BMP4 promotes a phenotype change of an esophageal squamous epithelium via up-regulation of KLF4.
BACKGROUND
Barrett's esophagus is a metaplastic lesion. However, the cellular and molecular mechanisms involved are poorly understood. The aim of this study was to investigate the roles of KLF4 and BMP4 in the pathogenesis of Barrett's epithelium.


METHODS
Immunohistochemistry was used to analyse the expression of KLF4, BMP4, CDX2, MUC2 and MUC5AC in human esophageal specimens. Human esophageal squamous epithelial cells were subjected to bile acid treatment and used in transfection experiments. Quantitative real-time PCR and Western blot analysis were used to detect the expression of KLF4, BMP4, CDX2, MUC2 and MUC5ac.


RESULTS
In human tissues, Barrett's epithelium strongly expressed BMP4, p-Smad1/5/8 and KLF4. Furthermore, bile acids increased the expression of BMP4, KLF4, p-Smad1/5/8, CDX2, MUC2 and MUC5ac in esophageal epithelial cells in a time-dependent manner. Moreover, we found that BMP4 up-regulated the expression of KLF4, CDX2, MUC2 and MUC5ac, but Noggin, a specific BMP4 antagonist, can block the expression of KLF4, CDX2, MUC2 and MUC5ac induced by BMP4. However, BMP4 cannot induce the expression of CDX2, MUC2 and MUC5ac in cells with KLF4 siRNA, and Noggin cannot block the expression of KLF4, CDX2, MUC2 and MUC5ac in cells transfected with the KLF4 expression vector.


CONCLUSIONS
Our results demonstrate that BMP4 promotes a phenotype change of an esophageal squamous epithelium via up-regulation of KLF4.
Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, PR China.
Wu
W
Yan
Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, PR China.
Haoxiang
H
Zhang
Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, PR China.
Jingwen
J
Li
Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, PR China.
Caifei
C
Shen
Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, PR China.
Yiju
Y
Xia
Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, PR China.
Pu
P
Wang
Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, PR China.
Yafei
Y
Zhang
Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, PR China.
Ji
J
Feng
Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, PR China.
Shunzi
S
Shao
Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, PR China.
Xiaona
X
Yu
Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, PR China. Electronic address: fang_dianchun@163.com.
Dianchun
D
Fang
D000328:Adult; D000368:Aged; D001471:Barrett Esophagus / Q000473:pathology*; D015415:Biomarkers / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000494:pharmacology; D002460:Cell Line; D003840:Deoxycholic Acid; D015536:Down-Regulation; D004947:Esophagus / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009077:Mucins / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D015854:Up-Regulation; D000099176:Noggin Protein
D015415:Biomarkers; D055415:Bone Morphogenetic Protein 4; D002352:Carrier Proteins; D003840:Deoxycholic Acid; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D009077:Mucins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051785:Smad Proteins; D000099176:Noggin Protein; C000715467:KLF4 protein, human
BMP4 signalling; Barrett' s esophagus; DCA; HET-1A; KLF4