Inactivation of NKX6.3 in the stomach leads to abnormal expression of CDX2 and SOX2 required for gastric-to-intestinal transdifferentiation
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 st...
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| Veröffentlicht in: | Modern pathology 2016-02, Vol.29 (2), p.194-208 |
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| creator | Yoon, Jung H Choi, Sung S Kim, Olga Choi, Won S Park, Yong K Nam, Suk W Lee, Jung Y Park, Won S |
| description | 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. |
| doi_str_mv | 10.1038/modpathol.2015.150 |
| format | Article |
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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.</description><identifier>ISSN: 0893-3952</identifier><identifier>EISSN: 1530-0285</identifier><identifier>DOI: 10.1038/modpathol.2015.150</identifier><identifier>PMID: 26743476</identifier><identifier>CODEN: MODPEO</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>13/109 ; 14/35 ; 45/15 ; 692/699/1503/1828/1500 ; Animals ; Antigens, Bacterial - genetics ; Antigens, Bacterial - metabolism ; Area Under Curve ; Bacterial Proteins - genetics ; Bacterial Proteins - metabolism ; Binding Sites ; Bone Morphogenetic Protein 4 - genetics ; Bone Morphogenetic Protein 4 - metabolism ; CDX2 Transcription Factor ; Cell Line, Tumor ; Cell Transdifferentiation ; Cell Transformation, Neoplastic - genetics ; Cell Transformation, Neoplastic - metabolism ; Cell Transformation, Neoplastic - pathology ; Disease Models, Animal ; Female ; Gastric Mucosa - metabolism ; Gastric Mucosa - microbiology ; Gastric Mucosa - pathology ; Gene Expression Regulation, Neoplastic ; Gene Silencing ; Genetic Predisposition to Disease ; Helicobacter Infections - genetics ; Helicobacter Infections - metabolism ; Helicobacter Infections - pathology ; Helicobacter pylori - genetics ; Helicobacter pylori - metabolism ; Homeodomain Proteins - genetics ; Homeodomain Proteins - metabolism ; Humans ; Laboratory Medicine ; Medicine ; Medicine & Public Health ; Metaplasia ; Mice, Inbred C57BL ; original-article ; Pathology ; Phenotype ; Precancerous Conditions - genetics ; Precancerous Conditions - metabolism ; Precancerous Conditions - microbiology ; Precancerous Conditions - pathology ; Promoter Regions, Genetic ; Proteins - genetics ; Proteins - metabolism ; Risk Assessment ; Risk Factors ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; ROC Curve ; SOXB1 Transcription Factors - genetics ; SOXB1 Transcription Factors - metabolism ; Stomach Neoplasms - genetics ; Stomach Neoplasms - metabolism ; Stomach Neoplasms - microbiology ; Stomach Neoplasms - pathology ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Transfection</subject><ispartof>Modern pathology, 2016-02, Vol.29 (2), p.194-208</ispartof><rights>United States & Canadian Academy of Pathology 2016</rights><rights>Copyright Nature Publishing Group Feb 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c555t-2f399a3f6dc0cde295d300656786c71053371f3b863cbacc048a8bf4f76666383</citedby><cites>FETCH-LOGICAL-c555t-2f399a3f6dc0cde295d300656786c71053371f3b863cbacc048a8bf4f76666383</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.proquest.com/docview/1760836720?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,64385,64389,72469</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26743476$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yoon, Jung H</creatorcontrib><creatorcontrib>Choi, Sung S</creatorcontrib><creatorcontrib>Kim, Olga</creatorcontrib><creatorcontrib>Choi, Won S</creatorcontrib><creatorcontrib>Park, Yong K</creatorcontrib><creatorcontrib>Nam, Suk W</creatorcontrib><creatorcontrib>Lee, Jung Y</creatorcontrib><creatorcontrib>Park, Won S</creatorcontrib><title>Inactivation of NKX6.3 in the stomach leads to abnormal expression of CDX2 and SOX2 required for gastric-to-intestinal transdifferentiation</title><title>Modern pathology</title><addtitle>Mod Pathol</addtitle><addtitle>Mod Pathol</addtitle><description>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.</description><subject>13/109</subject><subject>14/35</subject><subject>45/15</subject><subject>692/699/1503/1828/1500</subject><subject>Animals</subject><subject>Antigens, Bacterial - genetics</subject><subject>Antigens, Bacterial - metabolism</subject><subject>Area Under Curve</subject><subject>Bacterial Proteins - genetics</subject><subject>Bacterial Proteins - metabolism</subject><subject>Binding Sites</subject><subject>Bone Morphogenetic Protein 4 - genetics</subject><subject>Bone Morphogenetic Protein 4 - metabolism</subject><subject>CDX2 Transcription Factor</subject><subject>Cell Line, Tumor</subject><subject>Cell Transdifferentiation</subject><subject>Cell Transformation, Neoplastic - genetics</subject><subject>Cell Transformation, Neoplastic - metabolism</subject><subject>Cell Transformation, Neoplastic - pathology</subject><subject>Disease Models, Animal</subject><subject>Female</subject><subject>Gastric Mucosa - metabolism</subject><subject>Gastric Mucosa - microbiology</subject><subject>Gastric Mucosa - pathology</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene Silencing</subject><subject>Genetic Predisposition to Disease</subject><subject>Helicobacter Infections - genetics</subject><subject>Helicobacter Infections - metabolism</subject><subject>Helicobacter Infections - pathology</subject><subject>Helicobacter pylori - genetics</subject><subject>Helicobacter pylori - metabolism</subject><subject>Homeodomain Proteins - genetics</subject><subject>Homeodomain Proteins - metabolism</subject><subject>Humans</subject><subject>Laboratory Medicine</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metaplasia</subject><subject>Mice, Inbred C57BL</subject><subject>original-article</subject><subject>Pathology</subject><subject>Phenotype</subject><subject>Precancerous Conditions - 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genetics</topic><topic>Antigens, Bacterial - metabolism</topic><topic>Area Under Curve</topic><topic>Bacterial Proteins - genetics</topic><topic>Bacterial Proteins - metabolism</topic><topic>Binding Sites</topic><topic>Bone Morphogenetic Protein 4 - genetics</topic><topic>Bone Morphogenetic Protein 4 - metabolism</topic><topic>CDX2 Transcription Factor</topic><topic>Cell Line, Tumor</topic><topic>Cell Transdifferentiation</topic><topic>Cell Transformation, Neoplastic - genetics</topic><topic>Cell Transformation, Neoplastic - metabolism</topic><topic>Cell Transformation, Neoplastic - pathology</topic><topic>Disease Models, Animal</topic><topic>Female</topic><topic>Gastric Mucosa - metabolism</topic><topic>Gastric Mucosa - microbiology</topic><topic>Gastric Mucosa - pathology</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Gene Silencing</topic><topic>Genetic Predisposition to Disease</topic><topic>Helicobacter Infections - genetics</topic><topic>Helicobacter Infections - metabolism</topic><topic>Helicobacter Infections - pathology</topic><topic>Helicobacter pylori - genetics</topic><topic>Helicobacter pylori - metabolism</topic><topic>Homeodomain Proteins - genetics</topic><topic>Homeodomain Proteins - metabolism</topic><topic>Humans</topic><topic>Laboratory Medicine</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Metaplasia</topic><topic>Mice, Inbred C57BL</topic><topic>original-article</topic><topic>Pathology</topic><topic>Phenotype</topic><topic>Precancerous Conditions - genetics</topic><topic>Precancerous Conditions - metabolism</topic><topic>Precancerous Conditions - microbiology</topic><topic>Precancerous Conditions - pathology</topic><topic>Promoter Regions, Genetic</topic><topic>Proteins - genetics</topic><topic>Proteins - metabolism</topic><topic>Risk Assessment</topic><topic>Risk Factors</topic><topic>RNA, Messenger - genetics</topic><topic>RNA, Messenger - metabolism</topic><topic>ROC Curve</topic><topic>SOXB1 Transcription Factors - genetics</topic><topic>SOXB1 Transcription Factors - metabolism</topic><topic>Stomach Neoplasms - genetics</topic><topic>Stomach Neoplasms - metabolism</topic><topic>Stomach Neoplasms - microbiology</topic><topic>Stomach Neoplasms - pathology</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><topic>Transfection</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yoon, Jung H</creatorcontrib><creatorcontrib>Choi, Sung S</creatorcontrib><creatorcontrib>Kim, Olga</creatorcontrib><creatorcontrib>Choi, Won S</creatorcontrib><creatorcontrib>Park, Yong K</creatorcontrib><creatorcontrib>Nam, Suk W</creatorcontrib><creatorcontrib>Lee, Jung Y</creatorcontrib><creatorcontrib>Park, Won S</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><jtitle>Modern pathology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yoon, Jung H</au><au>Choi, Sung S</au><au>Kim, Olga</au><au>Choi, Won S</au><au>Park, Yong K</au><au>Nam, Suk W</au><au>Lee, Jung Y</au><au>Park, Won S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inactivation of NKX6.3 in the stomach leads to abnormal expression of CDX2 and SOX2 required for gastric-to-intestinal transdifferentiation</atitle><jtitle>Modern pathology</jtitle><stitle>Mod Pathol</stitle><addtitle>Mod Pathol</addtitle><date>2016-02-01</date><risdate>2016</risdate><volume>29</volume><issue>2</issue><spage>194</spage><epage>208</epage><pages>194-208</pages><issn>0893-3952</issn><eissn>1530-0285</eissn><coden>MODPEO</coden><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.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>26743476</pmid><doi>10.1038/modpathol.2015.150</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; ProQuest Central UK/Ireland; Alma/SFX Local Collection |
| subjects | 13/109 14/35 45/15 692/699/1503/1828/1500 Animals Antigens, Bacterial - genetics Antigens, Bacterial - metabolism Area Under Curve Bacterial Proteins - genetics Bacterial Proteins - metabolism Binding Sites Bone Morphogenetic Protein 4 - genetics Bone Morphogenetic Protein 4 - metabolism CDX2 Transcription Factor Cell Line, Tumor Cell Transdifferentiation Cell Transformation, Neoplastic - genetics Cell Transformation, Neoplastic - metabolism Cell Transformation, Neoplastic - pathology Disease Models, Animal Female Gastric Mucosa - metabolism Gastric Mucosa - microbiology Gastric Mucosa - pathology Gene Expression Regulation, Neoplastic Gene Silencing Genetic Predisposition to Disease Helicobacter Infections - genetics Helicobacter Infections - metabolism Helicobacter Infections - pathology Helicobacter pylori - genetics Helicobacter pylori - metabolism Homeodomain Proteins - genetics Homeodomain Proteins - metabolism Humans Laboratory Medicine Medicine Medicine & Public Health Metaplasia Mice, Inbred C57BL original-article Pathology Phenotype Precancerous Conditions - genetics Precancerous Conditions - metabolism Precancerous Conditions - microbiology Precancerous Conditions - pathology Promoter Regions, Genetic Proteins - genetics Proteins - metabolism Risk Assessment Risk Factors RNA, Messenger - genetics RNA, Messenger - metabolism ROC Curve SOXB1 Transcription Factors - genetics SOXB1 Transcription Factors - metabolism Stomach Neoplasms - genetics Stomach Neoplasms - metabolism Stomach Neoplasms - microbiology Stomach Neoplasms - pathology Transcription Factors - genetics Transcription Factors - metabolism Transfection |
| title | Inactivation of NKX6.3 in the stomach leads to abnormal expression of CDX2 and SOX2 required for gastric-to-intestinal transdifferentiation |
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