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Conference Paper: Investigation of signaling pathways that regulate human colon crypt maturation and their dysregulation in tumorigenesis

TitleInvestigation of signaling pathways that regulate human colon crypt maturation and their dysregulation in tumorigenesis
Authors
Issue Date2007
PublisherAmerican Association for Cancer Research
Citation
AACR 98th Annual Meeting, Los Angeles, CA, 14–18 April 2007. In Cancer Research, 2007, v. 67 n. 9S, p. 2048 How to Cite?
AbstractIntestinal epithelial cell polarity and lineages along the crypt-villus axis provide an excellent model in studying genetic programs controlling cellular proliferation and differentiation. Multipotent stem cells residing at the bottom of the intestinal crypts undergo cell division, where daughter cells will migrate upwards and undergo cell cycle arrest and differentiation. Although the biological and genetic regulation of these processes still remains unclear, there has been report on several key pathways regarding this regulation, including Wnt, Notch and TGF signaling pathways. This study is based on the hypothesis that perturbation of the signaling pathways that regulate cellular polarity and maturation along the colon crypt axis is closely related to tumor development and progression in gastrointestinal tract cancers. To study the differential gene expression between upper and bottom part of colon crypt, a total of 18 cDNA microarray experiments were performed using RNA extracted from 9 paired upper and bottom parts of the colon crypts. Gene expression data were extracted, and Significance Analysis of Microarrays (SAM) was performed to identify genes with significant correlating expression at bottom compartment of the crypts. 969 cDNA clones with significant differential expression were identified, in which 367 and 602 cDNA clones were preferentially upregulated and downregulated respectively in bottom proliferative compartment of the crypts. A significant correlation of these 969 SAM list genes with WNT target genes (obtained from inducible dominant negative TCF4 transfection in CRC cell lines by van de Watering et al) was observed, demonstrating that colon development is tightly regulated by WNT-signaling pathway through TCF4 transcription regulation. Biological pathway analysis using GenMapp illustrated that the colon crypt development involved multiple molecular pathways, including cell cycle, apoptosis, MAP kinase, WNT and BMP pathways etc. Strikingly, we have identified a set of genes that code for secretory proteins of several key pathways where most of them have been previously demonstrated to be expressed in connective tissues, postulating that intestinal myofibroblasts were playing important roles in maintaining the microenvironment for epithelial cells development. With the help of the colon top/bottom array data set obtained here, we hope to provide a comprehensive picture for understanding the global regulation in colonic epithelial cells maturation by in depth analysis of the gene expression profile.
Persistent Identifierhttp://hdl.handle.net/10722/104771
ISSN
2015 Impact Factor: 8.556
2015 SCImago Journal Rankings: 5.372

 

DC FieldValueLanguage
dc.contributor.authorLi, VSWen_HK
dc.contributor.authorYuen, STen_HK
dc.contributor.authorChan, ASYen_HK
dc.contributor.authorTsui, WYen_HK
dc.contributor.authorChen, Xen_HK
dc.contributor.authorLeung, SYen_HK
dc.date.accessioned2010-09-25T22:06:40Z-
dc.date.available2010-09-25T22:06:40Z-
dc.date.issued2007en_HK
dc.identifier.citationAACR 98th Annual Meeting, Los Angeles, CA, 14–18 April 2007. In Cancer Research, 2007, v. 67 n. 9S, p. 2048-
dc.identifier.issn0008-5472-
dc.identifier.urihttp://hdl.handle.net/10722/104771-
dc.description.abstractIntestinal epithelial cell polarity and lineages along the crypt-villus axis provide an excellent model in studying genetic programs controlling cellular proliferation and differentiation. Multipotent stem cells residing at the bottom of the intestinal crypts undergo cell division, where daughter cells will migrate upwards and undergo cell cycle arrest and differentiation. Although the biological and genetic regulation of these processes still remains unclear, there has been report on several key pathways regarding this regulation, including Wnt, Notch and TGF signaling pathways. This study is based on the hypothesis that perturbation of the signaling pathways that regulate cellular polarity and maturation along the colon crypt axis is closely related to tumor development and progression in gastrointestinal tract cancers. To study the differential gene expression between upper and bottom part of colon crypt, a total of 18 cDNA microarray experiments were performed using RNA extracted from 9 paired upper and bottom parts of the colon crypts. Gene expression data were extracted, and Significance Analysis of Microarrays (SAM) was performed to identify genes with significant correlating expression at bottom compartment of the crypts. 969 cDNA clones with significant differential expression were identified, in which 367 and 602 cDNA clones were preferentially upregulated and downregulated respectively in bottom proliferative compartment of the crypts. A significant correlation of these 969 SAM list genes with WNT target genes (obtained from inducible dominant negative TCF4 transfection in CRC cell lines by van de Watering et al) was observed, demonstrating that colon development is tightly regulated by WNT-signaling pathway through TCF4 transcription regulation. Biological pathway analysis using GenMapp illustrated that the colon crypt development involved multiple molecular pathways, including cell cycle, apoptosis, MAP kinase, WNT and BMP pathways etc. Strikingly, we have identified a set of genes that code for secretory proteins of several key pathways where most of them have been previously demonstrated to be expressed in connective tissues, postulating that intestinal myofibroblasts were playing important roles in maintaining the microenvironment for epithelial cells development. With the help of the colon top/bottom array data set obtained here, we hope to provide a comprehensive picture for understanding the global regulation in colonic epithelial cells maturation by in depth analysis of the gene expression profile.-
dc.languageengen_HK
dc.publisherAmerican Association for Cancer Research-
dc.relation.ispartofCancer Researchen_HK
dc.titleInvestigation of signaling pathways that regulate human colon crypt maturation and their dysregulation in tumorigenesisen_HK
dc.typeConference_Paperen_HK
dc.identifier.emailLi, VSW: vswli81@graduate.hku.hken_HK
dc.identifier.emailYuen, ST: styuen@hkucc.hku.hken_HK
dc.identifier.emailChan, ASY: asychan@HKUCC.hku.hken_HK
dc.identifier.emailTsui, WY: wendy@pathology.hku.hken_HK
dc.identifier.emailLeung, SY: suetyi@hkucc.hku.hken_HK
dc.identifier.authorityLeung, SY=rp00359en_HK
dc.identifier.hkuros126945en_HK

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