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.
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