SOX2表达是表皮生长因子受体（EGFR）突变型肺癌小鼠模型中的早期事件，并促进一部分EGFR突变型肺腺癌细胞系的增殖。
SOX2 expression is an early event in a murine model of EGFR mutant lung cancer and promotes proliferation of a subset of EGFR mutant lung adenocarcinoma cell lines.
作者信息
Dogan Irem, Kawabata Shigeru, Bergbower Emily, Gills Joell J, Ekmekci Abdullah, Wilson Willie, Rudin Charles M, Dennis Phillip A
机构信息
Medical Oncology Branch, National Cancer Institute, Bethesda, MD, USA; Gazi University, Faculty of Medicine, Department of Medical Biology and Genetics, Ankara, Turkey.
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
出版信息
Lung Cancer. 2014 Jul;85(1):1-6. doi: 10.1016/j.lungcan.2014.03.021. Epub 2014 Mar 29.
OBJECTIVES
Primary and acquired resistance to EGFR TKIs in EGFR mutant lung cancer occurs primarily through secondary mutations in EGFR or Met amplification. Drug resistance can also be mediated by expression of pluripotency transcription factors, such as OCT4, SOX2 and NANOG that decrease terminal differentiation. In this study, we investigated the expression and role of SOX2 in model systems of EGFR mutant tumors.
MATERIALS AND METHODS
Immunoblotting or immunohistochemistry was used to assess expression of pluripotency transcription factors in lungs of transgenic mice or in human NSCLC cell lines. Expression of SOX2 was reduced by shRNA knockdown, and response to erlotinib and cellular proliferation were assessed.
RESULTS AND CONCLUSION
Induction of mutant EGFR in transgenic CCSP-rtTA/TetO-EGFR(L858R/T790M) mice correlated with increased OCT4 and SOX2 expression in lung tissue prior to tumor development. Established lung tumors retained SOX2 expression. To assess a role for SOX2 in tumorigenesis, a panel of NSCLC cell lines with activating EGFR mutations was assessed for SOX2 expression. Two of six cell lines with mutant EGFR showed detectable SOX2 levels, suggesting SOX2 expression did not correlate with EGFR mutation status. To assess the role of SOX2 in these cell lines, HCC827 and H1975 cells were infected with lentivirus containing SOX2 shRNA. Knockdown of SOX2 decreased proliferation in both cell lines and increased sensitivity to erlotinib in HCC827 cells. Because constitutive activation of the PI3K/Akt pathway is associated with EGFR TKI resistance, cells were treated with PI3K/AKT inhibitors and expression of SOX2 was examined. PI3K/Akt inhibitors decreased SOX2 expression in a time-dependent manner. These data suggest targeting SOX2 may provide therapeutic benefit in the subset of EGFR-mutant tumors with high constitutive levels of SOX2, and that until more direct means of inhibiting SOX2 are developed, PI3K/Akt inhibitors might be useful to inhibit SOX2 in EGFR TKI resistant tumors.
目的
表皮生长因子受体（EGFR）突变型肺癌对EGFR酪氨酸激酶抑制剂（TKIs）的原发性和获得性耐药主要通过EGFR的继发性突变或Met扩增产生。耐药性也可由多能性转录因子如OCT4、SOX2和NANOG的表达介导，这些因子会降低终末分化。在本研究中，我们在EGFR突变肿瘤模型系统中研究了SOX2的表达及作用。
材料与方法
采用免疫印迹法或免疫组化法评估转基因小鼠肺组织或人非小细胞肺癌（NSCLC）细胞系中多能性转录因子的表达。通过短发夹RNA（shRNA）敲低来降低SOX2的表达，并评估对厄洛替尼的反应和细胞增殖情况。
结果与结论
在转基因CCSP-rtTA/TetO-EGFR（L858R/T790M）小鼠中，突变型EGFR的诱导与肿瘤发生前肺组织中OCT4和SOX2表达增加相关。已形成的肺肿瘤保留SOX2表达。为评估SOX2在肿瘤发生中的作用，对一组具有激活型EGFR突变的NSCLC细胞系进行了SOX2表达评估。6个具有EGFR突变的细胞系中有2个显示出可检测到的SOX2水平，这表明SOX2表达与EGFR突变状态无关。为评估SOX2在这些细胞系中的作用，用含有SOX2 shRNA的慢病毒感染HCC827和H1975细胞。敲低SOX2可降低两个细胞系的增殖，并增加HCC827细胞对厄洛替尼的敏感性。由于PI3K/Akt通路的组成性激活与EGFR TKI耐药相关，用PI3K/AKT抑制剂处理细胞并检测SOX2的表达。PI3K/Akt抑制剂以时间依赖性方式降低SOX2表达。这些数据表明，靶向SOX2可能对SOX2组成性水平高的EGFR突变肿瘤亚群具有治疗益处，并且在开发出更直接的抑制SOX2的方法之前，PI3K/Akt抑制剂可能有助于抑制EGFR TKI耐药肿瘤中的SOX2。
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