Down-regulation of a gastric transcription factor, Sox2, and ectopic expression of intestinal homeobox genes, Cdx1 and Cdx2: inverse correlation during progression from gastric/intestinal-mixed to complete intestinal metaplasia.
OBJECTIVE
The molecular mechanisms underlying the development of intestinal metaplasia (IM) of the human stomach have yet to be clarified in detail. Besides ectopic expression of intestinal transcription factors, Cdx1 and Cdx2, little information is available regarding other regulatory factors. Hence, we here analyzed Sox2, a human homolog of a chicken gastric transcription factor, with reference to our new classification for gastric/intestinal (GI)-mixed type IM.


METHODS
Twenty specimens of surgically resected antral mucosa were subjected to a gland isolation technique. Isolated glands were classified into gastric (G), GI-mixed, and solely intestinal (I) types according to Alcian blue and paradoxical concanavalin A staining and were quantified for mRNA levels of gastrointestinal markers.


RESULTS
MUC5AC and MUC6 transcripts decreased with the progression of IM, while MUC2 and villin-1 were inversely correlated. Sox2 showed a gradual decrease from G, through GI, to the I type (G vs GI and GI vs I, P<0.01 and P<0.005, respectively). On the other hand, Cdx1 (G vs GI and GI vs I, P<0.0001 and P=0.337, respectively) and Cdx2 (G vs GI and GI vs I, P<0.0001 and P<0.05, respectively) appeared in IM. Immunohistochemical study confirmed decreased expression of Sox2 and ectopic emergence of Cdx2 protein in IM glands.


CONCLUSIONS
Down-regulation of Sox2, besides ectopic expression of Cdx genes, may be important factors for the development of IM.
Tsukamoto
Tetsuya
T
Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Nagoya, Chikusa-ku, Japan. ttsukamt@aichi-cc.jp
Inada
Kenichi
K
Tanaka
Harunari
H
Mizoshita
Tsutomu
T
Mihara
Mami
M
Ushijima
Toshikazu
T
Yamamura
Yoshitaka
Y
Nakamura
Shigeo
S
Tatematsu
Masae
M
D030161:Avian Proteins / Q000235:genetics / Q000378:metabolism; D003208:Concanavalin A; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D015536:Down-Regulation; D005753:Gastric Mucosa / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D024002:HMGB Proteins; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D008679:Metaplasia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055271:Mucin 5AC; D055257:Mucin-5B; D055272:Mucin-6; D009077:Mucins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; 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
D030161:Avian Proteins; D004268:DNA-Binding Proteins; D024002:HMGB Proteins; D018398:Homeodomain Proteins; C524678:MUC5AC protein, human; C524578:MUC5B protein, human; C524734:MUC6 protein, human; D055271:Mucin 5AC; D055257:Mucin-5B; D055272:Mucin-6; D009077:Mucins; D009687:Nuclear Proteins; D012333:RNA, Messenger; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D014157:Transcription Factors; D003208:Concanavalin A