Microarray-based Identification of Individual HERV Loci Expression: Application to Biomarker Discovery in Prostate Cancer

Abstract

The prostate-specific antigen (PSA) is the main diagnostic biomarker for prostate cancer in clinical use, but it lacks specificity and sensitivity, particularly in low dosage values 1 . 'How to use PSA' remains a current issue, either for diagnosis as a gray zone corresponding to a concentration in serum of 2.5-10 ng/ml which does not allow a clear differentiation to be made between cancer and noncancer 2 or for patient follow-up as analysis of post-operative PSA kinetic parameters can pose considerable challenges for their practical application 3,4 . Alternatively, noncoding RNAs (ncRNAs) are emerging as key molecules in human cancer, with the potential to serve as novel markers of disease, e.g. PCA3 in prostate cancer 5,6 and to reveal uncharacterized aspects of tumor biology. Moreover, data from the ENCODE project published in 2012showed that different RNA types cover about 62% of the genome. It also appears that the amount of transcriptional regulatory motifs is at least 4.5x higher than the one corresponding to protein-coding exons. Thus, long terminal repeats (LTRs) of human endogenous retroviruses (HERVs) constitute a wide range of putative/candidate transcriptional regulatory sequences, as it is their primary function in infectious retroviruses. HERVs, which are spread throughout the human genome, originate from ancestral and independent infections within the germ line, followed by copy-paste propagation processes and leading to multicopy families occupying 8% of the human genome (note that exons span 2% of our genome). Some HERV loci still express proteins that have been associated with several pathologies including cancer [7][8][9][10]

Prostate-specific loss of UXT promotes cancer progression

“…The mechanism underlying reactivation of normally silenced retroelements in prostate cancer remains unclear. Increased mRNA expression of HERV-K is detected in prostate cancer, and may be involved in chromosomal translocation and cancer initiation [31]. Expression of HERV-K is inducible by androgens in LNCaP cells [32, 33].…”

Human endogenous retrovirus HERV-K(HML-2) activity in prostate cancer is dominated by a few loci

“…Given the accumulating evidence that HERV expression may contribute to prostate cancer , we characterized the range of HML‐2 proviruses expressed in PCa and benign prostatic tissue. A general difficulty in this characterization lies in the nature of the HML‐2 repeat sequences, which are very similar to each other.…”

Molecular functions of human endogenous retroviruses in health and disease

“…Not only proteins, but also non-coding sequences including viral regulatory elements, considerably shaped human genome and transcriptome [32, [102][103][104]. HERV LTRs have functional enhancers, promoters, polyadenylation signals and splice sites.…”