Perturbation of DROSHA and DICER expression by human papillomavirus 16 oncoproteins

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DROSHA frequently overexpressed due to gene amplification

Text by Mallory Harden and Karl Munger

High-risk human papillomaviruses (HPV) are best known as the causative agents of cervical cancers.  However, these viruses also cause several other human cancers.  The two viral oncoproteins, E6 and E7, are consistently expressed in HPV-associated cancers.  Our study focuses on the most frequently detected high-risk HPV type, HPV16, and how the E6 and E7 oncoproteins alter small, non-coding RNAs called microRNAs (miRs).  Most HPVs do not encode their own miRs, however, it is well known that HPVs alter expression of host miRs.  In particular, we, and others, have shown that miR expression is perturbed when E6 and E7 are expressed.  A question that has not been well studied, however, is how E6 and E7 alter host miR expression.  There are likely several mechanisms by which the oncoproteins alter miR expression but, in this study, we show the E6 and E7 alter expression of key miR biogenesis enzymes.

The idea for this study came from evidence in the literature that the miR biogenesis pathway is dysregulated in human cancers. Given that high-risk HPVs cause human cancers through E6 and E7 oncoprotein expression, we hypothesized that one mechanism by which HPV16 E6/E7 may alter host miR expression was manipulation of the miR biogenesis pathway.  We utilized primary epithelial cells derived from neonatal human foreskins for our studies.  We use these cells as they are the biologically relevant targets of HPV infection in males.  However, these cells are much more difficult to work with as they take a long time to generate, they do not grow quickly and they can only be used in experiments for a short number of passages.  Additionally, these cells are generated from three or more different patient samples each time they are isolated, resulting in quite a bit of genetic diversity.  These problems had to be overcome in many of the experiments in this study.

The biggest surprise we encountered along the way was that our experiments supported our initial hypothesis.  Hypotheses are always to be tested and, even when the experimental data do not support the hypothesis, the results can be interesting. However, we are excited and intrigued by the results that manipulation of miR biosynthesis enzymes may be one of the mechanisms by which HPV E6/E7 expression changes the abundance of cellular miRs. Future studies will be focused on uncovering the mechanistic basis for this finding.Virology Highlights Graphic

Figure legend

Perturbation of expression of key microRNA biogenesis enzymes, DROSHA and DICER, is one mechanism the Human Papillomavirus 16 oncoproteins utilize to alter microRNA expression.

Introducing the authors

hardenmunger

Pictured are Mallory Harden and Karl Munger from the Karl Munger Laboratory, Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, USA

About the research

Perturbation of DROSHA and DICER expression by human papillomavirus 16 oncoproteins
Mallory E. Harden, Karl Munger
Virology, Volume 507, July 2017, Pages 192–198