A microRNA gene expression signature predicts response to erlotinib in epithelial cancer cell lines and targets EMT.
A microRNA gene expression signature predicts response to erlotinib in epithelial cancer cell lines and targets EMT.
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DOI：
10.1038/bjc.2011.465
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发表时间：
2012-01-03
影响因子：
8.8
通讯作者：
Black, E. P.
中科院分区：
文献类型：
--
作者：
Bryant, J. L.;Britson, J.;Balko, J. M.;Willian, M.;Timmons, R.;Frolov, A.;Black, E. P.
表皮生长因子受体（EGFR）抑制剂治疗可使某些非小细胞肺癌（NSCLC）和胰腺导管腺癌（PDAC）患者产生临床缓解。EGFR和KRAS突变状态、EGFR扩增或反应的基因表达预测因子可预测对EGFR抑制的敏感性。使用NSCLC细胞系模型系统，我们鉴定并表征了预测EGFR抑制反应的microRNA（miRNA）基因表达。13种miRNA基因的表达预测癌细胞系和肿瘤对EGFR抑制的反应，并区分原发性和转移性肿瘤。特征基因靶向富含上皮-间充质转化（EMT）基因的蛋白质。上皮-间质转化预测EGFR抑制剂耐药性和转移行为EMT转录因子ZEB 1在厄洛替尼敏感的NSCLC和PDAC中表达改变，其中许多标志性miRNA基因上调。mir-200 c的异位表达改变了EMT蛋白的表达、对厄洛替尼的敏感性和肺细胞的迁移。TGFβ1治疗改变了标志性miRNA和EMT蛋白的表达，并调节了肺细胞的迁移。根据这些数据，我们假设肿瘤微环境刺激TGFβ1并刺激miRNA基因表达程序，该程序诱导对抗EGFR治疗的抗性并驱使肺肿瘤细胞发生EMT、侵袭和转移。
Treatment with epidermal growth factor receptor (EGFR) inhibitors can result in clinical response in non-small-cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC) for some unselected patients. EGFR and KRAS mutation status, amplification of EGFR, or gene expression predictors of response can forecast sensitivity to EGFR inhibition. Using an NSCLC cell line model system, we identified and characterised microRNA (miRNA) gene expression that predicts response to EGFR inhibition. Expression of 13 miRNA genes predicts response to EGFR inhibition in cancer cell lines and tumours, and discriminates primary from metastatic tumours. Signature genes target proteins that are enriched for epithelial-to-mesenchymal transition (EMT) genes. Epithelial-to-mesenchymal transition predicts EGFR inhibitor resistance and metastatic behaviour. The EMT transcription factor, ZEB1, shows altered expression in erlotinib-sensitive NSCLC and PDAC, where many signature miRNA genes are upregulated. Ectopic expression of mir-200c alters expression of EMT proteins, sensitivity to erlotinib, and migration in lung cells. Treatment with TGFβ1 changes expression of signature miRNA and EMT proteins and modulates migration in lung cells. From these data, we hypothesise that the tumour microenvironment elicits TGFβ1 and stimulates a miRNA gene expression program that induces resistance to anti-EGFR therapy and drives lung tumour cells to EMT, invasion, and metastasis.
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