Inhibition of TNF alpha-interacting protein alpha (Tip alpha)-associated gastric carcinogenesis by BTG2(/TIS21) via downregulating cytoplasmic nucleolin expressionInhibition of TNFα-interacting protein α (Tipα)-associated gastric carcinogenesis by BTG2/TIS21 via downregulating cytoplasmic nucleolin expression
- Authors
- Devanand, Preethi; Oya, Yukiko; Sundaramoorthy, Santhoshkumar; Song, Kye Yong; Watanabe, Tatsuro; Kobayashi, Yasuhito; Shimizu, Yoshihiko; Hong, Soon Auck; Suganuma, Masami; Lim, In Kyoung
- Issue Date
- Feb-2018
- Publisher
- NATURE PUBLISHING GROUP
- Citation
- EXPERIMENTAL AND MOLECULAR MEDICINE, v.50, no.2, pp 1 - 13
- Pages
- 13
- Journal Title
- EXPERIMENTAL AND MOLECULAR MEDICINE
- Volume
- 50
- Number
- 2
- Start Page
- 1
- End Page
- 13
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/45342
- DOI
- 10.1038/emm.2017.281
- ISSN
- 1226-3613
2092-6413
- 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 Tip alpha, 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 Tip alpha activity in MKN-1 and MGT-40, human and mouse gastric cancer cells, respectively, thereby downregulating tumor necrosis factor-alpha (TNF alpha) expression and Erk1/2 phosphorylation by reducing expression of nucleolin, a Tip alpha 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.
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