Bone morphogenic protein 3 inactivation is an early and frequent event in colorectal cancer development

Loh, K, Chia, J. A., Greco, S., Cozzi, S.J., Buttenshaw, R.L., Bond, C.E., Simms, L.A., Pike, T., Young, J. P., Jass, J.R., Spring, K. J., Leggett, B. A. and Whitehall, V.L.J. (2008) Bone morphogenic protein 3 inactivation is an early and frequent event in colorectal cancer development. Genes, Chromosomes & Cancer, 47 6: 449-460. doi:10.1002/gcc.20552


Author Loh, K
Chia, J. A.
Greco, S.
Cozzi, S.J.
Buttenshaw, R.L.
Bond, C.E.
Simms, L.A.
Pike, T.
Young, J. P.
Jass, J.R.
Spring, K. J.
Leggett, B. A.
Whitehall, V.L.J.
Title Bone morphogenic protein 3 inactivation is an early and frequent event in colorectal cancer development
Journal name Genes, Chromosomes & Cancer   Check publisher's open access policy
ISSN 1098-2264
1045-2257
Publication date 2008-06
Year available 2008
Sub-type Article (original research)
DOI 10.1002/gcc.20552
Volume 47
Issue 6
Start page 449
End page 460
Total pages 12
Editor Gough, I
Chapius, P.H.
Hall, J.C.
Place of publication New York
Publisher Wiley-Liss
Collection year 2009
Language eng
Subject C1
920102 Cancer and Related Disorders
111201 Cancer Cell Biology
11 Medical and Health Sciences
1112 Oncology and Carcinogenesis
1103 Clinical Sciences
Abstract Bone morphogenic proteins (BMPs) are members of the TGFB growth factor superfamily with well-described functions in bone formation. Although disrupted BMP signalling in tumor development has more recently been investigated, a role for BMP3 in colorectal cancer (CRC) has remained largely unexplored. The aim of this study was to investigate BMP3 disruption in CRCs in relation to both the traditional and serrated pathways of tumor progression. BMP3 was down-regulated as assessed by real-time PCR in 50 of 56 primary tumors (89%). Bisulfite sequencing of the putative promoter revealed extensive hypermethylation in the cell line HT29, in which expression could be restored by treatment with a methyltransferase inhibitor. Aberrant hypermethylation was observed in 33/60 (55%) tumors and was highly correlated with microsatellite instability (P < 0.01), the CpG Island Methylator Phenotype (P < 0.01), BRAF oncogene mutation (P < 0.01), and proximal location (P < 0.001). Methylation was also frequently observed in serrated and traditional adenomatous polyps (22/29, 76%). Re-introduction of BMP3 into cell lines revealed marked growth suppression supporting the functional relevance of this alteration in colorectal tumor development. This study provides molecular and functional data supporting the importance of BMP3 silencing as an early and frequent event in colorectal tumors progressing via the serrated and traditional pathways.
Formatted abstract
Bone morphogenic proteins (BMPs) are members of the TGFB growth factor superfamily with well-described functions in bone formation. Although disrupted BMP signalling in tumor development has more recently been investigated, a role for BMP3 in colorectal cancer (CRC) has remained largely unexplored. The aim of this study was to investigate BMP3 disruption in CRCs in relation to both the traditional and serrated pathways of tumor progression. BMP3 was down-regulated as assessed by real-time PCR in 50 of 56 primary tumors (89%). Bisulfite sequencing of the putative promoter revealed extensive hypermethylation in the cell line HT29, in which expression could be restored by treatment with a methyltransferase inhibitor. Aberrant hypermethylation was observed in 33/60 (55%) tumors and was highly correlated with microsatellite instability (P < 0.01), the CpG Island Methylator Phenotype (P < 0.01), BRAF oncogene mutation (P < 0.01), and proximal location (P < 0.001). Methylation was also frequently observed in serrated and traditional adenomatous polyps (22/29, 76%). Re-introduction of BMP3 into cell lines revealed marked growth suppression supporting the functional relevance of this alteration in colorectal tumor development. This study provides molecular and functional data supporting the importance of BMP3 silencing as an early and frequent event in colorectal tumors progressing via the serrated and traditional pathways.
Q-Index Code C1
Q-Index Status Confirmed Code

 
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Created: Tue, 07 Apr 2009, 12:25:42 EST by Amanda Jones on behalf of School of Medicine