Going viral? Linking the etiology of human prostate cancer to the PCA3 long noncoding RNA and oncogenic viruses

Prostate cancer, the most frequent type of cancer in men, is surpassed only by lung cancer in causing cancer‐related death. Despite major progress in defining the mutational landscape of this tumor, its etiology remains obscure. The intronic long‐noncoding RNA (lncRNA) PCA3 is a specific marker of prostate cancer that acts as a trans‐dominant negative oncogene to down‐regulate the tumor suppressor gene PRUNE2 . The unusual genomic organization and sequence of PCA3 leads us to hypothesize that it was introduced into the human genome by an as‐yet undefined oncogenic virus. We further suggest viral infection‐related mechanisms as functional in PCA3 overexpression and involved in prostate cancer initiation and/or progression. This is supported by known links between viral infections and prostate cancer, and the lack of this tumor in other mammals despite its high incidence in humans. Finally, we suggest that genomic sequence‐based approaches might help us uncover the potential role of viruses in prostate cancer etiology. The intronic lncRNA Prostate Cancer Antigen 3 ( PCA3 ) is a highly specific biomarker: While only present at low levels in normal or benign hyperplastic prostate, its expression is increased up to 100‐fold in about 95% of prostatic carcinomas (Schalken et al , 2003). Despite this strong correlation, the biological function of PCA3 remained elusive for almost two decades after its discovery (Bussemakers et al , 1999), until we established its role as a trans‐dominant negative oncogene that downregulates a protein‐coding tumor suppressor gene, prune homolog 2 ( PRUNE2 ) (Salameh et al , 2015). In experimental models of human prostate cancer, PCA3 overexpression as well as PRUNE2 silencing accelerates the growth of tumor xenografts in vivo , while increasing cell proliferation, adhesion, and migration in vitro (Salameh et al , 2015). In prostate cancer patients, …