Role of hepatitis C virus induced osteopontin in epithelial to mesenchymal transition, migration and invasion of hepatocytes.
Role of hepatitis C virus induced osteopontin in epithelial to mesenchymal transition, migration and invasion of hepatocytes.
复制标题
DOI：
10.1371/journal.pone.0087464
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Waris G
中科院分区：
文献类型：
--
作者：
Iqbal J;McRae S;Mai T;Banaudha K;Sarkar-Dutta M;Waris G
骨桥蛋白（OPN）是一种分泌性磷蛋白，与包括肝细胞癌（HCC）在内的多种癌症的肿瘤进展和转移有关。先前的研究表明，OPN在肝损伤和炎症期间上调。然而，OPN在丙型肝炎病毒（HCV）诱导的肝病发病机制中的作用尚不清楚。在这项研究中，我们确定了OPN的诱导，然后研究了OPN在上皮细胞向间质转化（EMT）、迁移和侵袭肝细胞中的分泌形式的影响。我们展示了hcv感染诱导OPN mRNA和蛋白的表达。我们的研究结果还表明，在hcv感染细胞中，前体OPN （75 kDa）被加工成55 kDa、42 kDa和36 kDa形式的OPN。此外，我们发现分泌的OPN与细胞表面的整合素αVβ3和CD44结合，导致下游细胞激酶如局灶黏附激酶（FAK）、Src和Akt的激活。重要的是，我们的研究结果显示，hcv感染细胞中上皮标志物（E-cadherin）的表达降低，间充质标志物（N-cadherin）的表达诱导。我们还利用伤口愈合实验和基质涂膜Boyden室显示了hcv感染细胞的迁移和侵袭。此外，我们利用感染日本暴发性肝炎(JFH)-1型HCV的原代人肝细胞，证明了上述EMT标记的激活，以及参与opn介导的细胞信号级联的关键参与者。综上所述，这些研究提示OPN在慢性HCV感染相关的慢性肝病和HCC诱导中的潜在作用。
Osteopontin (OPN) is a secreted phosphoprotein which has been linked to tumor progression and metastasis in a variety of cancers including hepatocellular carcinoma (HCC). Previous studies have shown that OPN is upregulated during liver injury and inflammation. However, the role of OPN in hepatitis C virus (HCV)-induced liver disease pathogenesis is not known. In this study, we determined the induction of OPN, and then investigated the effect of secreted forms of OPN in epithelial to mesenchymal transition (EMT), migration and invasion of hepatocytes. We show the induction of OPN mRNA and protein expression by HCV-infection. Our results also demonstrate the processing of precursor OPN (75 kDa) into 55 kDa, 42 kDa and 36 kDa forms of OPN in HCV-infected cells. Furthermore, we show the binding of secreted OPN to integrin αVβ3 and CD44 at the cell surface, leading to the activation of downstream cellular kinases such as focal adhesion kinase (FAK), Src, and Akt. Importantly, our results show the reduced expression of epithelial marker (E-cadherin) and induction of mesenchymal marker (N-cadherin) in HCV-infected cells. We also show the migration and invasion of HCV-infected cells using wound healing assay and matrigel coated Boyden chamber. In addition, we demonstrate the activation of above EMT markers, and the critical players involved in OPN-mediated cell signaling cascade using primary human hepatocytes infected with Japanese fulminant hepatitis (JFH)-1 HCV. Taken together, these studies suggest a potential role of OPN in inducing chronic liver disease and HCC associated with chronic HCV infection.
登录
查看更多内容
DOI：
10.1073/pnas.171311298
发表时间：
2001-08-14
影响因子：
11.1
作者：
Gong, GZ;Waris, G;Siddiqui, A
通讯作者：
Siddiqui, A
影响因子：
4.8
作者：
Christensen, Brian;Schack, Lotte;Sorensen, Esben S.
通讯作者：
Sorensen, Esben S.
影响因子：
6.7
作者：
Huang, YH;Wu, JC;Lee, SD
通讯作者：
Lee, SD
影响因子：
13.5
作者：
Banaudha, Krishna;Orenstein, Jan M.;Kumar, Ajit
通讯作者：
Kumar, Ajit
影响因子：
3.6
作者：
Johnson, GA;Burghardt, RC;Pfarrer, C
通讯作者：
Pfarrer, C