Activating transcription factor 4 (ATF4) is a member of the cAMP response element binding (CREB) protein family and has been reported to participate in cancer progression; however, its molecular mechanism is not fully understood. In this study, we investigated the function of ATF4 in non-small cell lung cancer and its molecular regulation. We detected cytoplasmic and nuclear ATF4 expression in lung cancer A549, H1299, and LK2 cells, and the total expression of ATF4 was higher than that in HBE cells (p < 0.05). Higher nuclear ATF4 expression was detected in all these cells compared to cytoplasmic ATF4 expression (p < 0.05). Overexpression of ATF4 in A549 cells significantly promoted cancer cell growth and invasion (p < 0.05). Expression of Wnt signaling molecules, including β-catenin, MMP7, and cyclin D1, and the activity of canonical Wnt signaling were also significantly promoted by ATF4 (p < 0.05). ICG001, a canonical Wnt signaling inhibitor that selectively inhibits β-catenin/ cyclic adenosine monophosphate response element binding protein (CBP) interaction, significantly inhibited cancer cell invasion and Wnt signaling. The function of ATF4 was also significantly inhibited by ICG001 (p < 0.05). However, compared to treatment with ICG001, the invasion ability of cancer cells treated with both ICG001 and ATF4 cDNA significantly increased (p < 0.05), which indicates that the function of ATF4 was not dependent only on Wnt/β-catenin signaling. The function of ATF4 in the regulation of β-catenin expression was not significantly affected by ICG001 (p > 0.05). The function of ATF4 to promote the activity of Wnt/β-catenin signaling in cancer cells was abolished by treatment with ICG001 (p > 0.05). These results indicate that ATF4 may contribute to lung cancer progression at least partly by regulating Wnt/β-catenin signaling.

Disorders of cell adhesion are critical steps in cancer progression in which varieties of markers including cadherins are involved in.Btbd7 was found to inhibit E-cadherin expression in MDCK cells and play important roles during branching morphogenesis of embryonic salivary glands and lungs. However its function in malignant tumors is largely unknown. The aim of this study is to investigate the clinicopathological significance and possible function of Btbd7 in non-small cell lung cancer. Immunohistochemistry and Western blotting were used to investigate Btbd7 expression in non-small cell lung cancer and lung tissues. The clinicopathological association and the overall survival was analyzed. In vitro experiments were performed using siRNA to investigate the function of Btbd7 in lung cancer cells. Btbd7 expression was elevated in non-small cell lung cancer tissues compared to normal lung tissues. Increased Btbd7 expression was significantly associated with lymph node metastasis, reduced E-cadherin expression and patients’ poor clinical outcome. Downregulation of Btbd7 expression in lung cancer cells by siRNA significantly inhibits cancer cell invasion and effectively restores E-cadherin expression in cancer cell membrane. Btbd7 contributes to reduced expression of E-cadherin and may be a promising cancer marker in non-small cell lung cancer.