Abstract A62: Human endogenous retrovirus activation in prostate cancer: Association with disease progression

Abstract

Abstract Introduction: In recent years scientists have observed that several tumor types, including prostate cancer, show increased expression of human endogenous retrovirus (HERV) when compared to normal tissue. The HERVs originated from germ cell infections by exogenous retroviruses during the course of evolution and became incorporated into the human genome. These elements are widely dispersed throughout the genome and are estimated to comprise of greater than >8% of genomic material. The HERV-K family, evolutionarily the youngest HERV, is the only HERV family with complete open reading frames for all viral genes, and thus are the most likely to be biologically active and potentially pathogenic. The HERV-K provirus encodes for the gag, pol and env genes flanked by two long terminal repeat regions. Both HERV-K type I and HERV-K type II proviruses exist: Type II proviruses are complete (and a such are chronological “older” with regard to their insertion into the genome), while Type I proviruses contain a 292-bp deletion at the boundary of the pol and env genes. Hypothesis: We hypothesize that HERV-K expression is activated with advancing prostate cancer progression and that as a result of this, HERV-K leads to a sustained inflammatory response and subsequent promotion of tumor progression. We believe that HERV-K is suitable target of therapeutic intervention. Experimental Procedures: RNA sequences for type II HERV-K108 (AF074086) were blasted against type I HERV-K102 (AF164610). Sequences were 99% homologous between nucleotides 1-6492 (K108) & 1-1691 (K102) (5′LTR-gag-pro-pol region), the type 1 del in K102 occurred between nucleotides 6493-6793 of K108, subsequent nucleotides 6794-9472 (K108) & 6501-9178 (K102) were 99% homologous (env-3′LTR region). For the detection of HERV-K gag, pol and env mRNA proteins were designed in Primer3, and verified for specificity in Primer-BLAST. Levels of HERV-K gag, pol and env type I or II mRNA were quantified in RWPE1 normal immortalized prostate cells, and CRW22 androgen dependent prostate cancer cell lines, and 22Rv1, PC-3 and DU145 androgen independent prostate cancer cell lines (22Rv1 AI variant of CRW22, PC-3 and DU145 derived from prostate cancer metastasis). HERV-K gag and env protein expression was detected in cell lines by western blotting and in prostate cancer tissue microarrays of hyperplasia and adenocarcinoma using anti-HERV-K gag monoclonal antibody (MAb) and anti-HERV-K env MAb. Effects of HERV-K env inhibition in prostate cancer cells were examined by inhibiting HERV-K env using a HERV-K env targeted MAb, and assessing its effect on cell proliferation and cell invasion using the xCelligence Real-Time Cell Analyser. Results: We found that HERV-K is activated in CRW22, 22Rv1, PC3 and DU145 prostate cancer cell lines, but not in RWPE1 normal prostate cells. Additionally, we observed the HERV-K levels were highest in the bone metastasis derived PC3 and brain metastasis derived DU145 cell lines. We also found that HERV-K was differentially expressed between prostate hyperplasia and adenocarcinoma. Inhibition of HERV-K env resulted in inhibition of PC3 and DU145 cell proliferation and cell invasion. Conclusions: HERV-K is activated in prostate cancer and represents a potential therapeutic target for metastatic prostate cancer. Citation Format: Ronan Downey, Amy Burke, Francis J. Giles, Frank Sullivan, Feng Wang-Johanning, Blanaid Mee, Eoin Gaffney, Sharon Anneve Glynn. Human endogenous retrovirus activation in prostate cancer: Association with disease progression [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A62.