Abstract
ABSTRACTThe E6 and E7 proteins are the major oncogenic drivers encoded by high-risk human papillomaviruses (HPVs). While many aspects of the transforming activities of these proteins have been extensively studied, there are fewer studies that have investigated how HPV E6/E7 expression affects the expression of cellular noncoding RNAs. The goal of our study was to investigate HPV16 E6/E7 modulation of cellular microRNA (miR) levels and to determine the potential consequences for cellular gene expression. We performed deep sequencing of small and large cellular RNAs in primary undifferentiated cultures of human foreskin keratinocytes (HFKs) with stable expression of HPV16 E6/E7 or a control vector. After integration of the two data sets, we identified 51 differentially expressed cellular miRs associated with the modulation of 1,456 potential target mRNAs in HPV16 E6/E7-expressing HFKs. We discovered that the degree of differential miR expression in HFKs expressing HPV16 E6/E7 was not necessarily predictive of the number of corresponding mRNA targets or the potential impact on gene expression. Additional analyses of the identified miR-mRNA pairs suggest modulation of specific biological activities and biochemical pathways. Overall, our study supports the model that perturbation of cellular miR expression by HPV16 E6/E7 importantly contributes to the rewiring of cellular regulatory circuits by the high-risk HPV E6 and E7 proteins that contribute to oncogenic transformation.
Highlights
The E6 and E7 proteins are the major oncogenic drivers encoded by high-risk human papillomaviruses (HPVs)
We used miR-seq to investigate the modulation of miR expression in two independent, donor- and passage-matched human foreskin keratinocytes (HFKs) populations, each with stable expression of HPV16 E6/E7 or a control vector
By applying the threshold cutoffs, 78 miRs were differentially expressed in HPV16 E6/E7-expressing HFKs compared to the control vector-transduced populations (Fig. 1A)
Summary
The E6 and E7 proteins are the major oncogenic drivers encoded by high-risk human papillomaviruses (HPVs). Small, noncoding human RNAs, termed microRNAs (miRs), regulate gene expression and have been implicated in almost all human cancers, including HPVassociated cancers. HPV E6 and E7 are small proteins with no intrinsic enzymatic or DNA-binding activities that function by targeting host pathways that modulate multiple downstream effectors (reviewed in reference 1), thereby causing alterations in critical physiological processes deemed “hallmarks of cancer” [3, 4]. High-risk HPV E6 and E7 interact with many other multifunctional, nonredundant proteins, including transcription factors and epigenetic regulators that, in turn, cause alterations in cellular gene expression. In addition to coding genes, high-risk HPV E6 and E7 cause alterations in the expression of noncoding RNAs, including microRNAs (miRs) [9]. Through manipulation of host miRs, HPV E6 and E7 may modulate many downstream mRNA targets involved in various biological processes
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