You Zhenyu, Zhou Yong, Guo Yuling, Chen Wenyan, Chen Shaoqing, Wang Xiaolang
Department of Oncology, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
Department of Pharmacy, Peking University, Beijing 100083, P.R. China.
Oncol Lett. 2016 Jan;11(1):760-766. doi: 10.3892/ol.2015.3922. Epub 2015 Nov 16.
Activating transcription factor 2 (ATF2) is a member of the cAMP response element binding protein family that heterodimerizes and activates other transcription factors involved in stress and DNA damage responses, growth, differentiation and apoptosis. ATF2 has been investigated as a potential carcinogenic biomarker in certain types of cancer, such as melanoma. However, its function and clinical significance in non-small cell lung cancer (NSCLC) has not been well studied. Therefore, the present study aimed to analyze the association between ATF2/phosphorylated (p)-ATF2 expression and NSCLC malignant behavior, and discuss its clinical significance. Reverse transcription-quantitative polymerase chain reaction and western blotting were used to detect the expression of ATF2 in NSCLC cell lines and fresh NSCLC tissue samples. In addition, immunohistochemistry (IHC) was performed to identify the location and expression of ATF2 and p-ATF2 (threonine 71) in paraffin-embedded sections of NSCLC and adjacent normal tissue. The results demonstrated that ATF2 was markedly overexpressed in the NSCLC cells and significantly overexpressed in the fresh NSCLC tissues compared with the control cells and samples (86 paraffin-embedded tissue sections), respectively (P<0.01). Further data demonstrated that ATF2 expression levels were significantly increased in tumor tissues compared to normal tissues and ATF2 was located in the cytoplasm and nucleus. ATF2 expression was closely associated with adverse clinical characteristics such as TNM stage (P=0.002), tumor size (P=0.018) and metastasis (P=0.027). In addition, nuclear p-ATF2 staining was positive in 65/86 samples of NSCLC. Furthermore, the Kaplan-Meier analysis indicated that patients with high levels of ATF2 and p-ATF2 expression had a significantly shorter overall survival compared with patients exhibiting a low expression (P<0.01 and P<0.05, respectively). Subsequent experiments revealed that cell growth decreased following knockdown of ATF2 expression using RNA interference, indicating that ATF2 may suppress cell proliferation. Taken together, the results of the present study demonstrated that ATF2 and p-ATF2 were significantly overexpressed in NSCLC tissues, and ATF2 and p-ATF2 overexpression predicted significantly worse outcomes for patients with NSCLC.
激活转录因子2（ATF2）是环磷酸腺苷反应元件结合蛋白家族的成员，它能形成异二聚体并激活其他参与应激和DNA损伤反应、生长、分化及凋亡的转录因子。ATF2已被作为某些类型癌症（如黑色素瘤）中一种潜在的致癌生物标志物进行研究。然而，其在非小细胞肺癌（NSCLC）中的功能及临床意义尚未得到充分研究。因此，本研究旨在分析ATF2/磷酸化（p）-ATF2表达与NSCLC恶性行为之间的关联，并探讨其临床意义。采用逆转录定量聚合酶链反应和蛋白质印迹法检测NSCLC细胞系及新鲜NSCLC组织样本中ATF2的表达。此外，进行免疫组织化学（IHC）以确定ATF2和p-ATF2（苏氨酸71）在NSCLC石蜡包埋切片及相邻正常组织中的定位和表达。结果表明，与对照细胞和样本（86个石蜡包埋组织切片）相比，ATF2在NSCLC细胞中显著过表达，在新鲜NSCLC组织中也明显过表达（P<0.01）。进一步的数据表明，与正常组织相比，肿瘤组织中ATF2表达水平显著升高，且ATF2定位于细胞质和细胞核。ATF2表达与不良临床特征密切相关，如TNM分期（P=0.002）、肿瘤大小（P=0.018）和转移（P=0.027）。此外，在86个NSCLC样本中，65个样本的细胞核p-ATF2染色呈阳性。此外，Kaplan-Meier分析表明，与低表达患者相比，ATF2和p-ATF2高表达患者的总生存期显著缩短（分别为P<0.01和P<0.05）。随后的实验表明，使用RNA干扰敲低ATF2表达后细胞生长减少，这表明ATF2可能抑制细胞增殖。综上所述，本研究结果表明，ATF2和p-ATF2在NSCLC组织中显著过表达，且ATF2和p-ATF2过表达预示NSCLC患者的预后明显更差。
