The Natural History of Cervical Cancer and the Case for MicroRNAs: Is Human Papillomavirus Infection the Whole Story?

MicroRNAs (miRNAs) are small non-coding RNAs (ncRNAs) that negatively regulate gene expression. MiRNAs regulate fundamental biological processes and have significant roles in several pathologies, including cancer. Cervical cancer is the best-known example of a widespread human malignancy with a demonstrated viral etiology. Infection with high-risk human papillomavirus (hrHPV) has been shown to be a causative factor for cervical carcinogenesis. Despite the occurrence of prophylactic vaccines, highly sensitive HPV diagnostics, and innovative new therapies, cervical cancer remains a main cause of death in developing countries. The relationship between hrHPV infection and cervical cancer depends on the integration of viral DNA to the host genome, disrupting the viral regulator E2 and the continuous production of the viral E6 and E7 proteins, which are necessary to acquire and maintain a transformed phenotype but insufficient for malignant cervical carcinogenesis. Lately, miRNAs, the tumor microenvironment, and immune evasion have been found to be major players in cervical carcinogenesis after hrHPV infection. Many miRNAs have been widely reported as deregulated in cervical cancer. Here, the relevance of miRNA in HPV-mediated transformation is critically reviewed in the context of the natural history of hrHPV infection and cervical cancer.