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.

Prognostic Significance of MiR-34a Expression in Patients with Gastric Cancer after Radical Gastrectomy

“…[ 25 ] In addition, it has been demonstrated that ectopic miR-34a could induce apoptosis when reintroduced into some cancer cells because it represses SIRT1, YY1, and Bcl-2, in which, miR-34a was identified as a p53 target, and miR-34a mediated apoptosis may be suppressed by the inactivation of p53. [ 15 26 27 ] MiR-34a was down-regulated in many cancers, including gastric cancer. [ 28 ] Bhatt et al .…”

p53 regulates CD46 expression and measles virus infection in myeloma cells

“…Because p53 is known to increase transcription of many microRNAs (miRNAs), we wondered whether some miRNAs could be involved in CD46 decrease, as miR31 and miR128 were shown to regulate PVRL4 expression and MV infection in nohematopoietic cells. [37][38][39] We treated 2 TP53 wt HMCLs with nutlin3a for 15 hours and analyzed miRNA expression using an miRNA PCR array (supplemental Table 3). Expression of 11 and 9 miRNAs with a significant score against CD46 was increased more than 1.4-fold in MM1S and BCN, respectively, and 3 were shared between the 2 HMCLs (miR34a#, miR192#, and miR571) (Figure 4B).…”

Systematic Identification and Bioinformatic Analysis of MicroRNAs in Response to Infections of Coxsackievirus A16 and Enterovirus 71

“…Each human tissue is characterized by a specific set of miRNAs which may constitute an innate characteristic of that tissue [11, 41]. Moreover, an increasing number of experimental researches have demonstrated that some miRNAs have the potential to modulate the in vivo tissue tropism of multiple viruses [42–44]. So it can be plausible that there is substantial heterogeneity in miRNA expression profile if different tissue cell models were used for the infection of certain pathogen, which depends on further investigation in the near future.…”