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The A9 Antigen Associated with Aggressive Human Squamous Carcinoma Is Structurally and Functionally Similar to the Newly Defined Integrin ⁶ß₄¹

Cancer Research Laboratory, Department of Otolaryngology/Head and Neck Surgery [C. V. W., A. B. W., L. K., D. P., T. E. C.], Section of Rheumatology, Department of Internal Medicine [K. F. K.], and Section of Urology, Department of Surgery [M. L.], University of Michigan, Ann Arbor, Michigan 48109

We previously reported that altered expression of the A9 antigen (defined by monoclonal antibody UM-A9) is a predictive marker of early recurrence and progression of squamous cell carcinoma (SCC). In normal squamous cells A9 expression is limited to the site of contact with the basement membrane in vivo and the culture surface in vitro, whereas aggressive SCCs exhibit loss of polarity and increased intensity of A9 expression. The potential relationship of the A9 antigen to structures known to be involved in cell adhesion was analyzed by immunobiochemical and cell adhesion assay. UM-A9 precipitates a complex of protein chains reminiscent of the and ß heterodimer glycoproteins that characterize the integrin family of extracellular matrix receptors. Proteins were isolated from A9-positive cells using UM-A9 and well-defined antibodies specific for integrin and ß chains. UM-A9, anti-⁶, and anti-ß₄ monoclonal antibodies (mAbs) all precipitated proteins with comparable electrophoretic mobilities. Furthermore, UM-A9 mAb precleared the SCC ⁶ß₄ integrin complex isolated with anti-⁶ or anti-ß₄ mAbs but not that isolated by anti-ß₁ mAb. The isoelectric points of the A9 complex chains were consistent with those reported for ⁶ and ß₄. Three of the polypeptide chains (140, 175, and 205 kDa) precipitated by UM-A9 showed peptide homology to one another and to the ß₄ chain precipitated by mAb 439-9B. The A9/⁶ subunit is composed of 125- and 30-kDa chains and was distinguished from ß₄ and ß₁ chains by its peptide map and isoelectric point. UM-A9 binds to an epitope common to the ß₄ subunits since in pulse-chase analysis the ß₄ species are precipitated at an early time point, whereas detection of -subunit synthesis is detected during assembly of the mature complex. Immunoprecipitation and preclearing experiments demonstrated that in SCC the ⁶ subunit is associated primarily with the ß₄ species and not with the 130-kDa ß₁ subunit. In cell adhesion assays on extracellular matrix proteins, the ⁶-specific GoH3 mAb inhibited binding of SCC to laminin, suggesting that ⁶ß₄ may function as a laminin receptor in SCC. These data and our prior observations showing an association between altered A9 expression and early recurrence in SCC provide the first evidence that altered expression of ⁶ß₄ integrin is associated with the clinical behavior of human squamous cell carcinomas.

¹ This work was supported by USPHS-National Cancer Institute Grant CA35929 awarded to T. E. C. C. V. W. was supported by NIH USPHS Grant T32 HD 07274 and an American Academy of Otolaryngology Norwich-Eaton Resident Research grant. K. F. K. was supported by NIH National Research Service Award Grant 1 F32 ARO 8060-01.

² To whom requests for reprints should be addressed, at Cancer Research Laboratory, 6020 KHRI, Box 0506, 1301 East Ann Street, Ann Arbor, MI 48109.

Received 10/16/90. Accepted 2/11/91.

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