Kikkawa Yamato, Sudo Ryo, Kon Junko, Mizuguchi Toru, Nomizu Motoyoshi, Hirata Koichi, Mitaka Toshihiro
Laboratory of Clinical Biochemistry, Tokyo University of Pharmacy and Life Sciences, Hachioji 192-0392, Japan.
Exp Cell Res. 2008 Aug 15;314(14):2579-90. doi: 10.1016/j.yexcr.2008.05.021. Epub 2008 Jun 7.
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 alpha 5. Little is known, however, about the expression and function of laminins containing the alpha 5 chain in human hepatocellular carcinoma (HCC). Here, using a specific antibody, we examined the expression of laminin alpha 5 in normal liver and in HCCs. In normal liver, although laminin alpha 5 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 alpha 5 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 alpha 5 heterotrimerized with beta and gamma chains and was secreted into the culture media. To attempt to understand the function of laminins containing alpha 5, the expression of its receptors in HCCs was also determined. In this regard, alpha 3 beta 1/alpha 6 beta 1 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 alpha 5 chain, more so than did primary hepatocytes. In addition to alpha 3 beta 1/alpha 6 beta 1 integrins and Lu/B-CAM, laminin alpha 5 was recognized by integrin alpha 1 beta 1, which also was expressed in HCC cells. These results suggest that laminins containing alpha 5 serve as functional substrates regulating progression of HCC.
层粘连蛋白是由五条α链、三条β链和三条γ链形成的多种α/β/γ异源三聚体；它们是所有基底膜（BLs）的主要成分。层粘连蛋白α5因其广泛的表达模式以及在发育过程中的重要性而备受关注。然而，关于含α5链的层粘连蛋白在人类肝细胞癌（HCC）中的表达和功能却知之甚少。在此，我们使用一种特异性抗体检测了层粘连蛋白α5在正常肝脏和肝癌中的表达。在正常肝脏中，尽管在血管和胆管下方的肝基底膜中观察到了层粘连蛋白α5，但在可能是肝癌起源的实质组织中却没有。另一方面，在所有检测的肝癌中均观察到了层粘连蛋白α5的沉积，无论肿瘤分级如何。在高分化肝癌中，它沿着肿瘤小梁定位。在低分化肝癌中，它存在于周围的肿瘤结节中。在肝癌细胞系中，层粘连蛋白α5与β链和γ链异源三聚化并分泌到培养基中。为了试图了解含α5的层粘连蛋白的功能，我们还测定了其受体在肝癌中的表达。在这方面，α3β1/α6β1整合素和路德维希/基底细胞黏附分子（Lu/B-CAM）在肝癌细胞中表达。体外研究表明，肝癌细胞比原代肝细胞更容易附着于含α5链的层粘连蛋白。除了α3β1/α6β1整合素和Lu/B-CAM外，层粘连蛋白α5还被整合素α1β1识别，而整合素α1β1也在肝癌细胞中表达。这些结果表明，含α5的层粘连蛋白作为功能性底物调节肝癌的进展。
