Abstract
Cancer of the stomach is among the leading causes of death from cancer worldwide. The transcription factor C/EBPβ is frequently overexpressed in gastric cancer and associated with the suppression of the differentiation marker TFF1. We show that the murine C/EBPβ knockout stomach displays unbalanced homeostasis and reduced cell proliferation and that tumorigenesis of human gastric cancer xenograft is inhibited by knockdown of C/EBPβ. Cross-species comparison of gene expression profiles between C/EBPβ-deficient murine stomach and human gastric cancer revealed a subset of tumors with a C/EBPβ 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/EBPβ and that cross-regulation between C/EBPβ-RUNX1t1-TFF1 plays an important role in gastric carcinogenesis.Key message C/EBPβ controls proliferation and differentiation balance in the stomach.Homeostatic differentiation/proliferation balance is altered in gastric cancer.RUNX1t1 is a C/EBPβ-associated tumor suppressor.RUNX1t1 negatively regulates C/EBPβ pro-oncogenic functions. Electronic supplementary materialThe online version of this article (doi:10.1007/s00109-016-1447-7) contains supplementary material, which is available to authorized users.
Highlights
Gastric cancer is one of the leading causes of cancer-related death in the developing world [1]
Knockdown cells in tissue culture required frequent sorting to prevent overgrowth of cells that regained CCAAT enhancer binding protein β (C/EBPβ) expression, suggesting selection for C/EBPβ re-expression as a growth advantage for gastric tumor cells. These results suggest that C/EBPβ plays an important role in gastric cancer cell proliferation
Comparison of gene expression profiles from C/EBPβ KO mice and human gastric cancer samples provided an insight in C/EBPβ-related molecular mechanisms
Summary
Gastric cancer is one of the leading causes of cancer-related death in the developing world [1]. Despite the histological coherence no central common molecular pathway has been convincingly shown as aberrantly regulated in intestinaltype gastric cancer development. This is in contrast to another type of stomach cancer coined diffuse-type gastric cancer. Among the known common molecular changes in intestinal-type gastric cancer are enhanced expression of cyclooxygenase-2 (COX2) and diminished expression of the mucous-associated protein trefoil factor 1 (TFF1). Altered expression of both proteins is associated with cancer progression, no recurrent mutations have been described [6,7,8,9]. CCAAT enhancer binding protein β (C/EBPβ) is frequently overexpressed in intestinaltype gastric cancer and associated with both enhanced COX2 expression and loss of TFF1 [12, 13]
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