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
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
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DOI：
10.1007/s10120-022-01334-5
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发表时间：
2022-09-12
期刊：
影响因子：
7.4
通讯作者：
Fujishiro, Mitsuhiro
中科院分区：
文献类型：
--
作者：
Fukagawa, Kazushi;Takahashi, Yu;Fujishiro, Mitsuhiro
背景胃底腺型胃腺癌（GA-FG）是一种与幽门螺杆菌关系不大的胃恶性肿瘤。GA-FG的临床特征已经确定，但导致肿瘤发生的分子机制尚未阐明。方法采用基因芯片技术对3个GA-FG肿瘤-正常黏膜组织进行分析。对前30个上调基因转录本进行网络分析，然后进行免疫组织化学染色以确认基因表达分析结果。用编码NK 2同源框1/甲状腺转录因子1（NKX 2 -1/TTF-1）的基因转染AGS和NUGC 4细胞，以评估其靶基因的转录变化。结果综合基因表达分析鉴定出1410个表达上调的基因探针和1395个表达下调的基因探针，表达差异>= 2倍。在GA-FG的前30个上调基因中，我们鉴定了转录因子NKX 2 -1/TTF-1，一种肺/甲状腺分化的主要调节因子，以及表面活性蛋白B（SFTPB）、SFTPC和分泌珠蛋白家族3A成员2（SCGB 3A 2），它们都受NKX 2 -1/TTF-1的调节。免疫组化结果显示16例GA-FG标本中NKX 2 -1/TTF-1和SFTPB的表达均显著高于癌旁正常粘膜（P < 0.05），而SCGB 3A 2的表达无显著差异（P = 0.341）。将NKX 2 -1/TTF-1转导入AGS和NUGC 4细胞诱导SFTPB和SFTPC的反式激活，表明NKX 2 -1/TTF-1在胃细胞中可以像在肺细胞中一样正常地起作用。结论首次对GA-FG进行转录组分析，发现GA-FG中存在NKX 2 -1/TTF 1的表达。免疫组织化学和细胞生物学显示NKX 2 -1/TTF-1的异位表达和正常的反式激活能力，表明它在GA-FG的发育中起着至关重要的作用。
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.