LAMA4 expression is activated by zinc finger E-box-binding homeobox 1 and independently predicts poor overall survival in gastric cancer

The present study aimed to investigate the association between the expression of ZEB1 and LAMA4 in gastric cancer and the possible underlying mechanisms of this. In addition, the present study also investigated the prognostic value of LAMA4 in gastric cancer. LAMA4, MMP2, MMP9 and ZEB1 expression and their associations were analyzed by data mining in The Cancer Genome Atlas-stomach adenocarcinoma (TCGA-STAD). Overall survival (OS) curves of patients with gastric cancer were generated using data from TCGA and Kaplan-Meier plotting. Gastric cancer HGC-27 and SGC-7901 cell lines were used as in vitro cell models to assess the effect of LAMA4 on cell migration and invasion and to study the regulatory effect of ZEB1 on LAMA4 expression. The results of the present study indicated that LAMA4 upregulation was associated with higher grade tumors. LAMA4-knockdown significantly reduced MMP2 expression in gastric cancer cells and impaired the speed of wound healing and the invasive capability of the cancer cells. ZEB1 was strongly co-expressed with LAMA4 in TCGA-STAD (Pearson's r=0.85). Induced ZEB1 expression significantly increased LAMA4 expression at the mRNA and protein level in HGC-27 and SGC-7901 cells. A dual-luciferase assay confirmed that ZEB1 directly binded to the promoter of LAMA4. High LAMA4 expression independently predicted a poor OS (HR, 1.614; 95% CI, 1.155-2.256; P=0.005) in patients with primary gastric cancer. These results indicated that ZEB1 was able to epigenetically activate LAMA4 expression via binding to its promoter in gastric cancer cells. High LAMA4 expression was an independent indicator of a poor OS in patients with gastric cancer.