C/EBPβ regulates homeostatic and oncogenic gastric cell proliferation

Cancer of the stomach is among the leading causes of death from cancer worldwide. The transcription factor C/EBP{beta} is frequently overexpressed in gastric cancer and associated with the suppression of the differentiation marker TFF1. We show that the murine C/EBP{beta} knockout stomach displays unbalanced homeostasis and reduced cell proliferation and that tumorigenesis of human gastric cancer xenograft is inhibited by knockdown of C/EBP{beta}. Cross-species comparison of gene expression profiles between C/EBP{beta}-deficient murine stomach and human gastric cancer revealed a subset of tumors with a C/EBP{beta} signature. Within this signature, the RUNX1t1 tumor suppressor transcript was down-regulated in 38 % of gastric tumor samples. The RUNX1t1 promoter was frequently hypermethylated and ectopic expression of RUNX1t1 in gastric cancer cells inhibited proliferation and enhanced TFF1 expression. These data suggest that the tumor suppressor activity of both RUNX1t1 and TFF1 are mechanistically connected to C/EBP{beta} and that cross-regulation between C/EBP{beta}-RUNX1t1-TFF1 plays an important role in gastric carcinogenesis.