Abstract
High-risk Human Papillomavirus infections are responsible for anogenital and oropharyngeal cancers. Alternative splicing is an important mechanism controlling HPV16 gene expression. Modulation in the splice pattern leads to polycistronic HPV16 early transcripts encoding a full length E6 oncoprotein or truncated E6 proteins, commonly named E6*. Spliced E6*I transcripts are the most abundant RNAs produced in HPV-related cancers. To date, the biological function of the E6*I isoform remains controversial. In this study, we identified, by RNA sequencing, cellular targets deregulated by E6*I, among which genes related to ROS metabolism. Concomitantly, E6*I-overexpressing cells display high levels of ROS. However, co-overexpression of both E6 and E6*I has no effect on ROS production. In HPV16-infected cells expressing different E6/E6*I levels, we show that the newly identified targets CCL2 and RAC2 are increased by E6*I but decreased by E6 expression, suggesting that E6 abrogates the effect of E6*I. Taken together, these data support the idea that E6*I acts independently of E6 to increase ROS production and that E6 has the ability to counteract the effects of E6*I. This asks the question of how E6*I can be considered separately of E6 in the natural history of HPV16 infection.
Highlights
Human papillomaviruses (HPVs) are small non-enveloped viruses that present a tropism for squamous epithelium
The U-2 OS cell line represents an adequate model for studying HPV gene expression and HPV-associated carcinogenesis because it expresses a wild-type p53, which can be targeted by E6
It was shown that viral gene expression of both alpha and beta papillomaviruses in U-2 OS is very similar to that described in keratinocytes[34]
Summary
Human papillomaviruses (HPVs) are small non-enveloped viruses that present a tropism for squamous epithelium. Even if HPV16 early transcripts detection is used as a tool in screening and investigating HPV-related neoplasia, the biological significance of E6 splicing and ensuing E6*I protein expression remains elusive. Other study showed that E7 is preferentially translated from the unspliced E6/E7 transcript rather than from the E6*I/E7 one, suggesting that this splicing event regulates E6 expression but not E718,19. Apart from HPV gene expression regulation, the roles of E6*I ORF product in HPV life cycle and carcinogenesis remains unclear, a variety of functions have been reported for the truncated isoform. To get a better understanding on the underlying molecular mechanisms driving HPV-related carcinogenesis, the present study used RNA sequencing technology to analyze the impact of HPV16 E6*I isoform on cellular gene expression
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