Revealing the role of cellular microRNAs in human papillomavirus (HPV) replication in oral keratinocytes

Human papillomaviruses are a large family of double-stranded DNA viruses. The high-risk human papillomavirus (HPV) subtypes, HPV16 and HPV18, are the main etiological agents in promoting epithelial cell carcinogenesis through dysregulation of its viral oncoproteins E6 and E7. This results in cancers of the cervix, anogenital tract and oropharynx. Despite the effectiveness of the quadrivalent HPV vaccination programme in preventing HPV-driven cervical cancer, HPV has now overtaken smoking as the leading causative agent in the development of oropharyngeal cancers, particularly in men. Due to the high incidence of cervical cancer, key viral targets in HPV-driven head and neck cancers are not well characterised.

In recent years, research into the roles of microRNAs in the development of an array of cancers has accelerated; and HPV has been no exception. MicroRNAs are crucial in oncogenic transformation through their ability to control gene expression. Indeed, the Macdonald lab previously uncovered the E6 dysregulated microRNA-18a as an integral component in Hippo signalling and thus for the promotion of cervical cancer cell proliferation (Morgan et al., 2020).

Therefore, this project aims to identify host microRNAs that are manipulated by HPV to promote the progression of cancers and propagation of viral infection in the oropharynx.

This will be a multidisciplinary project, and begin by analysing RNA-sequencing data of HPV-positive clinical head and neck samples compared to a HPV-negative proximal tissue. From there, we can work to uncover the 'how and why' behind the manipulation of particular microRNAs by HPV, and their contribution to promoting cellular transformation. This project will also explore how host microRNAs are harnessed to support the HPV viral lifecycle using organotypic raft cultures. This will potentially develop our understanding of the cellular mechanisms behind HPV infections that are successfully cleared, and those that become persistent.
In summary, this project will identify novel antiviral targets, that may be important in treating both HPV viral infection and HPV-driven carcinogenesis.