Title | Epigenetic inactivation of endothelin-2 and endothelin-3 in colon cancer. |
Publication Type | Journal Article |
Year of Publication | 2013 |
Authors | Wang, R, ,, Fischer, K, W Dashwood, M, Greenwood, JA, Ho, E, Williams, DE, Ashktorab, H, Dashwood, MR, Dashwood, RH |
Journal | International journal of cancer. Journal international du cancer |
Volume | 132 |
Issue | 5 |
Pagination | 1004-12 |
Date Published | 03/2013 |
Keywords | Messenger, RNA |
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. |
DOI | 10.1002/ijc.27762 |