Biology of Headpin (a novel serpin) in Oral Cancer

Headpin（一种新型丝氨酸蛋白酶抑制剂）在口腔癌中的生物学

• 批准号: 6438040
• 负责人: GARY L CLAYMAN
• 金额: $ 33.75万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-15 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6438040
• 关键词: DNA methylation; athymic mouse; biopsy; cell line; cell proliferation; disease /disorder model; gel mobility shift assay; gene expression; genetic regulatory element; human tissue; immunocytochemistry; loss of heterozygosity; messenger RNA; neoplasm /cancer genetics; neoplasm /cancer invasiveness; neoplastic cell; oral mucosa; oral pharyngeal neoplasm; protease inhibitor; protein sequence; serine proteinases; site directed mutagenesis; squamous cell carcinoma; transcription factor; transfection /expression vector; tumor suppressor genes

DESCRIPTION: Squamous cell carcinoma (SCC) of the oral cavity is a debilitating and often fatal disease afflicting approximately 30,000 individuals annually in the United States and is a major health problem worldwide. To better understand the molecular biology governing the invasive and aggressive behavior of these tumors, differences in gene expression have been studied between non-malignant oral mucosa and SCC derived from the oral cavity. Using differential display reverse transcription-based PCR, a novel serine proteinase inhibitor (serpin) was cloned, called headpin, that is down regulated in SCC biopsies and in 50 percent of established head and neck squamous cell carcinoma (HNSCC) tumor lines. Headpin was mapped to a serpin cluster on chromosome 18q21, which is a region that often exhibits loss of heterozygosity in head and neck cancers. Purified and functional recombinant human headpin (rHeadpin) has been generated and kinetic analysis indicates it is a bona fide suicide-inhibitor of both cathepsin L (catL) and cathepsin K (catK). Immunohistochemistry using a highly specific mAb raised against headpin has confirmed that the protein is abundant in non-malignant oral epithelium and lost or down-regulated in primary and metastatic SCC from the oral cavity. Based on the current body of literature linking expression of catL to progression of tumors, the implicit role of catK in degrading bone extracellular matrix, and the ability of headpin to inhibit both of these enzymes, suggest that loss of headpin protein expression from oral SCCs contributes to their aggressive clinical behavior. To test this hypothesis, the full target spectrum of proteinases inhibited by headpin will be assessed, while investigating the in vitro and in vivo consequences of headpin re-expression in tumors, define the mechanism(s) of headpin loss in tumor specimens, and analyze the predictive clinical SIGNIFICANCE of headpin expression in archival specimens from patients with oral SCC. Progress in this area could lead to development of new molecular based targets for the management of oral cancer.

描述：口腔鳞状细胞癌(SCC)是一种令人衰弱的疾病 而且往往是致命的疾病，每年困扰着大约30,000人 在美国，是世界范围内的一个主要健康问题。为了更好地理解 支配这些动物入侵和攻击行为的分子生物学 肿瘤，基因表达的差异已被研究在非恶性之间 口腔粘膜和来源于口腔的鳞癌。使用差异显示 逆转录基聚合酶链式反应--一种新的丝氨酸蛋白酶抑制剂(丝氨酸蛋白酶抑制剂) 被克隆，被称为Headpin，在鳞癌活检组织中下调，在50 已确诊的头颈部鳞状细胞癌(HNSCC)肿瘤的百分比 台词。Headpin被定位在染色体18q21上的一个serp簇上，这是一个 在头颈癌中经常表现出杂合性缺失的区域。 纯化的具有功能的重组人头夹(RHeadpin)已被生产出来 动力学分析表明，它是一种真正的自杀抑制剂 组织蛋白酶L(CATL)和组织蛋白酶K(CatK)。免疫组织化学使用高度的 针对头针的特异性单抗证实了该蛋白的丰度 在非恶性口腔上皮中，在原发和非恶性口腔上皮中表达缺失或下调 口腔转移的鳞状细胞癌。基于当前的文学主体 CATL的表达与肿瘤进展的关系--CatK的隐性作用 在降解骨细胞外基质中，以及头针抑制的能力 这两种酶都表明头针蛋白表达的丧失 口腔鳞状细胞是导致其攻击性临床行为的重要因素。为了测试这一点 假设，头针抑制的蛋白水解酶的全靶向谱将 在研究体外和体内后果的同时，进行评估 头针在肿瘤中的重新表达，确定头针丢失的机制(S) 肿瘤标本，并分析头针的临床预测意义 口腔鳞癌患者档案标本中的表达。这方面的进展 区域可能导致开发新的基于分子的靶标 口腔癌的治疗。