Activating transcription factor 2 expression mediates cell proliferation and is associated with poor prognosis in human non-small cell lung carcinoma

Abstract

Abstract. 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 paraffinembedded 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 in vitro 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.

Silencing of ATF2 inhibits growth of pancreatic cancer cells and enhances sensitivity to chemotherapy

“…ATF2 is highly expressed in non small cell lung cancer and renal cell carcinoma, and is associated with the poor outcomes (Wu and Chen, 2016;You and Zhou, 2016). Our data showed that ATF2 was highly expressed in the pancreatic cancer tissues.…”

“…ATF2 is highly expressed in non small cell lung cancer and renal cell carcinoma, and is associated with the poor outcomes (Wu and Chen, 2016;You and Zhou, 2016). Our clinical data showed that the expression of ATF2 in the tumor tissues of pancreatic cancer was higher than that in the adjacent non-tumor tissues, which prompted us to the hypothesis that ATF2 may play an oncogenic role in pancreatic cancer.…”

“…Moreover, ATF2 can be activated by stress or cytokine stimuli in response to DNA damage, viral infection and cell death (Bhoumik et al, 2007). In addition, ATF2 is regarded as a potential prognosis predictor for certain types of cancers, such as non-small cell lung cancer and renal cell carcinoma (Wu and Chen, 2016;You et al, 2016). ATF2 has been demonstrated to act as either an oncogene or a tumor suppressor Lopez-Bergami et al, 2010;Duffey et al, 2011;Walluscheck et al, 2013;Wu et al, 2016), depending on the tumor type and the subcellar localization Gozdecka and Breitwieser, 2012).…”

“…ATF2 has been demonstrated to act as either an oncogene or a tumor suppressor Lopez-Bergami et al, 2010;Duffey et al, 2011;Walluscheck et al, 2013;Wu et al, 2016), depending on the tumor type and the subcellar localization Gozdecka and Breitwieser, 2012). In addition, ATF2 is regarded as a potential prognosis predictor for certain types of cancers, such as non-small cell lung cancer and renal cell carcinoma (Wu and Chen, 2016;You et al, 2016).…”

6′-O-galloylpaeoniflorin regulates proliferation and metastasis of non-small cell lung cancer through AMPK/miR-299-5p/ATF2 axis

“…Evidence suggests that ATF2 is imbalanced in individuals with cancer, whereas complete loss of ATF2 in somatic cells leads to cell death [39,41,42]. ATF2 is overexpressed in non-small cell lung cancer cells [43], and studies have shown that ATF2 increases the resistance of nonsmall cell lung cancer to cisplatin and radiotherapy by repairing DNA [44,45].…”