It has been almost a century since the discovery of virus-induced cancers. Studies on tumor-causing viruses have led to many landmark breakthroughs that have revolutionized cell biology and the principles of medicine, helped to establish virology as a discipline, and paved the way for most of the subsequent advances and ideas on the molecular basis of viral carcinogenesis. These milestone discoveries include the identification of RNA-dependent DNA polymerase (reverse transcriptase) in Rous sarcoma virus by Howard Temin and David Baltimore 258,259
, viral oncogenes and their cellular counterparts (proto-oncogenes) from Rous sarcoma virus by Harold Varmus and Michael Bishop 260,261
, and RNA splicing in adenovirus-2 by Philip Sharp and Richard Roberts 262,263
Viral strategies for manipulating the expression of cellular genes to enhance viral persistence, viral latency, and survival of infected cells have provided numerous clues to the mechanisms of gene expression and their dysregulation during tumor development. These functions are mainly undertaken by virus-encoded oncogenes, which are present in virtually all well-characterized tumor viruses except the hepatitis C virus. The fact that all characterized viral oncoproteins are “sticky” and interact with cellular proteins in infected cells makes each of them multifunctional and essential for cell immortalization and transformation. By interacting with several dozens or even hundreds of cellular factors, viral oncoproteins from different tumor viruses eventually end up in apparently similar scenarios of viral carcinogenesis by targeting cellular tumor suppressors, deregulating signal transduction pathways, redirecting gene transcription, and/or stimulating anti-apoptotic programs in the host. In the past two decades, the study of cancer biology has been driven by the dynamic networking capacity of individual viral oncoproteins.
RNA splicing plays an important role in regulating viral oncogene expression and is highly conserved among tumor viruses. Through alternative RNA splicing, several species of mRNAs can be derived from a primary transcript of a single viral oncogene to encode different truncated proteins or different oncoproteins. Although various studies over the years have shown that the levels and status of individual cellular splicing factors in virus-infected cells modulate alternative splicing of viral oncogene transcripts, a clear picture of how this modulation might take place during viral oncogene expression has not yet emerged. Because viral RNA transcripts are not naked in the cells and the movement of different sets of RNA-binding proteins on and off a particular RNA molecule is dynamic, it will be very interesting to know how the selection of alternative splice sites in an RNA is precisely defined and triggered. In the case of an HPV16 or HPV18 E6E7 bicistronic transcript, retention of the first intron is needed to express E6, but splicing of this intron promotes E7 translation initiation to produce E7174
. What is required for the decision to splice this intron or not, resulting in the expression of two different oncoproteins from the same transcript, and when this decision occurs are intriguing questions. A recent finding of EGF pathway that might be involved in this regulation is fascinating 170
. Thus, investigation into these questions will not only help to resolve this puzzle in tumor virology, but will also shed some light on complex biology as a whole.
Noncoding RNAs, including microRNAs and endogenous siRNAs, have profound roles in the regulation of gene expression 264-268
. During latent virus infection, DNA tumor viruses, except papillomaviruses, generate abundant noncoding RNAs. Although we know very little at the present why viruses produce them and what their functions are, the production of these noncoding RNAs by these groups of tumor viruses means that the function of the tumor virus genome has been highly conserved during virus evolution. Noncoding RNAs are not a consequence of virus latency; rather, their function might be necessary for the maintenance of virus latency. Given that each microRNA subtly influences the translation of hundreds of different gene transcripts 264,265
, viral microRNAs must be involved in many key biological processes in virus-infected cells during latent infection, leading to establishment of latency in tumor cells. Thus, one can imagine that viral oncogenes do not act alone but perhaps coordinate extensively with other viral products to induce oncogenesis during persistent infection.