Claudin-1 Acts through c-Abl-Protein Kinase Cδ (PKCδ) Signaling and Has a Causal Role in the Acquisition of Invasive Capacity in Human Liver Cells
Claudin-1 Acts through c-Abl-Protein Kinase Cδ (PKCδ) Signaling and Has a Causal Role in the Acquisition of Invasive Capacity in Human Liver Cells
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DOI：
10.1074/jbc.m109.054189
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发表时间：
2010-01-01
影响因子：
4.8
通讯作者：
Lee, Su-Jae
中科院分区：
文献类型：
--
作者：
Yoon, Chang-Hwan;Kim, Min-Jung;Lee, Su-Jae
紧密连接蛋白被鉴定为四跨膜蛋白家族的成员，其是紧密连接的结构和功能的组成部分。最近的研究表明，在肿瘤发生过程中，claudins的表达增加，这与细胞-细胞接触，去分化和侵袭性的丧失有关。然而，密蛋白表达与癌症进展之间因果关系的分子基础尚未完全清楚。在这项研究中，我们表明，claudin-1在人类肝细胞的侵袭能力的获得中起着因果作用，并且c-Abl-蛋白激酶C δ（PKC δ）信号传导对于claudin-1诱导的恶性进展至关重要。claudin-1的过表达明显诱导基质金属蛋白酶-2（MMP-2）的表达以及正常肝细胞和非侵袭性人肝细胞癌（HCC）细胞中的细胞侵袭和迁移。相反，靶向侵袭性HCC细胞中的claudin-1的小干扰RNA完全抑制细胞侵袭。发现c-Abl和PKC δ在稳定过表达claudin-1的正常肝细胞系克隆中被激活。单独抑制c-Abl或PKC δ明显减弱MMP-2活化，并阻碍表达claudin-1的人HCC和正常肝细胞的细胞侵袭和迁移。这些结果表明，claudin-1是诱导人肝细胞中的侵袭行为所必需且足够的，并且c-Abl-PKC δ信号传导途径的激活对于claudin-1诱导的恶性表型的获得是至关重要的。目前的观察结果提出了利用claudin-1作为肝癌扩散的潜在生物标志物的可能性，并可能为HCC的治疗干预提供关键点。
Claudins are identified as members of the tetraspanin family of proteins, which are integral to the structure and function of tight junction. Recent studies showed an increase in expression of claudins during tumorigenesis, which is associated with loss of cell-cell contact, dedifferentiation, and invasiveness. However, the molecular basis for the causal relationship between claudin expression and cancer progression is not fully understood yet. In this study, we show that claudin-1 plays a causal role in the acquisition of invasive capacity in human liver cells and that c-Abl-protein kinase C delta (PKC delta) signaling is critical for the malignant progression induced by claudin-1. Overexpression of claudin-1 clearly induced expression of matrix metalloproteinase-2 (MMP-2) and cell invasion and migration in normal liver cells as well as in non-invasive human hepatocellular carcinoma (HCC) cells. Conversely, small interfering RNA targeting of claudin-1 in invasive HCC cells completely inhibited cell invasion. Both c-Abl and PKC delta are found to be activated in normal liver cell line clones that stably overexpress claudin-1. Inhibition of either c-Abl or PKC delta alone clearly attenuated MMP-2 activation and impeded cell invasion and migration in both human HCC and normal liver cells expressing claudin-1. These results indicate that claudin-1 is both necessary and sufficient to induce invasive behavior in human liver cells and that activation of c-Abl-PKC delta signaling pathway is critically required for the claudin-1-induced acquisition of the malignant phenotype. The present observations raise the possibility of exploiting claudin-1 as a potential biomarker for the spread of liver cancer and might provide pivotal points for therapeutic intervention in HCC.