Article

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

Linus Pauling Institute, Oregon State University, Corvallis, OR.
International Journal of Cancer (Impact Factor: 5.01). 03/2013; 132(5). DOI: 10.1002/ijc.27762
Source: PubMed

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.

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    • "While in premalignant adenomas and malignant colon carcinomas, exhibit increased levels of pre- proET-1, endothelin-converting enzymes, and ET-1 [7] [8], there is no consensus about how the ETA and ETB receptors behave [9] [10]. On the other hand, it has been recently proved that ET-2 and ET-3 are silenced in colon cancer and their induced overexpressions inhibit cell migration and invasion [11]. In that work, it was hypothesized that ET-2 and ET-3 might be silenced in early stages of cancer avoiding " mixed messages " in the ET axis. "
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