EWS-FLI1-mediated tenascin-C expression promotes tumour progression by targeting MALAT1 through integrin α5β1-mediated YAP activation in Ewing sarcoma
EWS-FLI1-mediated tenascin-C expression promotes tumour progression by targeting MALAT1 through integrin α5β1-mediated YAP activation in Ewing sarcoma
复制标题
EWS-FLI1 介导的腱蛋白-C 表达通过整合素 α5β1 介导的 YAP 激活靶向 MALAT1 促进肿瘤进展尤文肉瘤
DOI：
10.1038/s41416-019-0608-1
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发表时间：
2019-11-26
影响因子：
8.8
通讯作者：
Xiao, Jianru
中科院分区：
文献类型：
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作者：
He, Shaohui;Huang, Quan;Xiao, Jianru
研究背景细胞外基质与尤文肉瘤（Ewing sarcoma，ES）的发生、发展密切相关.然而，生腱蛋白-C（TNC）在ES中的调节和预后作用仍不清楚。MethodsTNC表达在标本中进行了检查，免疫组化，并与ES患者生存的TNC表达的关联也进行了分析。使用CRISPR/Cas9方法构建TNC敲除细胞系。采用BALB/c裸鼠进行体外实验和体内生物发光成像，以评估TNC对ES肿瘤进展的影响。RNA测序进行，和TNC的潜在机制进一步explored.ResultsTNC在ES组织和细胞系中过表达，和TNC过表达与ES患者生存不良。TNC在体外促进ES细胞增殖、迁移和血管生成，在体内促进ES细胞转移。癌蛋白EWS-FLI 1通过直接结合TNC启动子区域显著增加TNC表达。由Yes相关蛋白（雅普）激活诱导的转移相关肺腺癌转录本1（MALAT 1）上调是TNC调节的ES肿瘤进展的原因。结论TNC可能通过整合素α 5 β 1介导的雅普活化，以MALAT 1为靶点，促进ES肿瘤的进展。
BackgroundThe extracellular matrix has been critically associated with the tumorigenesis and progression of Ewing sarcoma (ES). However, the regulatory and prognostic roles of tenascin-C (TNC) in ES remain unclear.MethodsTNC expression was examined in specimens by immunohistochemistry, and the association of TNC expression with ES patient survival was also analysed. TNC-knockout cell lines were constructed using CRISPR/Cas9 methods. In vitro experiments and in vivo bioluminescent imaging using BALB/c nude mice were conducted to evaluate the effect of TNC on ES tumour progression. RNA sequencing was performed, and the underlying mechanism of TNC was further explored.ResultsTNC was overexpressed in ES tissue and cell lines, and TNC overexpression was associated with poor survival in ES patients. TNC enhanced cell proliferation, migration and angiogenesis in vitro and promoted ES metastasis in vivo. The oncoprotein EWS-FLI1 profoundly increased TNC expression by directly binding to the TNC promoter region. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) upregulation induced by Yes-associated protein (YAP) activation was responsible for TNC-regulated ES tumour progression. Activated integrin α5β1 signalling might be correlated with YAP dephosphorylation and nuclear translocation.ConclusionsTNC may promote ES tumour progression by targeting MALAT1 through integrin α5β1-mediated YAP activation.