Epigenetic inactivation of endothelin-2 and endothelin-3 in colon cancer

Rong Wang, Christiane V. Löhr, Kay Fischer, W. Mohaiza Dashwood, Jeffrey A. Greenwood, Emily Ho, David E. Williams, Hassan Ashktorab, Michael R. Dashwood, Roderick H. Dashwood

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Endothelin-1 (ET-1) and its receptors are overexpressed in human cancers, but much less is known about the roles of ET-2 and ET-3 in cancer etiology. We sought to examine human and rat colon tumors for dysregulation of ET-2 and ET-3 expression and determine the underlying mechanisms. Human primary colon cancers and carcinogen-induced rat colon tumors were subjected to real-time RT-PCR, immunoblotting and immunohistochemistry; EDN2 and EDN3 genes were examined by methylation-specific PCR, bisulfite sequencing and pyrosequencing; and forced expression of ET-2 and ET-3 was conducted in human colon cancer cells followed by real-time cell migration and invasion assays. Rat and human colon tumors had markedly reduced expression of ET-2 and ET-3 mRNA and protein compared with matched controls. Mechanistic studies revealed hypermethylation of EDN2 and EDN3 genes in human primary colon cancers and in a panel of human colon cancer cell lines. Forced expression of ET-2 and ET-3 attenuated significantly the migration and invasion of human colon cancer cells. We conclude that epigenetic inactivation of ET-2 and ET-3 occurs frequently in both rat and human colon cancers. Current therapeutic strategies target overexpressed members of the ET axis via small molecule inhibitors and receptor antagonists, but this work supports a complementary approach based on the re-expression of ET-2 and ET-3 as natural antagonists of ET-1 in colon cancer.

Original languageEnglish (US)
Pages (from-to)1004-1012
Number of pages9
JournalInternational Journal of Cancer
Volume132
Issue number5
DOIs
StatePublished - Mar 1 2013

Keywords

  • DNA methylation
  • colorectal cancer
  • endothelin axis
  • epigenetics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Wang, R., Löhr, C. V., Fischer, K., Dashwood, W. M., Greenwood, J. A., Ho, E., Williams, D. E., Ashktorab, H., Dashwood, M. R., & Dashwood, R. H. (2013). Epigenetic inactivation of endothelin-2 and endothelin-3 in colon cancer. International Journal of Cancer, 132(5), 1004-1012. https://doi.org/10.1002/ijc.27762