Cdx2 transcription factor regulates claudin-3 and claudin-4 expression during intestinal differentiation of gastric carcinoma.
According to the expression of gastric (claudin-18) and intestinal claudins (claudin-3 and claudin-4), the authors have previously proposed a new phenotypic classification of gastric carcinoma (GC): the gastric (G-CLDN), intestinal (I-CLDN) and unclassified claudin (U-CLDN) phenotypes. The aim of the present study was to examine the role of Cdx2, the caudal-related transcription factor, on the regulation of intestinal claudins expression in vitro and in vivo. It was confirmed on immunohistochemistry that non-neoplastic gastric mucosa with intestinal metaplasia (IM) expressed Cdx2 with increased levels of intestinal claudin expression. In addition, Cdx2 expression was detected in 28 (30%) of 94 GC at the invasive front. Interestingly, Cdx2 expression had a significant association with the I-CLDN phenotype (P < 0.001), which was almost identical to the established gastric and intestinal mucin-based GC classification. Furthermore, the transfection of a recombinant human CDX2-expressing vector into TMK-1 (Cdx2-negative) GC cells specifically elevated the expression of claudin-3 and claudin-4 at the mRNA (CLDN3, 3.9-fold; CLDN4, 2.8-fold) and protein levels (claudin-3, 8.6-fold; claudin-4, 9.8-fold), whereas no induction of the other claudins was detected. These findings suggest that Cdx2 plays an important role in the regulation of intestinal claudin expression not only in gastric mucosa with IM but also GC.
Satake
Shinya
S
Division of Pathology, Department of Pathology and Microbiology, Kobe University Graduate School of Medicine, Kobe, Japan.
Semba
Shuho
S
Matsuda
Yoshiko
Y
Usami
Yu
Y
Chiba
Hideki
H
Sawada
Norimasa
N
Kasuga
Masato
M
Yokozaki
Hiroshi
H
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000378:metabolism; D000071616:CDX2 Transcription Factor; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D062465:Claudin-3; D062506:Claudin-4; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008679:Metaplasia; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013270:Stomach / Q000473:pathology; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014162:Transfection
D014408:Biomarkers, Tumor; D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; C568122:CLDN3 protein, human; C568157:CLDN4 protein, human; D062465:Claudin-3; D062506:Claudin-4; D018398:Homeodomain Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins