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Laboratory of Comparative Carcinogenesis

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Mechanisms linking nitric oxide and cyclooxygenase-2 in colorectal cancer

The Metabolism and Cancer Susceptibility Section, headed by James Phang, recently reported in the Journal of Biological Chemistry (279:18694-18700, 2004) the molecular mechanisms linking nitric oxide (NO), an inflammatory signal, and cyclooxygenase-2 (COX-2). These studies help to explain the increased cancer susceptibility in patients with inflammatory bowel disease.

Using cultured colorectal cancer cells, Yongmin Liu and co-workers showed that COX-2, an enzyme involved in carcinogenesis, is increased in cells treated exogenously with NO or transfected with the iNOS gene to endogenously generate NO. This COX-2 increase was mediated by at least two mechanisms. First, NO increased the induction of COX-2 by polyoma enhancer activator 3 (PEA3), a member of the Ets family of transcriptional factors. In studies using a COX-2 promoter/luciferase construct, the effect of NO was selective for cells expressing PEA3 and required intact ETS-1 and NF-IL6 sites on the COX-2 promoter. Secondly, NO augmented the production of PEA3 through β-catenin/Wnt signaling by causing the release of β-catenin from membrane binding sites to form a transcriptional complex mediating PEA3 expression. These findings emphasize the interaction of inflammatory signals (NO) with metabolic mediators of carcinogenesis and provide a model for the molecular mechanisms mediating this interaction.

Study links In Utero Arsenic Exposure to Estrogen Signaling in Liver Cancer

Michael Waalkes' Inorganic Carcinogenesis Section recently reported in the Journal of the National Cancer Institute, 96, 466-474, 2004 a link in mice between estrogen signaling and hepatocellular carcinoma (HCC) caused by in utero exposure to arsenic. Tumors from HCC, a specific type of liver cancer, have previously been reported to be associated with arsenic exposure in humans.

The researchers found higher expression levels of the estrogen receptor-α (ER-α) gene, an indicator of changes in estrogen signaling, in the livers of adult male mice that had developed the tumors after in utero arsenic exposure. Another gene, cyclin D1, a cell cycle regulator that responds to estrogen signaling, also demonstrated increased expression levels when compared to levels found in control mice. The mice with HCC had decreased methylation of the promoter region of their ER-α gene, which may be the cause for these changes in expression levels. Furthermore, the researchers looked at human liver biopsy samples from men who were exposed to high levels of arsenic and found that ER-α and cyclin D1 were also overexpressed, compared to genes in samples from people not exposed to high levels of arsenic. "Taken together," the study concludes, "these data indicate that aberrant expression of the ER-α gene, as a result of changes in methylation, could be an important molecular event in carcinogenesis induced by inorganic arsenic, at least in the liver."

From the NCI Cancer Bulletin, 1: 2004, 5

This page was last updated on 11/28/2007.