Human Papillomavirus and non-coding RNAs: from basics to diagnostic
Human Papillomavirus (HPV) is the etiological agent of cervical cancer. Like other oncogenic viruses HPV encode oncoproteins and the role of HPV oncogenes in cellular immortalization and transformation has been extensively investigated. HPV E6 and E7 proteins disable tumor suppressors p53 and Rb and up-regulate telomerase, fundamental changes for cell immortalization. Another important step in the induction of cancer by oncogenic viruses seems to be the specific interaction of some viral proteins with mitochondria, an organelle that has been implicated for decades in carcinogenesis. The identification of non-coding RNAs (ncRNAs) has opened new research areas and there has been an explosive increase of reports showing that the expression of these RNAs is deregulated in many different human diseases, including cancer. The ncRNAs can be classified into two groups based on their length: small transcripts (20–200 nucleotides), such as microRNAs (miRs), piwi-interacting RNAs and long transcripts (higher than 200 nucleotides). While the function of small ncRNAs has been well documented, the role of long ncRNAs is still not completely understood. MicroRNAs are small 21–22 nt non-protein-coding RNAs that regulate mRNA translation and decay. It has become evident that miRs plays a pivotal role in the development of human cancer. Some miRs have been characterized as tumor suppressors and others as oncogenic (onco-miRs). MiR patterns are tissue specific, and the expression profile could allow to distinguish carcinomas from normal cells. Moreover, miR expression profiles of cervix, head and neck cancers have been carried out in different studies associated to HPV infection. In this scenario, the HPV E5, E6 and E7 proteins modulate the expression of several cellular miRs. Deregulation of microRNAs expression might be used to identify cancer progression and also as potential target for therapy against HPV infection and cervical cancer development. The differential expression of a family of long non-coding mitochondrial RNAs (ncmtRNAs) in response to HPV infection has been recently reported. The expression profile of these transcripts allows distinguishing between normal, pre-tumoral and cancer cells. One of these transcripts, SncmtRNA-1, has been characterized as a regulator of cell cycle progression while two others, ASncmtRNA-1 and 2, has been suggested to act as 3 tumor suppressors. HPV E2, E6 and E7 modulate the expression of this family of mitochondrial long ncRNAs. Further evidence suggests that other viruses such a Hepatitis B virus, Human T-cell lymphotropic Virus type 1 and Epstein Barr virus can also modulate the expression of these long ncRNAs in human cells. In this chapter we will discuss how the differential expression of both, microRNAs and long ncRNAs, in response to HPV infection, might serve as early biomarkers for progression of cervical dysplasia in PAP smears and biopsies allowing the detection of precursor lesion of cervical cancer.