The Bone Morphogenetic Protein Pathway Is Inactivated in the Majority of Sporadic Colorectal Cancers

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