title: Inactivation of NKX6.3 in the stomach leads to abnormal expression of CDX2 and SOX2 required for gastric-to-intestinal transdifferentiation.
abstract: Intestinal metaplasia in gastric mucosa is considered a preneoplastic lesion that progresses to gastric cancer. However, the molecular networks underlying this lesion formation are largely unknown. NKX6.3 is known to be an important regulator in gastric mucosal epithelial differentiation. In this study, we characterized the effects of NKX6.3 that may contribute to gastric intestinal metaplasia. NKX6.3 expression was significantly reduced in gastric mucosae with intestinal metaplasia. The mRNA expression levels of both NKX6.3 and CDX2 predicted the intestinal metaplasia risk, with an area under the receiver operating characteristic curve value of 0.9414 and 0.9971, respectively. Notably, the NKX6.3 expression level was positively and inversely correlated with SOX2 and CDX2, respectively. In stable AGS(NKX6.3) and MKN1(NKX6.3) cells, NKX6.3 regulated the expression of CDX2 and SOX2 by directly binding to the promoter regions of both genes. Nuclear NKX6.3 expression was detected only in gastric epithelial cells without intestinal metaplasia. Furthermore, NKX6.3-induced TWSG1 bound to BMP4 and inhibited BMP4-binding activity to BMPR-II. These data suggest that NKX6.3 might function as a master regulator of gastric differentiation by affecting SOX2 and CDX2 expression and the NKX6.3 inactivation may result in intestinal metaplasia in gastric epithelial cells.
authors.affiliation: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Jung H
authors.initials: JH
authors.lastname: Yoon
authors.affiliation: College of Pharmacy, Sahmyook University, Seoul, South Korea.
authors.forename: Sung S
authors.initials: SS
authors.lastname: Choi
authors.affiliation: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Olga
authors.initials: O
authors.lastname: Kim
authors.affiliation: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Won S
authors.initials: WS
authors.lastname: Choi
authors.affiliation: Department of Biostatistics, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Yong K
authors.initials: YK
authors.lastname: Park
authors.affiliation: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Suk W
authors.initials: SW
authors.lastname: Nam
authors.affiliation: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Jung Y
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Won S
authors.initials: WS
authors.lastname: Park
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics / Q000378:metabolism; D019540:Area Under Curve; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism; D000071616:CDX2 Transcription Factor; D045744:Cell Line, Tumor; D054338:Cell Transdifferentiation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D016481:Helicobacter Infections / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016480:Helicobacter pylori / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008679:Metaplasia; D008810:Mice, Inbred C57BL; D010641:Phenotype; D011230:Precancerous Conditions / Q000235:genetics* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012372:ROC Curve; D018570:Risk Assessment; D012307:Risk Factors; D055748:SOXB1 Transcription Factors / Q000235:genetics* / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: D000942:Antigens, Bacterial; C525809:BMP4 protein, human; D001426:Bacterial Proteins; D055415:Bone Morphogenetic Protein 4; D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D018398:Homeodomain Proteins; C000609453:Nkx6-3 protein, human; D011506:Proteins; D012333:RNA, Messenger; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C576635:TWSG1 protein, human; D014157:Transcription Factors; C080866:cagA protein, Helicobacter pylori