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: 6150537
• 负责人: JOHN J SAUK
• 金额: $ 25.1万
• 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/6150537
• 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，一种胶原蛋白结合糖蛋白 Hsp47（colligin） 已被证明是肿瘤恶性肿瘤的潜在标志物 (4,5)。 然而，Hsp47 的恶性抑制作用的机制 迄今为止尚未受到调查。 这个假设是基于 该提议的基础是 Hsp47 是一种 47-kD 胶原蛋白结合内质 网状[ER]糖蛋白，仅限于可以产生的细胞 胶原蛋白。 然而，Hsp47 可以逃避其 COOH 末端的保留 机制并在鳞状癌细胞表面表达 [SCC]。 SCC 细胞表面 Hsp47 的存在抑制细胞 运动性，从而阻止 SCC 细胞侵入细胞外 矩阵。 抑制肿瘤细胞侵袭的机制在于 a) Hsp47 作为抑制性丝氨酸蛋白酶抑制剂的特性； b) 的 Hsp47/TM4Sf蛋白/？的细胞膜复合物影响膜的 信号发送；或c)作为肿瘤细胞运动的自分泌抑制剂。 这 假设将通过四个具体的完成来检验 目标。 具体如下： 1. 验证 Hsp47，这是明显的 位于人类 SCC 的细胞表面，与 SCC 的能力相关 使用体外测定和体内测定侵入细胞外基质 无胸腺裸鼠模型。 2. 判断Hsp47是否表达于 人类鳞状细胞表面和/或培养介质中的存在 通过充当抑制性丝氨酸蛋白酶抑制剂蛋白来阻止鳞状细胞癌的侵袭。 3. 确定 Hsp47 对肿瘤发挥作用的其他机制 细胞运动和侵袭。