Background and purpose: Cigarette smoke-induced inflammatory response remarkably promotes lung tumor growth. This study aimed to elucidate the mechanism of Wnt/β-catenin signaling activation by cigarette smoke in lung cancer cells. Methods: To understand the effect of cigarette smoke on mice

a kind of metastatic lung cancer mouse model which was established by intravenous injection of Lewis lung carcinoma cells. By immunohistochemical analysis

we analyzed the expression of CD68 (macrophage marker)

TNF-α and unphosphorylated β-catenin in mice and human lung cancer samples. To coculture human lung adenocarcinoma cell line A549 cells with macrophages

the “Transwell® Inserts” system was used in coculturing model. The expressions of unphosphorylated β-catenin

phosphorylated GSK-3β and Akt in A549 cells were detected by Western blot assay. Results: The immunohistochemical results showed positive staining for CD68

TNF-α and unphosphorylated β-catenin increased significantly in smoke-exposed mice compared to air exposure mice. In human lung cancer samples

CD68 and TNF-α expressions were significantly higher than in healthy lung tissue. The positive staining rates of unphosphorylated β-catenin in lung adenocarcinoma and squamous cell carcinoma were 68.9% and 62.2%

respectively. This positive rate had a relationship with smoking status and tumor stage

there was statistical significance (both P0.05). It also showed the number of CD68+ cells had a significant increase in tumors positive for unphosphorylated β-catenin (P0.01). Western blot results showed that the expression of unphosphorylated β-catenin in A549 cells had a significant concentration-dependent increase of CSE after coculturing with macrophages. The neutralizing antibody against TNF-α could significantly suppressed unphosphorylated β-catenin in A549 cells. TNF-α exposure resulted in phosphorylation of GSK-3β and Akt in A549 cells after 2 h and the expression of unphosphorylated β-catenin increased 4 h later. Conclusion: Cigarette smoke induces TNF-α release from macrophages in lung tumor tissue

which could activate the Wnt/β-catenin pathway of tumor cells through Akt/GSK-3β.