The A9 Antigen Associated with Aggressive Human Squamous Carcinoma Is Structurally and Functionally Similar to the Newly Defined Integrin α6β4
The A9 Antigen Associated with Aggressive Human Squamous Carcinoma Is Structurally and Functionally Similar to the Newly Defined Integrin α6β4
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发表时间：
1991-05
期刊：
影响因子：
11.2
通讯作者：
C. Waes;K. Kozarsky;A. Warren;L. Kidd;D. Paugh;Monica Lieber;T. Carey
中科院分区：
文献类型：
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作者：
C. Waes;K. Kozarsky;A. Warren;L. Kidd;D. Paugh;Monica Lieber;T. Carey
我们之前报道过，A9抗原（由单克隆抗体UM-A9定义）的表达改变是鳞状细胞癌（SCC）早期复发和进展的预测标志物。在正常鳞状细胞中，A9表达仅限于与体内基底膜和体外培养表面接触的部位，而侵袭性SCC表现出极性丧失和A9表达强度增加。通过免疫生物化学和细胞粘附测定分析A9抗原与已知参与细胞粘附的结构的潜在关系。UM-A9沉淀蛋白链复合物，使人联想到表征细胞外基质受体的整联蛋白家族的α和β异二聚体糖蛋白。使用UM-A9和对整联蛋白α和β链具有特异性的明确抗体从A9阳性细胞中分离蛋白质。UM-A9、抗α6和抗β4单克隆抗体（mAb）均以相当的电泳迁移率沉淀蛋白质。此外，UM-A9单抗可预先清除抗α6或抗β4单抗分离的SCC α6β4整合素复合物，但不能清除抗β1单抗分离的SCC α6β4整合素复合物。A9复合物链的等电点与α6和β4报告的等电点一致。通过UM-A9沉淀的三条多肽链（140、175和205 kDa）显示出彼此之间以及与mAb 439- 9 B沉淀的β4链之间的肽同源性。A9/α6亚基由125-和30-kDa链组成，并通过其肽图和等电点与β4和β1链区分。UM-A9与β4亚基共有的表位结合，因为在脉冲追踪分析中，β4物质在早期时间点沉淀，而在成熟复合物组装期间检测到α亚基合成。免疫沉淀和预清除实验表明，在SCC中，α6亚基主要与β4种类相关，而不与130 kDa的β1亚基相关。在细胞外基质蛋白的细胞粘附试验中，α6特异性GoH 3 mAb抑制SCC与层粘连蛋白的结合，表明α6β4可能在SCC中起层粘连蛋白受体的作用。这些数据和我们先前的观察结果表明，A9表达改变与SCC早期复发之间存在相关性，这首次证明α6β4整合素表达改变与人类鳞状细胞癌的临床行为相关。
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 α and β 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 α and β chains. UM-A9, anti-α6, and anti-β4 monoclonal antibodies (mAbs) all precipitated proteins with comparable electrophoretic mobilities. Furthermore, UM-A9 mAb precleared the SCC α6β4 integrin complex isolated with anti-α6 or anti-β4 mAbs but not that isolated by anti-β1 mAb. The isoelectric points of the A9 complex chains were consistent with those reported for α6 and β4. Three of the polypeptide chains (140, 175, and 205 kDa) precipitated by UM-A9 showed peptide homology to one another and to the β4 chain precipitated by mAb 439-9B. The A9/α6 subunit is composed of 125- and 30-kDa chains and was distinguished from β4 and β1 chains by its peptide map and isoelectric point. UM-A9 binds to an epitope common to the β4 subunits since in pulse-chase analysis the β4 species are precipitated at an early time point, whereas detection of α-subunit synthesis is detected during assembly of the mature complex. Immunoprecipitation and preclearing experiments demonstrated that in SCC the α6 subunit is associated primarily with the β4 species and not with the 130-kDa β1 subunit. In cell adhesion assays on extracellular matrix proteins, the α6-specific GoH3 mAb inhibited binding of SCC to laminin, suggesting that α6β4 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 α6β4 integrin is associated with the clinical behavior of human squamous cell carcinomas.