HOXA4, down-regulated in lung cancer, inhibits the growth, motility and invasion of lung cancer cells

The involvement of HOXA4 in colorectal cancer and epithelial ovarian cancer has been reported. Although it has been reported that the Hoxa4 gene is involved in the patterning of the mouse lung during embryonic development, little is known about the biological functions of HOXA4 in lung cancer. In the current study, HOXA4 expression was down-regulated in lung cancer tissues when compared with non-cancerous tissues. HOXA4 expression was associated with tumor size, TNM stage, lymph node metastasis and prognosis. Bioinformatics analysis revealed that HOXA4 expression was negatively correlated with cell cycle, metastasis, and the Wnt signaling pathway. Moreover, HOXA4 overexpression in lung cancer cell lines suppressed cell proliferation, migration, and invasion. HOXA4 decreased the protein expression levels of β-catenin, Cyclin D1, c-Myc and Survivin, indicating the inhibition of Wnt signaling. HOXA4 significantly increased the protein and mRNA levels of glycogen synthase kinase-3β (GSK3β) by promoting its transcription. Furthermore, inhibition of GSK3β by LiCl abolished the suppression of cell growth, migration, and invasion mediated by HOXA4. Overexpression of HOXA4 in xenograft tumors also decreased tumor growth and Wnt signaling. Collectively, these data suggest that HOXA4 is a potential diagnostic and prognostic marker in lung cancer, and its overexpression could inhibit lung cancer progression in part by promoting GSK3β transcription.