School of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China.
Division of Chest Medicine, Department of Medicine, National Yang-Ming University Hospital, Yilan, Taiwan, Republic of China.
Cancer Gene Ther. 2017 Sep;24(9):373-380. doi: 10.1038/cgt.2017.26. Epub 2017 Aug 4.
Lung cancer is one of the leading causes of death from cancer worldwide, with a poor prognosis in advanced cases. In the past decade, epidermal growth factor receptor (EGFR) inhibitors have shown significant efficacy towards treatment for EGFR mutant lung cancer. Expanding our knowledge of oncogenic EGFR signaling pathways is therefore of highly importance for the cancer field. Recently it has been proposed that mutant EGFR transcriptionally silences the TET1 (ten-eleven translocation methylcytosine dioxygenase 1) gene in cellular and animal models of lung cancer. Since TET1 is a known DNA demethylase, EGFR-mediated TET1 silencing therefore downregulates demethylation of tumor suppressor genes, which then leads to tumor growth inhibition, potentiating the role of TET1 as a tumor suppressor gene in NSCLC. In our study, we examined the role of EGFR-TET1 silencing in NSCLC patient samples. By independently analyzing the TCGA (The Cancer Genome Atlas) NSCLC data set as well as a cohort of patient samples from our hospital and a data set from publicly deposited databases, we did not observe the aforementioned mutant EGFR silencing of TET1. Conversely, in our cohort, TET1 expression levels were significantly elevated in EGFR mutant samples (P=0.007). Patients with higher TET1 levels showed a trend of better response rates to EGFR inhibitors compared to low TET1 staining levels, although the result was not significant (P=0.08). Furthermore, we did not observe a correlation between TET1 expression levels and patient survival. We conclude that while oncogenic EGFR suppression of TET1 is established in cellular and animal models of lung cancer, its role in patient outcome and prognosis remains inconclusive and warrants further investigation.
肺癌是全球癌症死亡的主要原因之一，晚期病例预后较差。在过去的十年中，表皮生长因子受体 (EGFR) 抑制剂已显示出对 EGFR 突变型肺癌治疗的显著疗效。因此，扩展我们对致癌 EGFR 信号通路的认识对于癌症领域非常重要。最近有人提出，在肺癌的细胞和动物模型中，突变型 EGFR 转录沉默 TET1（ten-eleven translocation methylcytosine dioxygenase 1）基因。由于 TET1 是一种已知的 DNA 去甲基化酶，因此 EGFR 介导的 TET1 沉默下调肿瘤抑制基因的去甲基化，从而导致肿瘤生长抑制，增强了 TET1 作为非小细胞肺癌 (NSCLC) 肿瘤抑制基因的作用。在我们的研究中，我们研究了 EGFR-TET1 沉默在 NSCLC 患者样本中的作用。通过独立分析 TCGA（癌症基因组图谱）NSCLC 数据集以及来自我们医院的患者样本队列和公开存储数据库中的数据集，我们没有观察到上述突变型 EGFR 对 TET1 的沉默。相反，在我们的队列中，EGFR 突变样本中 TET1 的表达水平显着升高（P=0.007）。与低 TET1 染色水平相比，TET1 水平较高的患者对 EGFR 抑制剂的反应率有改善的趋势，尽管结果不显著（P=0.08）。此外，我们没有观察到 TET1 表达水平与患者生存之间的相关性。我们得出的结论是，虽然致癌 EGFR 抑制 TET1 在肺癌的细胞和动物模型中已得到证实，但它在患者结局和预后中的作用仍不确定，需要进一步研究。
