Laminin-5 stimulates hepatocellular carcinoma growth through a different function of α6β4 and α3β1 integrins
Laminin-5 stimulates hepatocellular carcinoma growth through a different function of α6β4 and α3β1 integrins
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DOI：
10.1002/hep.21936
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发表时间：
2007-12-01
期刊：
影响因子：
13.5
通讯作者：
Giannelli, Gianluigi
中科院分区：
文献类型：
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作者：
Bergamini, Carlo;Sgarra, Concetta;Giannelli, Gianluigi
肝细胞癌的生长严重影响预后。Ki-67是一种已知的细胞增殖标志物，是HCC的不良预后因素。生长因子如表皮生长因子（EGF）诱导HCC细胞增殖，但不能解释HCC生长的巨大异质性。层粘连蛋白-5 （Ln-5）是存在于HCC组织微环境中的细胞外基质蛋白（ECM）。Ln-5的两个主要受体，整合素α 3 β 1和α 6 β 4，在HCC细胞的细胞表面表达。本研究的目的是探讨肝癌生长的另一种机制，即Ln-5通过α 3 β 1和α 6 β 4促进肝癌细胞增殖。通过显微解剖组织的双重免疫荧光染色和实时PCR检测，含有Ln-5的HCC组织显示出更大的直径和更多的Ki-67阳性细胞，Ki-67是一种众所周知的增殖指数。在体外，Ln-5，而不是胶原1、胶原IV或纤维连接蛋白，通过β 4整合素磷酸化导致的Erk磷酸化，像EGF一样诱导增殖。然而，尽管β 4整合素和Erk1/2被激活，两种HCC细胞系在Ln-5的存在下不增殖。在α 3整合素转染后，在Ln-5存在的情况下，其中一种HCC细胞系获得了增殖活性，而另一种增殖性HCC细胞系由于a3整合素的缺失而失去了增殖活性。结论：我们的研究提示了肝癌生长的新机制，即Ln-5通过α 6 β 4和α 3 β 1的不同功能刺激增殖。
Hepatocellular carcinoma (HCC) growth severely affects prognosis. Ki-67, a known marker of cell proliferation, is a negative prognostic factor in HCC. Growth factors such as the epidermal growth factor (EGF) induce HCC cell proliferation but do not explain the great heterogeneity of HCC growth. Laminin-5 (Ln-5) is an extracellular matrix protein (ECM) present in the tissue microenvironment of HCC. The two main receptors for Ln-5, integrins alpha 3 beta 1 and alpha 6 beta 4, are expressed on the cell surface of HCC cells. The aim of this study is to investigate an alternative mechanism of HCC growth whereby Ln-5 promotes HCC cell proliferation through alpha 3 beta 1 and alpha 6 beta 4. HCC tissues containing Ln-5 display a larger diameter and higher number of positive cells for Ki-67, a well known proliferative index, as determined by double immunofluorescence staining and real-time PCR on microdissected tissues. In vitro, Ln-5, but not collagen 1, collagen IV or fibronectin, induces proliferation as much as EGF does, via Erk phosphorylation as a consequence of beta 4 integrin phosphorylation. However, the two HCC cell lines do not proliferate in presence of Ln-5 despite beta 4 integrin and Erk1/2 activation. After transfection with alpha 3 integrin, in the presence of Ln-5 one of these HCC cell lines acquires a proliferative activity whereas one of the proliferative HCC cell lines, knocked-down for a3 integrin, loses its proliferative activity. Conclusions: Our study suggests a new mechanism of HCC growth whereby Ln-5 stimulates proliferation via a different function of alpha 6 beta 4 and alpha 3 beta 1.