Journal Article

Convergence of three steroid receptor pathways in the mediation of nongenotoxic hepatocarcinogenesis

M.L. O'Brien, S.M. Rangwala, K.W. Henry, C. Weinberger, D.C. Crick, C.J. Waechter, D.R. Feller and D.J. Noonan

in Carcinogenesis

Volume 17, issue 2, pages 185-190
Published in print February 1996 | ISSN: 0143-3334
Published online February 1996 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/17.2.185
Convergence of three steroid receptor pathways in the mediation of
                    nongenotoxic hepatocarcinogenesis

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The mechanisms by which peroxisome proliferators are able to regulate metabolic processes such as fat metabolism, whileat the same time creating an environment for the development of hepatocellular carcinomas, is a central issue in the non-genotoxic carcinogenesis field. The convergence of two members of the steroid receptor family (peroxisome proliferator-activated receptor, PPAR; and retinold X receptor, RXR) has provided strong support for an oxidative stress component in this carcinogenesis process, but has yet to define clearly a pathway for the classical tumor promotion events associated with peroxi-some proliferation. The findings presented here integrate a third member of the steroid receptor family into this process and suggest a novel autocrine loop and mechanism for creating both oxidative stress and tumor promotion. A central regulatory component in this pathway is farnesol which has recently been shown to induce transcription mediated by the steroid receptor family member, farnesoid X receptor (FXR). In this report, it is clearly demonstrated that farnesol can also upregulate the transcriptional events of PPAR, but most likely through a different farnesoid metabolite, resulting in the regulation of an entirely different set of genetic components. Deregulation of the activities of these receptors offers a provocative mechanism for explaning the hepatocarcinogenic effects of peroxisome proliferators in chronically treated rodents.

Journal Article.  0 words. 

Subjects: Clinical Cytogenetics and Molecular Genetics

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