NOVEL SERPIN INHIBITOR OF ORAL SQUAMOUS CARCINOMA

最近，一种与胶原结合的糖蛋白Hsp47(胶原素)已经 已被证明是一种潜在的肿瘤恶性标志物(4，5)。 然而，Hsp47抑制肿瘤作用的机制 至今还没有被调查过。这一假设的基础是 推测Hsp47是一种47kD的胶原结合内质 网状[内质网]糖蛋白，仅限于能产生 胶原蛋白。然而，Hsp47可以逃脱其COOH末端保留 鳞状癌细胞的作用机制及其在细胞表面的表达 [SCCS]。热休克蛋白47在细胞表面的存在对细胞的抑制作用 移动性，从而阻止鳞状细胞癌细胞侵袭细胞外 矩阵。抑制肿瘤细胞侵袭的机制在于 A)Hsp47‘S具有抑制性丝氨酸蛋白的特性；b) Hsp47/TM4SfProteins/？影响细胞膜的物质 信号传递；或c)作为肿瘤细胞运动的自分泌抑制物。这 假设将通过四个具体的完成来检验 目标。它们如下：1.验证Hsp47，这是一个清单 在人SCCs细胞表面，与SCCs的能力相关 用体外实验和体内实验侵袭细胞外基质 裸鼠裸鼠模型。2.确定Hsp47是否在 人干细胞的表面和/或存在于孵育液中 通过抑制丝氨酸蛋白的作用来阻止鳞状细胞的侵袭。3. 确定Hsp47可能对肿瘤产生影响的其他机制 细胞的运动和侵袭。

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.