Abstract
To understand the regulation of Helicobacter pylori (H. pylori)-associated gastric carcinogenesis, we examined the effect of B-cell translocation gene 2 (BTG2) expression on the biological activity of Tipα, an oncoprotein secreted from H. pylori. BTG2, the human ortholog of mouse TIS21 (BTG2/TIS21), has been reported to be a primary response gene that is transiently expressed in response to various stimulations. Here, we report that BTG2 is constitutively expressed in the mucous epithelium and parietal cells of the gastric gland in the stomach. Expression was increased in the mucous epithelium following H. pylori infection in contrast to its loss in human gastric adenocarcinoma. Indeed, adenoviral transduction of BTG2/TIS21 significantly inhibited Tipα activity in MKN-1 and MGT-40, human and mouse gastric cancer cells, respectively, thereby downregulating tumor necrosis factor-α (TNFα) expression and Erk1/2 phosphorylation by reducing expression of nucleolin, a Tipα receptor. Chromatin immunoprecipitation proved that BTG2/TIS21 inhibited Sp1 expression and its binding to the promoter of the nucleolin gene. In addition, BTG2/TIS21 expression significantly reduced membrane-localized nucleolin expression in cancer cells, and the loss of BTG2/TIS21 expression induced cytoplasmic nucleolin availability in gastric cancer tissues, as evidenced by immunoblotting and immunohistochemistry. Higher expression of BTG2 and lower expression of nucleolin were accompanied with better overall survival of poorly differentiated gastric cancer patients. This is the first report showing that BTG2/TIS21 inhibits nucleolin expression via Sp1 binding, which might be associated with the inhibition of H. pylori-induced carcinogenesis. We suggest that BTG2/TIS21 is a potential inhibitor of nucleolin in the cytoplasm, leading to inhibition of carcinogenesis after H. pylori infection.
Highlights
The proliferation of cancer cells should be supported by their clonal selection to obtain a growth advantage either by oncogene activation or tumor suppressor inactivation
The expression of B-cell translocation gene 2 (BTG2)/TIS21 is increased in mucous epithelium infected with H. pylori but is lost in human gastric adenocarcinoma BTG2/TIS21 expression is frequently lost in various cancers; we analyzed the changes in BTG2 expression in normal glandular epithelium and adenocarcinoma with or without H. pylori infection by IHC
BTG2/TIS21 expression was detected in the neck portion of gastric glands of the body of the human stomach with H. pylori infection at × 200 (Figure 1a), whereas the expression was absent in adenocarcinoma compared with the expression in normal mucous epithelium at × 40 (Figure 1b)
Summary
The proliferation of cancer cells should be supported by their clonal selection to obtain a growth advantage either by oncogene activation or tumor suppressor inactivation. To understand Helicobacter pylori (H. pylori)-associated gastric carcinogenesis, we examined the effect of the expression of B-cell translocation gene 2 (BTG2), the human ortholog of the mouse TIS21 gene (BTG2/TIS21), on the biological activity of Tipα, an oncoprotein secreted from H. pylori. Gastric cancer is the fifth most common malignant cancer in the world and the third leading cause of cancer death.[1] The incidence of gastric cancer remains the highest in Japan and Korea with a high prevalence of infection by H. pylori,[2] which is a Gram-negative, spiral-shaped bacteria colonized in the human stomach and recognized as a causative agent of chronic gastritis, ulceration and carcinoma based on Hill’s criteria.[3] cancer development by H. pylori infection has been reported to show a frequency less than 5%, and most cases remain asymptomatic.[4] The major antigen of H. pylori identified in 1993 is CagA, a component of cag pathogenicity,[5,6] and several other factors of H. pylori were identified later. Virulence factors of H. pylori, including the cytotoxin-associated gene
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