HERV-K Gag RNA and Protein Levels Are Elevated in Malignant Regions of the Prostate in Males with Prostate Cancer.

Simin D Rezaei,Gilda Tachedjian,John Mills,Sam Norden,John Pedersen,Joshua A Hayward,Anna C Hearps

doi:10.3390/v13030449

Simin D Rezaei, Gilda Tachedjian + Show 5 more

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https://doi.org/10.3390/v13030449

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Abstract

Heightened expression of human endogenous retrovirus (HERV) sequences has been associated with a range of malignancies, including prostate cancer, suggesting that they may serve as useful diagnostic or prognostic cancer biomarkers. We analysed the expression of HERV-K (Gag and Env/Np9 regions), HERV-E 4.1 (Pol and Env regions), HERV-H (Pol) and HERV-W (Gag) sequences in prostate cancer cells lines and normal prostate epithelial cells using qRT-PCR. HERV expression was also analysed in matched malignant and benign prostate tissue samples from men with prostate cancer (n = 27, median age 65.2 years (range 47–70)) and compared to prostate cancer-free male controls (n = 11). Prostate cancer epithelial cell lines exhibited a signature of HERV RNA overexpression, with all HERVs analysed, except HERV-E Pol, showing heightened expression in at least two, but more commonly all, cell lines analysed. Analysis of primary prostate material indicated increased expression of HERV-E Pol but decreased expression of HERV-E Env in both malignant and benign regions of the prostate in men with prostate cancer as compared to those without. Expression of HERV-K Gag was significantly higher in malignant regions of the prostate in men with prostate cancer as compared to matched benign regions and prostate cancer-free men (p < 0.001 for both), with 85.2% of prostate cancers donors showing malignancy-associated upregulation of HERV-K Gag RNA. HERV-K Gag protein was detected in 12/18 (66.7%) malignant tissues using immunohistochemistry, but only 1/18 (5.6%) benign tissue sections. Heightened expression of HERV-K Gag RNA and protein appears to be a sensitive and specific biomarker of prostate malignancy in this cohort of men with prostate carcinoma, supporting its potential utility as a non-invasive, adjunct clinical biomarker.

Highlights

This article is an open access articleProstate cancer is the second most common cancer in males worldwide and the second most common cause of cancer deaths amongst males in many high-income countries [1].Prostate-specific antigen (PSA)-based screening for prostate cancer was introduced in the late 1980s and has since contributed substantially to early disease detection and the subsequent decline in age-standardised mortality rates [1]
We determined the expression pattern of six Human endogenous retrovirus (HERV) transcripts in cDNA derived from primary prostate epithelial cells and three primary and two immortalised prostate cancer cell lines using qPCR, standardising expression relative to the housekeeping gene
A similar pattern of HERV transcript overexpression was largely observed for HERV-K Gag, -E Pol and -W Gag transcripts, irrespective of the gene used for standardisation

Summary

Introduction

Prostate-specific antigen (PSA)-based screening for prostate cancer was introduced in the late 1980s and has since contributed substantially to early disease detection and the subsequent decline in age-standardised mortality rates [1]. Prostate cancer in many settings are >90%, with some countries achieving early diagnosis in over 80% of cases in either stage I or II [2]. A greater understanding of additional, measurable parameters that may facilitate the identification of clinically relevant prostate cancers would be beneficial to prevent physical and psychosocial damages associated with over-diagnosis and treatment. Substantial deletions and inactivating mutations have rendered these viruses non-infectious, HERV elements can be transcriptionally active and many sequences retain open reading frames capable of producing viral proteins [5]. HERV regulatory elements located in viral long terminal repeat (LTR) regions can provide tissue-specific enhancers, promoters or alternative polyadenylation signals that may influence the expression of nearby genes [6,7]

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