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

Kazushi Fukagawa, Yu Takahashi, Nobutake Yamamichi, Natsuko Kageyama-Yahara, Yoshiki Sakaguchi, Miho Obata, Rina Cho, Nobuyuki Sakuma, Sayaka Nagao, Yuko Miura, Naoki Tamura, Daisuke Ohki, Hiroya Mizutani, Seiichi Yakabi, Chihiro Minatsuki, Keiko Niimi, Yosuke Tsuji, Mitsue Yamamichi, Narumi Shigi, Shuta TomidaHiroyuki Abe, Tetsuo Ushiku, Kazuhiko Koike, Mitsuhiro Fujishiro

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
JournalGastric Cancer
DOIs
Publication statusAccepted/In press - 2022
Externally publishedYes

Keywords

  • AGS cell transfection
  • Gastric carcinoma of fundic gland
  • Immunohistochemistry
  • NKX2-1/TTF-1
  • Transcriptome analysis

ASJC Scopus subject areas

  • Oncology
  • Gastroenterology
  • Cancer Research

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