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GASTROINTESTINAL CANCER |
1 Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
2 Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
3 Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Correspondence to:
Correspondence to:
Dr M Katano
Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; mkatano{at}tumor.med.kyushu-u.ac.jp
ABSTRACT
Background: Early events in the progression of 90% of sporadic colorectal cancers depend on constitutive activation of Wnt signalling. Recent data also indicate a close association between the Hedgehog (Hh) and Wnt pathways in colonic epithelial cell differentiation.
Aims: To investigate whether expression of Gli1, a transactivator of Hh signalling, can suppress Wnt signalling and inhibit proliferation of human colorectal cancer cells.
Methods: Gli1 and nuclear ß-catenin expression were examined in a series of 40 human colorectal cancers by immunohistochemistry. We quantified Gli1 and nuclear ß-catenin staining as markers of Hh and Wnt pathway activation, respectively. Two human colon cancer cell lines, SW480 and HCT116, with mutations in APC and ß-catenin, respectively, were used. The effects of Gli1 overexpression on Wnt transcriptional activity, ß-catenin subcellular distribution, and proliferation in these cells were analysed.
Results: Nuclear accumulation of ß-catenin and the Gli1 staining level were inversely associated in the 40 human colorectal cancers. Wnt transcriptional activity was reduced in Gli1 transfected cells. These effects were observed even in Gli1 transfected cells cotransfected with mutated ß-catenin. Furthermore, nuclear accumulation of ß-catenin was diminished compared with that in empty vector transfected cells, and downregulated transcription of c-Myc was observed in Gli1 transfected cells. Proliferation of Gli1 transfected cells was also significantly suppressed compared with that in empty vector transfected cells.
Conclusions: Our data suggest that Gli1 plays an inhibitory role in the development of colorectal cancer involving Wnt signalling, even in cases with the stabilising mutation of ß-catenin.
Abbreviations: APC, adenomatous polyposis coli; TCF, T cell factor; LEF, lymphoid enhancer factor; Hh, hedgehog; Shh, Sonic hedgehog; Ihh, Indian hedgehog; Ptch, patched; Smo, smoothened; PBS, phosphate buffered saline; UICC, International Union Against Cancer; HA, haemagglutinin; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; RT-PCR, reverse transcription-polymerase chain reaction; GSK3ß, glycogen synthase kinase 3ß
Keywords: Hedgehog signalling; Wnt signalling; Gli1; ß-catenin; colorectal cancer
Relevant Article
Gut 2006 55: 912-914.
This article has been cited by other articles:
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  J. He, T. Sheng, A. A. Stelter, C. Li, X. Zhang, M. Sinha, B. A. Luxon, and J. Xie Suppressing Wnt Signaling by the Hedgehog Pathway through sFRP-1 J. Biol. Chem., November 24, 2006; 281(47): 35598 - 35602. [Abstract] [Full Text] [PDF]
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 G R van den Brink and J C H Hardwick Hedgehog Wnteraction in colorectal cancer Gut, July 1, 2006; 55(7): 912 - 914. [Full Text] [PDF]
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