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: 6621981
• 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/6621981
• 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）是一种使人衰弱的疾病， 每年约有30，000人患有这种疾病， 这是美国的一个重大健康问题。更好地了解 控制这些入侵和攻击行为的分子生物学 基因表达的差异已经在非恶性肿瘤之间进行了研究。 口腔黏膜和口腔来源的SCC。使用差分显示 一种新的丝氨酸蛋白酶抑制剂（serpin） 被克隆，称为headpin，在SCC活检中下调，在50 已确诊的头颈部鳞状细胞癌（HNSCC）肿瘤百分比 线头蛋白定位于染色体18q21上的一个丝氨酸蛋白酶抑制剂簇，这是一个与丝氨酸蛋白酶抑制剂簇相关的基因。 在头颈癌中经常表现出杂合性丢失的区域。 纯化和功能性重组人头蛋白（rHeadpin）已产生 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 针对headpin的特异性mAb已经证实该蛋白质是丰富的 在非恶性口腔上皮中， 口腔转移性鳞状细胞癌根据目前的文献资料， 将catL的表达与肿瘤的进展联系起来，catK的隐含作用 在降解骨细胞外基质中， 这两种酶，表明头部蛋白表达的损失， 口腔SCC有助于其攻击性临床行为。为了验证这一 假设，头钉抑制的蛋白酶的全部靶谱将 在研究体外和体内结果的同时， 肿瘤中headpin的重新表达，定义了肿瘤中headpin丢失的机制。 肿瘤标本，并分析头钉的预测临床意义 口腔鳞状细胞癌患者的存档标本中的表达。的进展 这一领域可能导致开发新的基于分子的靶点， 口腔癌的治疗