Inactivation of NKX6.3 in the stomach leads to abnormal expression of CDX2 and SOX2 required for gastric-to-intestinal transdifferentiation

Autor: Jung Y Lee, Won Suh Choi, Yong K Park, Won Sang Park, Suk W Nam, Sung S Choi, Olga Kim, Jung H Yoon
Rok vydání: 2016
Předmět:
0301 basic medicine
Pathology
Bone Morphogenetic Protein 4
0302 clinical medicine
Risk Factors
Metaplasia
CDX2 Transcription Factor
Promoter Regions
Genetic
CDX2
Stomach
Transdifferentiation
Intestinal metaplasia
Gene Expression Regulation
Neoplastic
Cell Transformation
Neoplastic
Phenotype
medicine.anatomical_structure
Area Under Curve
030220 oncology & carcinogenesis
embryonic structures
Female
medicine.symptom
medicine.medical_specialty
animal structures
Biology
Transfection
Risk Assessment
Helicobacter Infections
Pathology and Forensic Medicine
03 medical and health sciences
Bacterial Proteins
Stomach Neoplasms
Cell Line
Tumor
medicine
Gastric mucosa
Animals
Humans
Gene silencing
Genetic Predisposition to Disease
Gene Silencing
RNA
Messenger
Homeodomain Proteins
Antigens
Bacterial
Binding Sites
Helicobacter pylori
SOXB1 Transcription Factors
Proteins
medicine.disease
biology.organism_classification
digestive system diseases
Mice
Inbred C57BL
Disease Models
Animal
030104 developmental biology
ROC Curve
Gastric Mucosa
Cell Transdifferentiation
Precancerous Conditions
Transcription Factors
Zdroj: Modern Pathology. 29:194-208
ISSN: 0893-3952
DOI: 10.1038/modpathol.2015.150
Popis: 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.
Databáze: OpenAIRE
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