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New fruit fly model may yield new clues, drug treatments for cervical cancer

Aug. 18, 2016

Drosophila melanogaster

A new study from the Zhang lab reports creation of the first fruit fly model of an HPV-induced human cancer. (Image by: André Karwath, Wikimedia Commons)

An international team of researchers has created fruit flies with a condition that mimics a form of human papillomavirus (HPV) induced cancer. The flies may help scientists understand the underlying mechanism by which this virus can cause cancer as well as identify potential drug treatments. The study appears in the 18 August issue of the journal PLoS Pathogens.

“This is the first in vivo model of an HPV-induced cancer in fruit flies,” says Bing Zhang, an expert on fruit fly (Drosophila melanogaster) genetics at the University of Missouri and a corresponding author of the study. “This new model will allow scientists to exploit a powerful genetic system to understand the molecular and biochemical pathways involved in tumor growth and malignancy caused by HPV as well as screen for potential drug targets.”

Mojgan Padash

The research was carried out by Dr. Mojgan Padash.

The research was led by Mojgan Padash, a postdoctoral fellow at the University of Missouri and the University of Oklahoma. The work was performed in collaboration with Vanessa Auld with the University of British Columbia in Canada and Lawrence Banks at the International Centre for Genetic Engineering and Biotechnology in Italy.

HPV, the most common sexually transmitted infection in the United States, is the primary cause of cervical cancer. Previous studies conducted in human cells and in mice have shown that the virus enters the body through epithelial skin cells and produces several oncoproteins. Oncoproteins have the ability to transform a normal cell into a tumor cell. One of these viral oncoproteins, called E6, plays an important role during the later stages of tumor formation and metastasis. To do this, the viral protein interacts with normal human proteins and makes the cells lose control.

In humans, E6 is known to partner with a human protein, called E6 associated protein, or E6AP. Together, they seek out human proteins with a feature called a PDZ domain and cause them to be degraded. In the absence of these normal human proteins, the epithelial cells become disorganized and start uncontrolled proliferation. One PDZ protein that is heavily targeted for degradation by E6 is called Magi.

In the new study, the researchers introduced viral E6 and human E6AP proteins into fruit flies and specifically expressed these proteins in just the wing and eye epithelial cells. When co-expressed, the proteins caused severe abnormalities in the epithelial cells. Coincident with these cellular abnormalities, the researchers show reduced levels of the same suite of PDZ proteins targeted by E6 in humans. Similar to human epithelia, they found the fruit fly version of the Magi protein is the major target of degradation. Further experiments done in human cell lines with the fruit fly version of the Magi protein yielded similar results, indicating that the mechanism is highly conserved.

“This finding prompted us to see if expression of Magi could suppress the E6-mediated cellular abnormalities in fruit fly, which it did, again reinforcing that Magi is an important player,” says Padash.

Although severe cellular abnormalities resulted, the scientists found that co-expression of E6 and E6AP was not sufficient to cause tumors in flies. According to the authors, this is consistent with findings HPV E6-induced cancer in humans.

“In humans, there is a period of 15-20 years from the time of HPV infection to the development of cancer, suggesting that cooperation between E6 and E6AP is not sufficient to induce cancer,” says Padash. “It is thought that mutations in another oncoprotein, called Ras, may contribute to the E6-mediated tumorigenesis in humans.”

To test this hypothesis in their new fly model, the scientists expressed E6 and E6AP in the presence of a mutated version of Ras. With all three of these proteins, the flies developed malignant tumors that metastasized from the eyes to the rest of the body.

“The take home message is that the same key molecular players that underlie HPV E6-mediated cancer in humans do the same things in flies, which suggests that the mechanism is highly conserved,” says Padash. “Practically speaking, this means we can now use this fly model to identify other essential components or elements that contribute to E6-mediated tumorigenesis.”

As a demonstration, the researchers conducted an initial genetic screen and identified an insulin receptor that interacts with E6. Cell proliferation resulted when the researchers expressed the insulin receptor in flies that had both the viral E6 and human E6AP proteins, suggesting that insulin may play a role in cancer progression induced by HPV.

Lawrence Banks, a prominent specialist in the field of human papillomaviruses (HPV) and a coauthor of the study, says the implications of this new fly model are several. “From a basic science point of view, it shows that the mechanisms by which the HPV E6 oncoprotein targets essential cellular regulatory pathways are conserved across evolution, suggesting that these targets, as exemplified by Magi, are of fundamental importance in controlling cell growth and proliferation,” says Banks, who heads the Tumor Virology group at the International Centre for Genetic Engineering and Biotechnology in Trieste, Italy. “From a more practical point of view, the power of this model is that it can be used now to screen for inhibitors of other pathways, which have the potential to translate into therapies for HPV-induced cancers.”

The study, titled “A Drosophila model of HPV E6-1 induced malignancy reveals essential roles for Magi and the insulin receptor,” was supported by grants from the National Institutes of Health (RO1NS060878), the University of Missouri, the Canadian Institutes of Health Research (MOP-123420), and the Italian Association for Cancer Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agency.

Figure 1

This figure shows fruit flies with only viral E6 (A, D, G), only human E6AP (B,E,H), and both E6+E6AP (C,F,I) proteins expressed in the wing and eye epithelial cells. As in human HPV E6-induced cancer, cellular abnormalities result when E6 and E6AP are co-expressed together.

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Written by: Melody Kroll

Related: MU News Bureau press release

Related research strengths:
Cell Biology, Development, Genetics & Genomics, Molecular Biology, Neurobiology