Human Molecular Genetics Advance Access published online on September 9, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn286
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Putative direct and indirect Wnt targets identified through consistent gene expression changes in APC-mutant intestinal adenomas from humans and mice
1 Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research UK, 44, Lincoln's Inn Fields, London WC2A 3PX, UK 2 Histopathology Laboratory, London Research Institute, Cancer Research UK, 44, Lincoln's Inn Fields, London WC2A 3PX, UK 3 Bioinformatics and Biostatistics, London Research Institute, Cancer Research UK, 44, Lincoln's Inn Fields, London WC2A 3PX, UK 4 In Situ Hybridisation Service, London Research Institute, Cancer Research UK, 44, Lincoln's Inn Fields, London WC2A 3PX, UK 5 Experimental Pathology Laboratory, London Research Institute, Cancer Research UK, 44, Lincoln's Inn Fields, London WC2A 3PX, UK 6 Polyposis Registry, St Mark's Hospital, Watford Road, Harrow HA1 3UJ, UK 7 Colon Cancer Genetics, Institute of Cell and Molecular Science, Bart's and the London Medical School, Whitechapel, London, UK 8 Department of Histopathology, University of Nottingham, Queen's Medical Centre, Nottingham, UK
* To whom correspondence should be addressed at Cancer Research UK, 44, Lincoln's Inn Fields, London WC2A 3PX, UK. Tel +44 (0)207 269 2884. Fax +44 (0)207 269 3093. Email stefania.segditsas{at}cancer.org.uk
Received August 13, 2008; Revised September 4, 2008; Accepted September 6, 2008
In order to identify new genes with differential expression in early intestinal tumours, we performed mRNA expression profiling of 16 human and 63 mouse adenomas. All individuals had germline APC mutations to ensure that tumorigenesis was driven by ‘second hits’ at APC. Using stringent filtering to identify changes consistent between humans and mice, we identified 60 genes up-regulated and 151 down-regulated in tumours. For 22 selected genes – including known Wnt targets – expression differences were confirmed by qRT-PCR. Most, but not all, differences were also present in colorectal carcinomas. In situ analysis showed a complex picture. Expression of up-regulated genes in adenomas was usually uniform/diffuse (for example, ITGA6) or prominent in the tumour core (for example, LGR5); in normal tissue, these genes were expressed at crypt bases or the transit amplifying zone. Down-regulated genes were often undetectable in adenomas, but in normal tissue were expressed in mesenchyme (for example, GREM1/2) or differentiated cells towards crypt tops (for example, SGK1). In silico analysis of TCF4-binding motifs showed that some of our genes were probably direct Wnt targets. Previous studies, mostly focussed on human tumours, showed partial overlap with our "expression signature", but 37 genes were unique to our study, including TACSTD2, SEMA3F, HOXA9 and IER3 (up-regulated), and TAGLN, GREM1, GREM2, MAB21L2 and RARRES2 (down-regulated). Combined analysis of our and published human data identified additional genes differentially expressed in adenomas, including decreased BMPs and increased BUB1/BUB1B. Several of the newly-identified, differentially-expressed genes represent potential diagnostic or therapeutic targets for intestinal tumours.
+ contributed equally to this work
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