The protein tyrosine phosphatase receptor type R gene is an early and frequent target of silencing in human colorectal tumorigenesis.
BACKGROUND
Tumor development in the human colon is commonly accompanied by epigenetic changes, such as DNA methylation and chromatin modifications. These alterations result in significant, inheritable changes in gene expression that contribute to the selection of tumor cells with enhanced survival potential.


RESULTS
A recent high-throughput gene expression analysis conducted by our group identified numerous genes whose transcription was markedly diminished in colorectal tumors. One of these, the protein-tyrosine phosphatase receptor type R (PTPRR) gene, was dramatically downregulated from the earliest stages of cellular transformation. Here, we show that levels of both major PTPRR transcript variants are markedly decreased (compared with normal mucosal levels) in precancerous and cancerous colorectal tumors, as well in colorectal cancer cell lines. The expression of the PTPRR-1 isoform was inactivated in colorectal cancer cells as a result of de novo CpG island methylation and enrichment of transcription-repressive histone-tail marks, mainly H3K27me3. De novo methylation of the PTPRR-1 transcription start site was demonstrated in 29/36 (80%) colorectal adenomas, 42/44 (95%) colorectal adenocarcinomas, and 8/8 (100%) liver metastases associated with the latter tumors.


CONCLUSIONS
Epigenetic downregulation of PTPRR seems to be an early alteration in colorectal cell transformation, which is maintained during the clonal selection associated with tumor progression. It may represent a preliminary step in the constitutive activation of the RAS/RAF/MAPK/ERK signalling, an effect that will later be consolidated by mutations in genes encoding key components of this pathway.
Menigatti
Mirco
M
Institute of Molecular Cancer Research, University of Zurich, Switzerland. menigatti@imcr.uzh.ch
Cattaneo
Elisa
E
Sabates-Bellver
Jacob
J
Ilinsky
Valery V
VV
Went
Philip
P
Buffoli
Federico
F
Marquez
Victor E
VE
Jiricny
Josef
J
Marra
Giancarlo
G
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D020868:Gene Silencing; D006801:Humans; D012333:RNA, Messenger / Q000235:genetics; D054634:Receptor-Like Protein Tyrosine Phosphatases, Class 7 / Q000235:genetics*
D012333:RNA, Messenger; C513469:PTPRR protein, human; D054634:Receptor-Like Protein Tyrosine Phosphatases, Class 7