Epiregulin reprograms cancer-associated fibroblasts and facilitates oral squamous cell carcinoma invasion via JAK2-STAT3 pathway
Epiregulin reprograms cancer-associated fibroblasts and facilitates oral squamous cell carcinoma invasion via JAK2-STAT3 pathway
复制标题
上皮调节蛋白通过 JAK2-STAT3 通路重新编程癌症相关成纤维细胞并促进口腔鳞状细胞癌侵袭
DOI：
10.1186/s13046-019-1277-x
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发表时间：
2019-06-24
影响因子：
11.3
通讯作者：
Hu, Qingang
中科院分区：
文献类型：
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作者：
Wang, Yujia;Jing, Yue;Hu, Qingang
背景：肿瘤相关成纤维细胞（CAFs）主要来源于肿瘤局部的正常成纤维细胞（NFs），CAFs与NFs的区别在于其支持肿瘤的特性。然而，在口腔鳞状细胞癌（OSCC）的NFs的CAFs的过渡的机制和影响仍然不清楚。MethodsFive对匹配的主要NFs和CAFs来自OSCC患者发送RNA测序。通过免疫组化分析表皮调节蛋白（EREG）在OSCC患者成纤维细胞中的表达。EREG的作用在NF-CAF过渡和相应的影响OSCC的进展进行了检查上调/下调EREG在NF/CAFs在体外和体内。ResultsHere，我们确定epiregulin（EREG）作为最显着上调基因CAFs。EREG在CAFs中的高表达与OSCC患者的高T分期、更深的浸润和较差的最差浸润模式（WPOI）相关，并预测总生存期较短。EREG在NF中的过表达激活了CAF表型。从机制上讲，JAK 2/STAT 3通路被EREG增强，同时IL-6表达增加，这可以被JAK 2抑制剂AG 490抑制。重组IL-6在反馈环中上调JAK 2/STAT 3/EREG通路。此外，EREG诱导的CAF活化促进了迁移和侵袭所必需的上皮-间质转化（EMT），这依赖于JAK 2/STAT 3信号传导和IL-6。在体内，EREG在基质成纤维细胞中的表达促进了肿瘤生长，具有高基质SMA，磷酸化JAK 2/STAT 3和IL-6表达，并上调EMT在HSC 3 cells.ConclusionsEREG是必需的NF-CAF转化需要诱导EMT的肿瘤细胞在JAK 2-STAT 3-和IL-6-依赖的方式在口腔鳞癌。
BackgroundLocal resident normal fibroblasts (NFs) are the major source of cancer-associated fibroblasts (CAFs), which are distinguishable from NFs by their tumor-supportive properties. However, the mechanism and the effects underlying the transition of NFs to CAFs in oral squamous cell carcinoma (OSCC) remain unclear.MethodsFive pairs of matching primary NFs and CAFs derived from OSCC patients were sent for RNA sequencing. Epiregulin (EREG) expression was analyzed by IHC in fibroblasts from OSCC patients. The role of EREG in the NF-CAF transition and the consequential effects on OSCC progression were examined by upregulation/downregulation of EREG in NFs/CAFs both in vitro and in vivo.ResultsHere, we identified epiregulin (EREG) as the most remarkably upregulated gene in CAFs. High EREG expression in CAFs correlated with higher T stage, deeper invasion and inferior worst pattern of invasion (WPOI) in OSCC patients and predicted shorter overall survival. Overexpression of EREG in NFs activated the CAF phenotype. Mechanistically, the JAK2/STAT3 pathway was enhanced by EREG in parallel with increased IL-6 expression, which could be inhibited by the JAK2 inhibitor AG490. Recombinant IL-6 upregulated the JAK2/STAT3/EREG pathway in a feedback loop. Moreover, EREG-induced CAF activation promoted the epithelial-mesenchymal transition (EMT) necessary for migration and invasion, which was dependent on JAK2/STAT3 signaling and IL-6. In vivo, EREG expression in stroma fibroblasts promoted tumor growth with high stromal -SMA, phospho-JAK2/STAT3, and IL-6 expression and upregulated EMT in HSC3 cells.ConclusionsEREG is essential for the NF-CAF transformation needed to induce EMT of tumor cells in a JAK2-STAT3- and IL-6-dependent manner in OSCC.