distinct signaling pathways. We also found that ectopic expression of TFF3 by human gastric cancers is associated with a poor prognosis, independent of tumor stage, and that transfecting TFF3 into TFF3(-) non-aggressive rat colon cancer cells converts them to a more aggressive phenotype. The overall goal of the present proposal is to better understand how the structurally related TFF1, mutant TFF1, and TFF3 peptides can have rather disparate functional effects on Gl cancer cells. Our hypothesis is that specific structural elements of TFF1 and TFF3 are responsible for the different functions of these peptides. The following Specific Aims will be explored: (1) Determine how TFF3 contributes to a more malignant phenotype in cancer cells; (2) Determine how TFF1 confers its tumor suppressor function; (3) Define key signaling pathways used by TFF1, mutant TFF1, and TFF3 during cancer cell invasion. The results of these studies could provide insights into novel treatment strategies for gastrointestinal malignancies.

描述（由申请人提供）：Trefoil因子家族由3种蛋白质组成：PS2/TFF1，痉挛性多肽（SP/TFF2）和肠Trefoil因子（ITF/TFF3），它们在胃肠道（GL）上皮细胞表面的体内稳态中起着至关重要的作用。这3个TFF具有许多结构和功能相似性。从功能上讲，已经证明每种都可以通过增强细胞迁移而在预防凋亡的同时通过增强细胞迁移来促进上皮愈合。从结构上讲，这些小蛋白具有绝对保守的基序（“ Trefoil结构域”），该基蛋白通过六个半胱氨酸残基之间的二硫化物连接形成三环结构。尽管结构相当大，但TFF1和TFF3似乎在癌细胞中起着不同的作用。 TFF1在胃中具有肿瘤抑制活性：TFF1敲除小鼠会发展出胃腺瘤和癌，在人类胃癌中，TFF1通过基因突变，杂合性丧失和甲基化沉默而发生。我们最近证明，与胃癌相关的TFF1突变失去了其肿瘤抑制功能，并通过不同的信号通路实际上增强了癌细胞侵袭。我们还发现，人类胃癌对TFF3的异位表达与预后不良有关，与肿瘤阶段无关，并且将TFF3转染到TFF3（ - ）非攻击性大鼠结肠癌细胞中，将它们转化为更具侵略性的表型。本提案的总体目标是更好地了解与结构相关的TFF1，突变体TFF1和TFF3肽如何对GL癌细胞产生相当不同的功能作用。我们的假设是，TFF1和TFF3的特定结构元素负责这些肽的不同功能。将探讨以下特定目标：（1）确定TFF3如何促进癌细胞中更恶性的表型； （2）确定TFF1如何赋予其肿瘤抑制功能； （3）定义癌细胞浸润期间TFF1，突变体TFF1和TFF3使用的关键信号通路。这些研究的结果可以为胃肠道恶性肿瘤的新型治疗策略提供见解。