Human endogenous retrovirus K (HERV-K) in prostate cancer
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Millions of years of infection by viral agents have left their mark on the human genome in the form of human endogenous retroviruses (HERVs). These retroelements integrated into our germline, became subject to Mendelian inheritance, and now occupy 8% of the genome. The majority of these HERVs are replication incompetent due to the accumulation of defective mutations. The most conserved HERV group is that of HERV-K – more specifically HERV-K (HML-2). A number of proviral members of this sub-family contain intact ORFs for all the canonical retroviral genes (gagpol-pro-env), including accessory proteins such as Rec. HERVs have been implicated in the etiology of cancers such as breast, ovarian and melanoma due to the observation of high levels of HERV-K (HML-2) mRNA and protein. However, a paucity of data exists regarding the expression of HERVs in prostate cancer. We set out to investigate HERV-K (HML-2) expression in prostate cancer. We analysed prostate cancer cell lines and clinical samples for HML-2 expression. Our results show that both HML-2 mRNA and protein is expressed in prostate cancer cell lines and in clinical samples. We also found evidence for the expression of spliced Rec and Np9 mRNA and Rec protein in prostate cancer cell lines. We completed a case-control study to investigate the potential of using HML-2 as a non invasive biomarker for the diagnosis of prostate cancer by analysing blood for HML-2 mRNA expression using qPCR. Univariate logistic regression analysis revealed that HML-2 gag mRNA expression in PBMCs was significantly associated with a prostate cancer diagnosis and that this association was strongest in older men and smokers. Further to this, we conducted immunohistochemistry on prostate tissue microarrays containing cores from prostate adenocarcinoma and benign prostatic hyperplasia (BPH) cases. We observed significantly greater epithelial x HERV-K gag protein expression in BPH cores versus prostate adenocarcinoma cores (Fisher exact test, p=0.001). Our data indicate that measuring HERV-K (HML-2) expression may improve the discriminatory ability of prostate specific antigen (PSA) in the diagnosis of prostate cancer versus BPH especially in older men. We also investigated whether Rec plays a functional role in prostate cancer initiation or progression. To this end, we created a construct to overexpress Rec in prostate cancer cells and transfected this into non tumorigenic RWPE-1 prostate cells. We found Rec expression to be low to negative in the transfected cell line but the cloning process did reveal the expression of a polymorphic provirus from chromosome 5 in LNCap cells which most likely represents ERVK-9. Overall, this thesis has demonstrated that HERV-K (HML-2) is expressed in prostate cancer and that this expression has the potential to be utilised as a biomarker for disease detection. Finally, the functional role of HML-2 expression in prostate cancer initiation and progression warrants further investigation.
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