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.

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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