EGFR regulation by microRNA in lung cancer: correlation with clinical response and survival to gefitinib and EGFR expression in cell lines
EGFR regulation by microRNA in lung cancer: correlation with clinical response and survival to gefitinib and EGFR expression in cell lines
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DOI：
10.1093/annonc/mdn006
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发表时间：
2008-06-01
影响因子：
50.5
通讯作者：
Franklin, W. A.
中科院分区：
文献类型：
--
作者：
Weiss, G. J.;Bemis, L. T.;Franklin, W. A.
背景：染色体3p等位基因缺失是肺癌发生中最常见和最早的遗传事件之一。我们研究了位于染色体3p上的microRNA-128B的缺失是否与靶向EGFR抑制的反应有关。失去microRNA-128B相当于失去了一个肿瘤抑制基因，因为它会增加EGFR的表达。研究对象和方法：我们最初证明了microRNA-128B在非小细胞肺癌(NSCLC)细胞系中是EGFR的调节因子。定量RT-PCR检测microRNA-128B的表达水平，定量PCR检测基因组拷贝数，测序检测成熟microRNA-128B的突变。我们检测了58例NSCLC患者的microRNA-128B杂合性缺失(LOH)是否与吉非替尼的疗效相关，并评估了EGFR的表达和突变状态。结果：我们确定microRNA-128B直接调节EGFR。MicroRNA-128B杂合性缺失在肿瘤样本中频繁出现，并与吉非替尼治疗后的临床反应和生存期显著相关。EGFR的表达和突变状态与患者的生存结果无关。结论：确定癌基因的microRNA调节因子可能对肺癌患者具有深远的意义，包括改进靶向药物的患者选择，开发新的治疗方法，或将其发展为疾病的早期生物标志物。
Background: Allelic loss in chromosome 3p is one of the most frequent and earliest genetic events in lung carcinogenesis. We investigated if the loss of microRNA-128b, a microRNA located on chromosome 3p and a putative regulator of epidermal growth factor receptor (EGFR), correlated with response to targeted EGFR inhibition. Loss of microRNA-128b would be equivalent to losing a tumor suppressor gene because it would allow increased expression of EGFR.Patients and Methods: We initially showed that microRNA-128b is a regulator of EGFR in non-small-cell lung cancer (NSCLC) cell lines. We tested microRNA-128b expression levels by quantitative RT-PCR, genomic copy number by quantitative PCR, and mutations in the mature microRNA-128b by sequencing. We determined whether microRNA-128b loss of heterozygosity (LOH) in 58 NSCLC patient samples correlated with response to gefitinib and evaluated EGFR expression and mutation status.Results: We determined that microRNA-128b directly regulates EGFR. MicroRNA-128b LOH was frequent in tumor samples and correlated significantly with clinical response and survival following gefitinib. EGFR expression and mutation status did not correlate with survival outcome.Conclusion: Identifying microRNA regulators of oncogenes could have far-reaching implications for lung cancer patients including improving patient selection for targeted agents, development of novel therapeutics, or development as early biomarkers of disease.