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肝癌干细胞中的骨桥蛋白-CD44 轴调节 IFN 信号和 HCV 复制。

The osteopontin-CD44 axis in hepatic cancer stem cells regulates IFN signaling and HCV replication.

机构信息

Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

Department of Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, Kanazawa, Japan.

出版信息

Sci Rep. 2018 Sep 3;8(1):13143. doi: 10.1038/s41598-018-31421-6.

DOI:10.1038/s41598-018-31421-6
PMID:30177680
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6120883/
Abstract

Osteopontin (OPN) is involved in cell proliferation, migration, inflammation, and tumor progression in various tissues. OPN induces stemness by interacting with CD44, but the functional relevance of OPN-mediated interferon (IFN) signaling and hepatitis C virus (HCV) replication in stem cell populations remains unclear. In this study, we investigated the effect of OPN on HCV replication and IFN signaling in cancer stem cells (CSCs) positive for epithelial cell adhesion molecule (EpCAM) and CD44. We show that the EpCAM/CD44 CSCs show marked HCV replication when compared to EpCAM/CD44 cells. In addition, OPN significantly enhances this HCV replication in EpCAM/CD44 CSCs and markedly suppresses IFN-stimulated gene expression. The GSK-3β inhibitor BIO increases the EpCAM/CD44 CSC population and OPN expression and impairs IFN signaling via STAT1 degradation. Taken together, our data suggest that OPN enhances HCV replication in the EpCAM/CD44 CSCs, while it also negatively regulates the IFN signaling pathway via inhibition of STAT1 phosphorylation and degradation. Therefore, OPN may represent a novel therapeutic target for treating HCV-related hepatocellular carcinoma.

摘要

骨桥蛋白 (OPN) 参与各种组织中的细胞增殖、迁移、炎症和肿瘤进展。OPN 通过与 CD44 相互作用诱导干细胞特性，但 OPN 介导的干扰素 (IFN) 信号和丙型肝炎病毒 (HCV) 在干细胞群体中的复制的功能相关性尚不清楚。在这项研究中，我们研究了 OPN 对上皮细胞黏附分子 (EpCAM) 和 CD44 阳性的癌症干细胞 (CSC) 中 HCV 复制和 IFN 信号的影响。我们表明，与 EpCAM/CD44 细胞相比，EpCAM/CD44 CSC 显示出明显的 HCV 复制。此外，OPN 显着增强了 EpCAM/CD44 CSC 中的这种 HCV 复制，并显着抑制 IFN 刺激基因的表达。GSK-3β 抑制剂 BIO 增加 EpCAM/CD44 CSC 群体和 OPN 表达，并通过 STAT1 降解损害 IFN 信号通路。总之，我们的数据表明，OPN 增强了 EpCAM/CD44 CSC 中的 HCV 复制，同时通过抑制 STAT1 磷酸化和降解来负调控 IFN 信号通路。因此，OPN 可能成为治疗 HCV 相关肝细胞癌的新的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daed/6120883/d5d529d264c5/41598_2018_31421_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daed/6120883/931e7acd0bc8/41598_2018_31421_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daed/6120883/167f1121fbef/41598_2018_31421_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daed/6120883/6322bd50a937/41598_2018_31421_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daed/6120883/76d853ff192d/41598_2018_31421_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daed/6120883/d5d529d264c5/41598_2018_31421_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daed/6120883/931e7acd0bc8/41598_2018_31421_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daed/6120883/167f1121fbef/41598_2018_31421_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daed/6120883/6322bd50a937/41598_2018_31421_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daed/6120883/76d853ff192d/41598_2018_31421_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/daed/6120883/d5d529d264c5/41598_2018_31421_Fig5_HTML.jpg

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