Role of laminin alpha5 and its receptors in fibrotic liver and hepatocellular carcinoma

层粘连蛋白是由五条α、三条β和三条γ链形成的一组不同的α/β/γ异源三聚体;它们是所有基底层（BL）的主要组分。层粘连蛋白α 5是一种层粘连蛋白链，由于其广泛的表达模式和在发育过程中的重要性而引起了特别的兴趣。然而，关于含有α 5链的层粘连蛋白在人肝细胞癌（HCC）中的表达和功能知之甚少。在此，我们使用特异性抗体检测了层粘连蛋白α 5在正常肝脏和HCC中的表达。在正常肝脏中，虽然层粘连蛋白α 5在血管和胆管下的肝BL中观察到，但在肝实质中不存在，这可能是HCC的起源。另一方面，在所有检测的HCC中均观察到层粘连蛋白α 5沉积，而与肿瘤分级无关。在分化良好的肝癌中，它沿着肿瘤的小梁定位。在低分化肝癌中，它存在于周围的肿瘤结节中。在HCC细胞系中，层粘连蛋白α 5与β和γ链异源三聚化并分泌到培养基中。为了试图理解含有α 5的层粘连蛋白的功能，还测定了其受体在HCC中的表达。在这方面，α 3 β 1/α 6 β 1整合素和Lutheran/基底细胞粘附分子（Lu/B-CAM）在HCC细胞中表达。体外研究表明，肝癌细胞容易附着到含有α 5链的层粘连蛋白，比原代肝细胞更容易。除了α 3 β 1/α 6 β 1整联蛋白和Lu/B-CAM外，层粘连蛋白α 5还被整联蛋白α 1识别，其也在HCC细胞中表达。这些结果表明，含有α 5的层粘连蛋白作为功能底物调节HCC的进展。

Laminins are a diverse group of alpha/beta/gamma heterotrimers formed from five alpha, three beta and three gamma chains ; they are major components of all basal laminae (BLs). One laminin chain that has garnered particular interest due to its widespread expression pattern and importance during development is laminin alpha5. Little is known, however, about the expression and function of laminins containing the alpha5 chain in human hepatocellular carcinoma (HCC). Here, using a specific antibody, we examined the expression of laminin alpha5 in normal liver and in HCCs. In normal liver, although laminin alpha5 was observed in hepatic BLs underlying blood vessels and bile ducts, it was absent from the parenchyma, which may be the origin of HCC. On the other hand, laminin alpha5 deposition was observed throughout all HCCs tested, regardless of tumor grade. In well differentiated HCCs, it localized along the trabecules of the tumor. In poorly-differentiated HCCs, it was present in surrounding tumor nodules. In HCC cell lines, laminin alpha5 heterotrimerized with beta and gamma chains and was secreted into the culture media. To attempt to understand the function of laminins containing alpha5, the expression of its receptors in HCCs was also determined. In this regard, alpha3betal/alpha6betal integrins and Lutheran/basal cell adhesion molecule (Lu/B-CAM) were expressed in HCC cells. In vitro studies showed that HCC cells readily attached to laminin containing the alpha5 chain, more so than did primary hepatocytes. In addition to alpha3betal/alpha6betal integrins and Lu/B-CAM, laminin alpha5 was recognized by integrin alphalbetal, which also was expressed in HCC cells. These results suggest that laminins containing alpha5 serve as functional substrates regulating progression of HCC.