NOVEL SERPIN INHIBITOR OF ORAL SQUAMOUS CARCINOMA

口腔鳞状细胞癌的新型丝氨酸蛋白酶抑制剂

• 批准号: 6350593
• 负责人: JOHN J SAUK
• 金额: $ 25.37万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6350593
• 关键词: SDS polyacrylamide gel electrophoresis; athymic mouse; cell membrane; cell motility; collagen; disease /disorder model; endoplasmic reticulum; extracellular matrix; flow cytometry; glycoproteins; neoplasm /cancer invasiveness; neoplastic cell; protease inhibitor; protein structure function; serine proteinases; site directed mutagenesis; squamous cell carcinoma; stress proteins

Most recently, a collagen-binding glycoprotein, Hsp47 (colligin), has been shown to be a potential marker for tumor malignancy (4,5). However, the mechanism for the malignancy suppresser effects of Hsp47 have to date not been investigated. The hypothesis upon which this proposal is based is that Hsp47 is a 47-kD collagen-binding endoplasmic reticulum [ER] glycoprotein that is limited to cells which can produce collagens. However, Hsp47 can elude its COOH-terminus retention mechanism and be expressed on the surface of squamous carcinoma cells [SCCs]. The presence of Hsp47 on the cell surface of SCCs inhibits cell motility and thereby impedes SCC cell invasion into extracellular matrices. The mechanism for inhibiting tumor cell invasion resides either in: a) Hsp47's properties as an inhibitory serpin protein; b) the cell membrane complexes of Hsp47/TM4Sfproteins/? that affect membrane signaling; or c) as an autocrine inhibitor of tumor cell motility. This hypothesis will be tested through the accomplishment of four specific aims. These are as follows: 1. Verify that Hsp47, which is manifest on the cell surface of human SCCs, correlates with the ability of SCCs to invade extracellular matrices using in vitro assays and an in vivo athymic nude mouse model. 2. Determine whether Hsp47 expressed on the surface of human SCCs and/or presence within the incubation medium impedes SCC invasion by acting as an inhibitory serpin protein. 3. Determine other mechanisms by which Hsp47 may exert an effect on tumor cell motility and invasion.

最近，一种胶原结合糖蛋白，Hsp 47（colligin）， 已被证明是恶性肿瘤的潜在标志物（4，5）。 然而，Hsp 47的恶性肿瘤抑制作用的机制 至今没有被调查过。 这一假设所依据的是 Hsp 47是一个47-kD的胶原结合内质网， 内质网[ER]糖蛋白，仅限于可产生 胶原蛋白 然而，热休克蛋白47可以逃避其羧基端的保留， 表达于鳞状细胞癌细胞表面 [SCC]。 SCC细胞表面Hsp 47的存在抑制了SCC细胞的增殖， 运动性，从而阻碍SCC细胞侵入细胞外 矩阵 抑制肿瘤细胞侵袭的机制在于 在以下两个方面：a）Hsp 47作为抑制性丝氨酸蛋白酶抑制剂蛋白的性质; B）Hsp 47作为抑制性丝氨酸蛋白酶抑制剂蛋白的性质。 Hsp 47/TM 4Sf蛋白/？影响细胞膜 信号传导;或c）作为肿瘤细胞运动性的自分泌抑制剂。 这 假设将通过完成四个具体的测试， 目标。 具体如下：1. 验证Hsp 47，这是明显的 在人SCC的细胞表面，与SCC的能力相关， 使用体外测定和体内测定来侵入细胞外基质， 无胸腺裸鼠模型 2. 确定Hsp 47是否表达在 人SCC表面和/或存在于孵育培养基中 通过作为抑制性丝氨酸蛋白酶抑制剂蛋白阻止SCC侵袭。 3. 确定Hsp 47可能对肿瘤产生影响的其他机制 细胞运动和侵袭。