Interaction between viral infection and host genetic susceptibility has increasingly become recognized as an important factor in the etiology of human cancer. Epidemiologic studies suggest that prostate cancer is a complex disease involving host genetic factors and environmental exposures that modify risk. Here we report a novel interaction between infection with human herpesvirus 8 (HHV8) and the human estrogen receptor alpha XbaI polymorphism which is associated with an increased risk of prostate cancer (p=0.032; OR=3.10 95%CI (1.42-6.77)) in an Afrocaribbean population from Tobago. HHV-8 is the causative agent in Kaposis sarcoma (KS). Despite similar HHV-8 seroprevalences, KS lesions are much less common in females, suggesting that sex hormones influence KS pathology. The estrogen receptor (ER) is a ligand-dependant transcription factor that mediates the genomic effects of hormone signaling. Because of the suggested role of sex hormones in KS development and prostate cancer risk, we hypothesized that some HHV-8 genes might be activated by ER. We computationally scanned the HHV-8 genome for estrogen response elements (EREs). Our analysis identified high scoring EREs in the promoter regions of several genes in the HHV-8 genome, including the regulatory gene K8. Binding of ERs to HHV-8 EREs was confirmed by electrophoretic mobility shift assay and ELISA. To demonstrate that HHV-8 EREs were functional, promoter regions were cloned into reporter plasmids and luciferase expression measured with and without estradiol. Our results demonstrated increased reporter transcription in response to estrogens in cells expressing ERĪ±. Further, we analyzed other gammaherpesviruses and identified several conserved EREs, including high-scoring EREs in the promoter of the EBV homolog of K8. These results indicate that estrogen may influence transcription from the HHV-8 genome, outside of the normal viral transcription pathway. Our findings may help to explain the differential risk of KS and could represent an important regulatory pathway in other gammaherpesviruses. Prostate cancer and KS present a tremendous burden on public health, not only in the US, but worldwide. Insights into the pathogenesis of these diseases may help us to understand their basic biology and provide potential screening and therapeutic targets.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-06132008-145343 |
| Date | 26 September 2008 |
| Creators | Shea, Patrick Ryan |
| Contributors | Frank J Jenkins, PhD, Robert E Ferrell, PhD, Panayiotis V. Benos, PhD, Clareann H Bunker, PhD |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-06132008-145343/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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