TitleEpigenetic inactivation of endothelin-2 and endothelin-3 in colon cancer.
Publication TypeJournal Article
Year of Publication2013
AuthorsWang, R, Löhr, CV, Fischer, KA, W Dashwood, M, Greenwood, JA, Ho, E, Williams, DE, Ashktorab, H, Dashwood, MR, Dashwood, RH
JournalInt J Cancer
Volume132
Issue5
Pagination1004-12
Date Published2013 Mar 01
ISSN1097-0215
KeywordsAnimals, Caco-2 Cells, Cell Line, Tumor, Cell Movement, Colonic Neoplasms, DNA Methylation, Endothelin-2, Endothelin-3, Epigenesis, Genetic, Epigenomics, Gene Expression Regulation, Neoplastic, Gene Silencing, HCT116 Cells, HT29 Cells, Humans, Immunohistochemistry, Neoplasm Invasiveness, Rats, RNA, Messenger
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.

DOI10.1002/ijc.27762
Alternate JournalInt. J. Cancer
PubMed ID22865632
PubMed Central IDPMC3500448
Grant ListCA122959 / CA / NCI NIH HHS / United States
P01 CA090890 / CA / NCI NIH HHS / United States
G12 RR003048 / RR / NCRR NIH HHS / United States
R01 CA080176 / CA / NCI NIH HHS / United States
ES00210 / ES / NIEHS NIH HHS / United States
R01 CA122906 / CA / NCI NIH HHS / United States
CA80176 / CA / NCI NIH HHS / United States
R29 CA065525 / CA / NCI NIH HHS / United States
CA090890 / CA / NCI NIH HHS / United States
R01 CA065525 / CA / NCI NIH HHS / United States
CA122906 / CA / NCI NIH HHS / United States
R01 CA122959 / CA / NCI NIH HHS / United States
CA65525 / CA / NCI NIH HHS / United States
P30 ES000210 / ES / NIEHS NIH HHS / United States