SOX2 Inhibition Promotes Promoter Demethylation of CDX2 to Facilitate Gastric Intestinal Metaplasia.

Abstract

Gastric intestinal metaplasia (IM) is regarded as a premalignant lesion, conferring risks for gastric cancer development. An intestinal transcription factor, CDX2, plays a vital role in establishing and maintaining IM. SOX2, an HMG-box transcription factor, is expressed in normal gastric mucosa and downregulated in IM. Therefore, it is important to elucidate the mutual interaction of SOX2 and CDX2 in gastric IM. This study aims to evaluate the negative correlation between SOX2 and CDX2 in mRNA expression and promoter methylation and to illuminate the effect of SOX2 on the promoter methylation of CDX2. Immunohistochemistry, real-time PCR and methylation-specific polymerase chain reaction assays were performed to evaluate the expression and promoter methylation of SOX2 and CDX2 in IM tissues from patients. SOX2 knockdown and CDX2 overexpression were performed in GES-1 cells to further clarify the relationship between SOX2 and CDX2. A negative correlation between SOX2 and CDX2 was found in 120 gastric IM specimens. Additionally, significant DNA demethylation of CDX2 promoter in clinical IM specimens was observed concomitantly with partial methylation of the SOX2 promoter. Furthermore, SOX2 knockdown in GES-1 cells triggered promoter demethylation of CDX2. Finally, the phenotype shift of gastric intestinal metaplasia in GES-1 cells, marked by MUC2 expression, was effectively induced by the combination of SOX2 RNAi and CDX2 overexpression. Aberrant DNA methylation of SOX2 and CDX2 genes contributes to the development of IM. Notably, SOX2 may play a role in establishing and maintaining the methylation status of the CDX2 gene in gastric tissues and cells.