The p53-microRNA-34a axis regulates cellular entry receptors for tumor-associated human herpes viruses

Abstract

A growing number of reports indicate the frequent presence of DNA sequences and gene products of human cytomegalovirus in various tumors as compared to adjacent normal tissues, the brain tumors being studied most intensely. The mechanisms underlying the tropism of human cytomegalovirus to the tumor cells or to the cells of tumor origin, as well as the role of the host's genetic background in virus-associated oncogenesis are not well understood. It is also not clear why cytomegalovirus can be detected in many but not in all tumor specimens. Our in silico prediction results indicate that microRNA-34a may be involved in replication of some human DNA viruses by targeting and downregulating the genes encoding a diverse group of proteins, such as platelet-derived growth factor receptor-alpha, complement component receptor 2, herpes simplex virus entry mediators A, B, and C, and CD46. Notably, while their functions vary, these surface molecules have one feature in common: they serve as cellular entry receptors for human DNA viruses (cytomegalovirus, Epstein-Barr virus, human herpes virus 6, herpes simplex viruses 1 and 2, and adenoviruses) that are either proven or suspected to be linked with malignancies. MicroRNA-34a is strictly dependent on its transcriptional activator tumor suppressor protein p53, and both p53 and microRNA-34a are frequently mutated or downregulated in various cancers. We hypothesize that p53-microRNA-34a axis may alter susceptibility of cells to infection with some viruses that are detected in tumors and either proven or suspected to be associated with tumor initiation and progression.

Figure 1. Predicted microRNA-34a seed matches to viral entry receptors mRNAs

Results of in silico analysis suggesting the presence of microRNA-34a (miR-34a) target sites on the genes encoding cellular entry receptors for the following viruses: platelet-derived growth factor receptor-alpha (PDGFRA) – cellular entry receptor for human cytomegalovirus; complement component receptor 2 (CCR2) – for Epstein-Barr virus; CD46 – for human herpes virus 6 and human adenoviruses group B; and herpes simplex virus entry mediators A, B, and C (HVEM-A, -B, -C). Phosphoprotein enriched in astrocytes-15 (PEA15) is a positive regulator for coxsackievirus adenovirus receptor, the cellular entry receptor for all other than group B serological groups of human adenoviruses.