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Epigenetic inactivation of calcium-sensing receptor in colorectal carcinogenesis

Keiichi Hizaki1, Hiroyuki Yamamoto, Hiroaki Taniguchi

  • 1First Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.

Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc
|February 15, 2011
PubMed

Insights

Epigenetic silencing of the calcium-sensing receptor (CASR) via methylation is a key event in colorectal cancer development. Restoring CASR expression can re-sensitize cancer cells to chemotherapy, highlighting CASR

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Ion transport systems are frequently altered in human cancers.
  • Calcium (Ca2+) acts as a chemopreventive agent for colon cancer.

Purpose of the Study:

  • To investigate alterations in the calcium-sensing receptor (CASR) during colorectal carcinogenesis.
  • To determine the role of CASR promoter methylation in colorectal cancer development.

Main Methods:

  • Analysis of CASR expression (mRNA and protein) in colorectal cancer cell lines and tissues using RT-PCR and immunostaining.
  • Assessment of CASR promoter methylation via bisulfite sequencing and methylation-specific PCR.
  • In vitro studies using demethylating agents and histone deacetylase inhibitors to restore CASR expression.

Main Results:

  • CASR expression was significantly downregulated in most colorectal cancer cell lines and tissues.
  • Dense methylation of CASR CpG islands correlated with reduced CASR expression in cancer cells.
  • Demethylating agents and histone deacetylase inhibitors restored CASR expression.
  • CASR methylation was detected in adenoma and cancer tissues, increasing with tumor progression.
  • Reduced CASR expression was inversely correlated with tumor differentiation and linked to invasive fronts.

Conclusions:

  • Epigenetic inactivation of CASR through promoter methylation plays a crucial role in colorectal carcinogenesis.
  • CASR methylation occurs early and progresses during colorectal cancer development.
  • Restoration of CASR expression can enhance the cytotoxic effects of chemotherapy, suggesting therapeutic potential.

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