TY - JOUR
T1 - Transcriptome analysis reveals the essential role of NK2 homeobox 1/thyroid transcription factor 1 (NKX2-1/TTF-1) in gastric adenocarcinoma of fundic-gland type
AU - Fukagawa, Kazushi
AU - Takahashi, Yu
AU - Yamamichi, Nobutake
AU - Kageyama-Yahara, Natsuko
AU - Sakaguchi, Yoshiki
AU - Obata, Miho
AU - Cho, Rina
AU - Sakuma, Nobuyuki
AU - Nagao, Sayaka
AU - Miura, Yuko
AU - Tamura, Naoki
AU - Ohki, Daisuke
AU - Mizutani, Hiroya
AU - Yakabi, Seiichi
AU - Minatsuki, Chihiro
AU - Niimi, Keiko
AU - Tsuji, Yosuke
AU - Yamamichi, Mitsue
AU - Shigi, Narumi
AU - Tomida, Shuta
AU - Abe, Hiroyuki
AU - Ushiku, Tetsuo
AU - Koike, Kazuhiko
AU - Fujishiro, Mitsuhiro
N1 - Publisher Copyright:
© 2022, The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.
PY - 2023/1
Y1 - 2023/1
N2 - Background: Gastric adenocarcinoma of fundic-gland type (GA-FG) is a gastric malignancy with little relation to Helicobacter pylori. Clinical characteristics of GA-FG have been established, but molecular mechanisms leading to tumorigenesis have not yet been elucidated. Methods: We subjected three GA-FG tumors-normal mucosa pairs to microarray analysis. Network analysis was performed for the top 30 up-regulated gene transcripts, followed by immunohistochemical staining to confirm the gene expression analysis results. AGS and NUGC4 cells were transfected with the gene-encoding NK2 homeobox 1/thyroid transcription factor 1 (NKX2-1/TTF-1) to evaluate transcriptional changes in its target genes. Results: Comprehensive gene expression analysis identified 1410 up-regulated and 1395 down-regulated gene probes with ≥ two-fold difference in expression. Among the top 30 up-regulated genes in GA-FG, we identified transcription factor NKX2-1/TTF-1, a master regulator of lung/thyroid differentiation, together with surfactant protein B (SFTPB), SFTPC, and secretoglobin family 3A member 2(SCGB3A2), which are regulated by NKX2-1/TTF-1. Immunohistochemical analysis of 16 GA-FG specimens demonstrated significantly higher NKX2-1/TTF-1 and SFTPB levels, as compared to that in adjacent normal mucosa (P < 0.05), while SCGB3A2 levels did not differ (P = 0.341). Transduction of NKX2-1/TTF-1 into AGS and NUGC4 cells induced transactivation of SFTPB and SFTPC, indicating that NKX2-1/TTF-1 can function as normally in gastric cells as it can in the lung cells. Conclusions: Our first transcriptome analysis of GA-FG indicates significant expression of NKX2-1/TTF1 in GA-FG. Immunohistochemistry and cell biology show ectopic expression and normal transactivation ability of NKX2-1/TTF-1, suggesting that it plays an essential role in GA-FG development.
AB - Background: Gastric adenocarcinoma of fundic-gland type (GA-FG) is a gastric malignancy with little relation to Helicobacter pylori. Clinical characteristics of GA-FG have been established, but molecular mechanisms leading to tumorigenesis have not yet been elucidated. Methods: We subjected three GA-FG tumors-normal mucosa pairs to microarray analysis. Network analysis was performed for the top 30 up-regulated gene transcripts, followed by immunohistochemical staining to confirm the gene expression analysis results. AGS and NUGC4 cells were transfected with the gene-encoding NK2 homeobox 1/thyroid transcription factor 1 (NKX2-1/TTF-1) to evaluate transcriptional changes in its target genes. Results: Comprehensive gene expression analysis identified 1410 up-regulated and 1395 down-regulated gene probes with ≥ two-fold difference in expression. Among the top 30 up-regulated genes in GA-FG, we identified transcription factor NKX2-1/TTF-1, a master regulator of lung/thyroid differentiation, together with surfactant protein B (SFTPB), SFTPC, and secretoglobin family 3A member 2(SCGB3A2), which are regulated by NKX2-1/TTF-1. Immunohistochemical analysis of 16 GA-FG specimens demonstrated significantly higher NKX2-1/TTF-1 and SFTPB levels, as compared to that in adjacent normal mucosa (P < 0.05), while SCGB3A2 levels did not differ (P = 0.341). Transduction of NKX2-1/TTF-1 into AGS and NUGC4 cells induced transactivation of SFTPB and SFTPC, indicating that NKX2-1/TTF-1 can function as normally in gastric cells as it can in the lung cells. Conclusions: Our first transcriptome analysis of GA-FG indicates significant expression of NKX2-1/TTF1 in GA-FG. Immunohistochemistry and cell biology show ectopic expression and normal transactivation ability of NKX2-1/TTF-1, suggesting that it plays an essential role in GA-FG development.
KW - AGS cell transfection
KW - Gastric carcinoma of fundic gland
KW - Immunohistochemistry
KW - NKX2-1/TTF-1
KW - Transcriptome analysis
UR - http://www.scopus.com/inward/record.url?scp=85137936280&partnerID=8YFLogxK
U2 - 10.1007/s10120-022-01334-5
DO - 10.1007/s10120-022-01334-5
M3 - Article
C2 - 36094595
AN - SCOPUS:85137936280
SN - 1436-3291
VL - 26
SP - 44
EP - 54
JO - Gastric Cancer
JF - Gastric Cancer
IS - 1
ER -
