title: NKX6.3 controls gastric differentiation and tumorigenesis.
abstract: NKX6.3 transcription factor is known to be an important regulator in gastric mucosal epithelial differentiation. The present study aimed to investigate whether NKX6.3 acts as an essential tumor suppressor in gastric carcinogenesis. Absent or reduced protein expression and decreased DNA copy number and mRNA transcript of the NKX6.3 gene were frequently observed in gastric cancers. Overexpression of NKX6.3 in AGSNKX6.3 and MKN1NKX6.3 cells markedly arrested cell proliferation by inhibiting cell cycle progression and induced apoptosis through both death receptor- and mitochondrial-pathways. In addition, stable NKX6.3 transfectants increased the expression of gastric differentiation markers, including SOX2 and Muc5ac, and decreased the expression of intestinal differentiation markers, CDX2 and Muc2. In ChIP-cloning and sequencing analyses, NKX6.3 coordinated a repertoire of target genes, some of which are clearly associated with cell cycle, differentiation and death. In particular, NKX6.3 transcriptional factor was found to bind specifically to the upstream sequences of GKN1, a gastric-specific tumor suppressor, and dramatically increase expression of the latter. Furthermore, there was a positive correlation between NKX6.3 and GKN1 expression in non-cancerous gastric mucosae. Thus, these data suggest that NKX6.3 may control the fate of gastric mucosal cells and function as a gastric tumor suppressor.
authors: Department of Pathology, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul, Korea.
authors: Jung Hwan
authors: JH
authors: Yoon
authors: Department of Pathology, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul, Korea.
authors: Won Suk
authors: WS
authors: Choi
authors: Department of Pathology, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul, Korea.
authors: Olga
authors: O
authors: Kim
authors: College of Pharmacy, Sahmyook University, Hwarangro, Nowon-gu, Seoul, Korea.
authors: Sung Sook
authors: SS
authors: Choi
authors: Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul, Korea.
authors: Eun Kyung
authors: EK
authors: Lee
authors: Department of Pathology, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul, Korea.|Department of Functional RNomics Reasearch Center, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul, Korea.
authors: Suk Woo
authors: SW
authors: Nam
authors: Department of Pathology, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul, Korea.|Department of Functional RNomics Reasearch Center, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul, Korea.
authors: Jung Young
authors: JY
authors: Lee
authors: Department of Pathology, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul, Korea.|Department of Functional RNomics Reasearch Center, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul, Korea.
authors: Won Sang
authors: WS
authors: Park
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D000071616:CDX2 Transcription Factor; D059447:Cell Cycle Checkpoints / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D019175:DNA Methylation; D005753:Gastric Mucosa / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D009154:Mutation; D036361:Peptide Hormones / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055748:SOXB1 Transcription Factors; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; C477000:GKN1 protein, human; D018398:Homeodomain Proteins; C000609453:Nkx6-3 protein, human; D036361:Peptide Hormones; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D014157:Transcription Factors
keywords: NKX6.3; cell death; cell proliferation; differentiation; stomach