Fornaro M, Manzotti M, Tallini G, Slear A E, Bosari S, Ruoslahti E, Languino L R
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Am J Pathol. 1998 Oct;153(4):1079-87. doi: 10.1016/s0002-9440(10)65652-0.
The expression of the beta1C integrin, an alternatively spliced variant of the beta1 subunit, was investigated in human adult and fetal tissues. In the adult, beta1C immunoreactivity was found in nonproliferative, differentiated simple, and/or pseudostratified epithelia in prostate glands and liver bile ducts. In contrast, beta1C was undetectable in stratified squamous epithelium of the epidermis and/or in hepatocytes. Luminal prostate epithelial cells expressed beta1C in vivo and in vitro, but no beta1C was seen in basal cells, which are proliferating cells. Fetal prostate expressed beta1C in differentiated glands that had a defined lumen, but not in budding glands, indicating that beta1C is a marker of prostate epithelium differentiation. The beta1C and the common beta1A variants are differentially distributed: beta1A was found in luminal and basal epithelial as well as in stromal cells in the prostate. In the liver, beta1C and beta1A were coexpressed in biliary epithelium, whereas vascular cells expressed only beta1A. Because we found beta1C in nonproliferative and differentiated epithelium, we investigated whether beta1C could have a causal role in inhibiting epithelial cell proliferation. The results showed that exogenous expression of a beta1C, but not of a beta1A, cytoplasmic domain chimeric construct, completely inhibited thymidine incorporation in response to serum by prostate cancer epithelial cells. Consistent with these in vitro results, beta1C appeared to be downregulated in prostate glands that exhibit regenerative features in benign hyperplastic epithelium. These data show that the presence of beta1C integrins in epithelial cells correlates with a nonproliferative, differentiated phenotype and is growth inhibitory to prostate epithelial cells in vitro. These findings indicate a novel pathophysiological role for this integrin variant in epithelial cell proliferation.
研究了β1亚基的一种选择性剪接变体β1C整合素在人类成人及胎儿组织中的表达情况。在成人中，β1C免疫反应性见于前列腺和肝胆管的非增殖性、分化的单层和/或假复层上皮。相比之下，在表皮的复层鳞状上皮和/或肝细胞中未检测到β1C。前列腺管腔上皮细胞在体内和体外均表达β1C，但在增殖的基底细胞中未见β1C。胎儿前列腺在有明确管腔的分化腺体中表达β1C，但在芽生腺体中不表达，这表明β1C是前列腺上皮分化的标志物。β1C和常见的β1A变体分布不同：β1A见于前列腺的管腔和基底上皮以及基质细胞。在肝脏中，β1C和β1A在胆管上皮中共表达，而血管细胞仅表达β1A。由于我们在非增殖性和分化上皮中发现了β1C，我们研究了β1C是否在抑制上皮细胞增殖中起因果作用。结果表明，β1C胞质结构域嵌合构建体而非β1A的外源表达完全抑制了前列腺癌上皮细胞对血清刺激的胸苷掺入。与这些体外结果一致，在良性增生上皮中表现出再生特征的前列腺腺体中，β1C似乎下调。这些数据表明，上皮细胞中β1C整合素的存在与非增殖性、分化表型相关，并且在体外对前列腺上皮细胞具有生长抑制作用。这些发现表明这种整合素变体在上皮细胞增殖中具有新的病理生理作用。
