Involvement of claudin-1 in the beta-catenin/Tcf signaling pathway and its frequent upregulation in human colorectal cancers.
Accumulation of beta-catenin in cytoplasm and nuclei is frequently observed in a wide variety of tumors arising, for example, in the colon, liver, uterus, or brain. In association with Tcf/LEF transcription factors, beta-catenin regulates expression of genes involved in the Wnt/wingless signaling pathway, but the precise mechanisms are unclear. Here we report evidence that the claudin-1 (CLDNI) gene is one of the genes regulated by beta-catenin. Not only did expression of CLDN1 decrease significantly in response to reduction of intracellular beta-catenin by adenovirus-mediated transfer of wild-type APC into the APC-deficient colon cancer cells, but also two putative Tcf4 binding elements in the 5' flanking region of CLDN1 were confirmed to be responsible for activating its transcription. We documented increased expression of CLDN1 in all 16 primary colorectal cancers we examined, compared with adjacent noncancerous mucosae. Furthermore, immunohistochemical staining demonstrated that claudin-1 was weakly stained at apical boarder of lateral membrane of noncancerous epithelial cells and that it was strongly stained at all cell-cell boundaries and in the cytoplasms of cancer cells. Our results imply that claudin-1 is involved in the beta-catenin-Tcf/LEF signaling pathway, and that increased expression of claudin-1 may have some role in colorectal tumorigenesis.
Miwa
N
N
Laboratory of Molecular Medicine, Institute of Medical Science, The University of Tokyo, Japan.
Furuse
M
M
Tsukita
S
S
Niikawa
N
N
Nakamura
Y
Y
Furukawa
Y
Y
D062445:Claudin-1; D003106:Colon / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000473:pathology / Q000503:physiopathology*; D003598:Cytoskeletal Proteins / Q000502:physiology*; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D010957:Plasmids; D012004:Rectal Neoplasms / Q000503:physiopathology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D019108:Tight Junctions / Q000235:genetics / Q000502:physiology*; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D014407:Tumor Cells, Cultured; D051176:beta Catenin
C568108:CLDN1 protein, human; C495270:CTNNB1 protein, human; D062445:Claudin-1; D003598:Cytoskeletal Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D008565:Membrane Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin