Liver-intestine cadherin induction by epidermal growth factor receptor is associated with intestinal differentiation of gastric cancer.

Gastric cancer (GC) is one of the most common malignancies worldwide. The epidermal growth factor receptor (EGFR) molecule is very important in GC progression. To examine the correlation between EGFR and GC-related genes, we analyzed gene expression profiles of HT-29 cells treated with EGFR ligands and identified six genes upregulated by epidermal growth factor (EGF) and transforming growth factor (TGF)-α treatment. Among these, we focused on cadherin 17 (CDH17) encoding liver-intestine cadherin (LI-cadherin). Expression of LI-cadherin was induced by both EGF and TGF-α, as detected by quantitative RT-PCR and Western blot analysis. A luciferase assay showed that LI-cadherin promoter activity was enhanced by EGF or TGF-α in both HT-29 cells and MKN-74 GC cells. Immunohistochemical analysis of 152 GC cases showed that out of 58 LI-cadherin-positive cases, 24 (41%) cases were also positive for EGFR, whereas out of 94 LI-cadherin-negative cases, only 9 (10%) cases were positive for EGFR (P < 0.0001). Double-immunofluorescence staining revealed that EGFR and LI-cadherin were coexpressed. Significant correlation was found between LI-cadherin expression and advanced T grade and N grade. Both EGFR and LI-cadherin expression were more frequently found in GC cases with an intestinal mucin phenotype than in cases with a gastric mucin phenotype. These results indicate that, in addition to the known intestinal transcription factor caudal type homeobox 2, EGFR activation induces LI-cadherin expression and participates in intestinal differentiation of GC.