HER2 通过调节胃癌中的骨桥蛋白促进上皮-间充质转化。
HER2 promotes epithelial-mesenchymal transition through regulating osteopontin in gastric cancer.
机构信息
Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Pathology, School of Basic Medical Sciences & Zhongshan Hospital, Fudan University, Shanghai, China.
Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Pathology, School of Basic Medical Sciences & Zhongshan Hospital, Fudan University, Shanghai, China.
出版信息
Pathol Res Pract. 2021 Nov;227:153643. doi: 10.1016/j.prp.2021.153643. Epub 2021 Oct 5.
AIMS
HER2 and osteopontin (OPN) are both important biomarkers in gastric cancer (GC). The relationships between them remain to be revealed. The purpose of this study is to explore the role of OPN in epithelial-mesenchymal transition (EMT) in HER2 positive GCs.
METHODS
Nanostring analysis was used to compare the mRNA levels of 730 cancer related genes between paired HER2 3+ and non-3+ areas in GC patients. Immunohistochemistry (IHC) staining was performed to analyze the expression levels of OPN, as well as EMT markers including E-cad, N-cad, twist and vimentin in both areas. To further verify the role of OPN in EMT, the expression levels of OPN and EMT markers, tumor invasion/migration were analyzed after down-regulating HER2 and OPN in GC cell lines MKN-45 and N-87.
RESULTS
Nanostring analysis identified 8 differential expression genes between HER2 3+ and non-3+ areas. Among them, the expression level of OPN was positively correlated with that of HER2. In GC specimens, OPN showed higher expression level in HER2 3+ areas where higher E-cad expression levels and lower N-cad and twist levels were also found. After knocking down OPN and HER2 by siRNA, both cell lines show decreased invasion/migration abilities, along with the down-regulation of the EMT phenotype, supporting by the decrease of E-cad, and the increase of N-cad and twist at both mRNA and protein levels. In addition, HER2 knock-down lead to a dramatic decrease of OPN expression.
CONCLUSIONS
These findings indicate that HER2 may promote EMT via the regulation of OPN in GCs.
目的
HER2 和骨桥蛋白（OPN）都是胃癌（GC）的重要生物标志物。它们之间的关系尚待揭示。本研究旨在探讨 OPN 在 HER2 阳性 GC 中的上皮-间充质转化（EMT）中的作用。
方法
使用 Nanostring 分析比较了配对的 HER2 3+和非 3+ GC 患者肿瘤组织中 730 个癌症相关基因的 mRNA 水平。免疫组织化学（IHC）染色分析了 OPN 以及 EMT 标志物（包括 E-cad、N-cad、twist 和 vimentin）在两个区域的表达水平。为了进一步验证 OPN 在 EMT 中的作用，在 GC 细胞系 MKN-45 和 N-87 中下调 HER2 和 OPN 后，分析了 OPN 和 EMT 标志物的表达水平以及肿瘤侵袭/迁移能力。
结果
Nanostring 分析确定了 HER2 3+和非 3+区域之间的 8 个差异表达基因。其中，OPN 的表达水平与 HER2 的表达水平呈正相关。在 GC 标本中，OPN 在 HER2 3+区域表达水平较高，该区域还发现 E-cad 表达水平较高，N-cad 和 twist 水平较低。用 siRNA 下调 OPN 和 HER2 后，两种细胞系的侵袭/迁移能力均降低，EMT 表型下调，支持 E-cad 表达下调，N-cad 和 twist 表达上调，mRNA 和蛋白水平均上调。此外，HER2 敲低导致 OPN 表达显著下降。
结论
这些发现表明，HER2 可能通过调节 OPN 促进 GC 中的 EMT。
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