Abstract:
BACKGROUND & AIMS:The finding of bone morphogenetic protein (BMP) receptor 1a mutations in juvenile polyposis suggests that BMPs are important in colorectal cancer (CRC). We investigated the BMP pathway in sporadic CRC. METHODS:We investigated BMP receptor (BMPR) expression using immunoblotting and sequenced BMPR2 in CRC cell lines. We assessed the expression of BMPRs, SMAD4, and pSMAD1/5/8 in 72 sporadic CRCs using a tissue microarray and immunohistochemistry. We assessed the effect of reintroduction of wild-type BMPR2 on BMP pathway activity and the effect of wild-type or mutated BMPR2 3' untranslated region (UTR) sequences on protein expression by attachment to pCMV-Luc. RESULTS:BMPR2 and SMAD4 protein expression is abrogated in microsatellite unstable (MSI) and microsatellite stable (MSS) cell lines, respectively. BMPR2 3'UTR is mutated in all MSI and in none of the MSS cell lines. Mutant BMPR2 3'UTR sequences reduced luciferase expression 10-fold compared with wild-type BMPR2 3'UTR. BMPR2 expression is impaired more frequently in MSI CRCs than MSS (85% vs 29%; P < .0001) and shows a mutually exclusive pattern of impaired expression compared with SMAD4. Nine of 11 MSI cancers with impaired expression of BMPR2 have microsatellite mutations. The BMP pathway is inactivated, as judged by nuclear pSMAD1/5/8 expression, in 70% of CRCs, and this correlates with BMPR and SMAD4 loss. CONCLUSIONS:Our data suggest that the BMP pathway is inactivated in the majority of sporadic CRCs. In MSI CRC this is associated predominantly with impaired BMPR2 expression and in MSS CRC with impaired SMAD4 expression.
journal_name
Gastroenterologyjournal_title
Gastroenterologyauthors
Kodach LL,Wiercinska E,de Miranda NF,Bleuming SA,Musler AR,Peppelenbosch MP,Dekker E,van den Brink GR,van Noesel CJ,Morreau H,Hommes DW,Ten Dijke P,Offerhaus GJ,Hardwick JCdoi
10.1053/j.gastro.2008.02.059subject
Has Abstractpub_date
2008-05-01 00:00:00pages
1332-41issue
5eissn
0016-5085issn
1528-0012pii
S0016-5085(08)00347-8journal_volume
134pub_type
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