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Updated: Jul 7, 2026

In vitro Organoid Culture of Primary Mouse Colon Tumors
Published on: May 17, 2013
Bone morphogenic protein 3 inactivation is an early and frequent event in colorectal cancer development
Kim Loh1, June A Chia, Sonia Greco
1Conjoint Gastroenterology Laboratory, Royal Brisbane and Women's Hospital Research Foundation Clinical Research Centre and Queensland Institute of Medical Research, Brisbane 4029, Australia.
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.
Insights
Bone morphogenic protein 3 (BMP3) is frequently silenced in colorectal cancer (CRC) due to gene promoter hypermethylation. This silencing is an early event linked to tumor progression pathways.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- Bone morphogenic proteins (BMPs), part of the TGF-beta superfamily, are crucial for bone formation.
- BMP signaling disruption is implicated in tumor development, but BMP3's role in colorectal cancer (CRC) is understudied.
Purpose of the Study:
- To investigate BMP3 disruption in colorectal cancers (CRCs).
- To correlate BMP3 alterations with traditional and serrated tumor progression pathways.
Main Methods:
- Real-time PCR to assess BMP3 down-regulation in primary tumors.
- Bisulfite sequencing to analyze promoter methylation.
- Methyltransferase inhibitor treatment to assess expression restoration.
- Functional assays involving BMP3 re-introduction into cell lines.
Main Results:
- BMP3 was down-regulated in 89% of primary CRCs.
- Extensive promoter hypermethylation was found in cell lines and 55% of tumors, correlating with microsatellite instability, CpG Island Methylator Phenotype, BRAF mutation, and proximal location.
- Methylation was also prevalent in serrated and traditional adenomatous polyps (76%).
- Restored BMP3 expression suppressed tumor cell growth.
Conclusions:
- BMP3 silencing, via promoter hypermethylation, is an early and frequent event in CRC development.
- This silencing occurs in both serrated and traditional colorectal tumor progression pathways.
- BMP3 plays a significant role in suppressing colorectal tumor growth.
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