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Johns Hopkins’ Joshua Mendell on Myc, microRNA, and Cancer

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NAME: Joshua Mendell
 
POSITION: Assistant professor, pediatrics/molecular biology and genetics, Johns Hopkins University School of Medicine
 
BACKGROUND:
Postdoc, Johns Hopkins University School of Medicine — 2003-2004
MD, Johns Hopkins University School of Medicine, — 2003
PhD, genetics, Johns Hopkins University School of Medicine — 2001
BA, biology/genetics/development, Cornell University — 1996
 

 
Earlier this month, a research team led by Johns Hopkins University School of Medicine investigator Joshua Mendell published a paper describing how they found the oncogenic transcription factor myc to regulate a greater number of microRNA than previously anticipated.
 
The findings, which appeared in the online version of Nature Genetics, suggest that the primary consequence of myc activation is widespread miRNA repression. Additional work showed that the “forced expression” of myc-repressed miRNA reduced the tumorigenic potential of certain cancer cells, according to the paper.
 
Last week, RNAi News spoke with Mendell about the findings.
 
You do a lot of work with microRNAs, with a particular focus on myc. Can you give a little background on myc and how it came into play when you were looking at microRNA and cancer?
 
One major question we have been interested in is whether microRNAs play important roles in pathways controlled by critical oncogenes and tumor suppressors in cancer.
 
It’s clear that in tumor cells, microRNA expression is abnormal compared to normal cells, and there are probably a lot of mechanisms that contribute to that. We decided a while back that one approach we’d take to find some of the most important changes in microRNA expression in cancer was to ask whether microRNAs were functionally important in these oncogenic and tumor suppressor pathways.
 
Our reasoning was that oncogenes are frequently activated and tumor suppressors are frequently lost in cancer cells, and if microRNAs are being regulated by those pathways then those events will cause the microRNAs to be abnormally expressed. Then those abnormal expression changes might have functional consequences on the behavior of the cell.
 
That was our initial thought process, and we chose to focus on myc for several reasons. One is that it is really one of the best studied oncogenic pathways; it’s really considered one of the classic oncogenes [having] been studied for a very long time. We have close collaborators here who have a lot of expertise on myc, namely Chi Dang who is a professor here at Hopkins.
 
Another thing that is appealing about the questions we wanted to ask in regard to myc is that it, itself, is a transcription factor. It is believed to function primarily by turning on and turning off many other genes in the cell. When myc becomes activated in cancer cells, or even normal cells, it really reprograms the gene expression in these cells to drive proliferation.
 
The protein-coding genes that are regulated by myc have been studied extensively by many different labs, but until the relatively recent appreciation of microRNAs, no one had yet asked if control of microRNAs is also important in the functions of the myc protein.
 
That’s what led us to begin asking questions about myc.
 
Going into the work described in Nature Genetics, you knew that myc affected at least one cluster of microRNA, right?
 
Right. We had previously shown that when myc is activated in cells, it directly turns on the miR-17-92 cluster. It’s been studied by several labs, including ours, and many people have now shown that this group of microRNAs themselves can act as oncogenes.
 
So myc, the oncogene, turns on a group of microRNAs that themselves promote tumorigenesis. That was what we knew, but we decided to continue looking for myc-regulated microRNAs using our newest technologies for profiling microRNAs and using multiple model systems — both human cells and mouse cells — where we could control myc activity with different agents.
 
When we looked in these tumors where we can control myc activity — we looked at the high myc state and the low myc state — we saw that the miR-17 cluster was being turned on in both human and mouse models. But we were intrigued and surprised to see that the predominant consequence of activating myc in these cells was actually a very widespread repression of microRNA expression where many microRNA genes seemed to be turned down.
 
As opposed to being activated.
 
As opposed to being activated. We saw this one microRNA gene that encodes the miR-17-92 cluster go up, but many more microRNA genes went down. This was intriguing to us for a few reasons. One, it had been shown previously … that very widespread microRNA repression seems to be fairly predominant in tumor cells. [Researchers] have also done experiments to show that if they experimentally down-regulate microRNAs by inhibiting the processing pathway, that can actually accelerate tumorigenesis.
 
Based on [this] work, we were interested in the possibility that some of this repression was due to the activation of myc, which is so predominant in many different types of cancer. That is why we were kind of excited by [our] observation.
 
So this is really a new role for myc in the whole cancer process?
 
Myc is known to repress some protein-coding genes, but it had never been shown that it turns down microRNAs. Whether that is important in cancer had not been established.
 
If you had to make an educated guess, should we expect to see other oncogenes having a similar kind of role when investigated further?
 
The answer to that is definitely yes. We actually know of some examples of other oncogenes that down-regulate microRNAs from our own research. It’s not published yet, but we believe that turning off microRNAs is not something that is unique to myc.
 
Where does this lead you in terms of your research?
 
When we made the observation that myc down-regulates microRNAs, we felt that it was very important to demonstrate experimentally that that was actually important in the ability of myc to drive tumorigenesis.
 
We teamed up with [University of Pennsylvania researcher and co-author on the Nature Genetics paper] Andrei Thomas-Tikhonenko to ask that question. He developed a [mouse] model in which we could use viruses to introduce microRNAs that are turned down by myc back into myc-transformed tumor cells [in order to] determine what happens to those tumor cells in mice.
 
What we found was that [in multiple cases] when we introduced even single microRNAs in the context of all the other things myc is doing in cells, including all the other microRNAs it is repressing … the cells could no longer form tumors. And we saw very dramatic effects, which was amazing to us.
We were surprised that even a single microRNA, in the context of hyperactive myc activity and transformation of the cell by all the things myc is doing … could block tumorigenesis.
 
What we don’t really know is how the microRNAs are having these potent effects. It’s always a big question in the microRNA field: What are the targets that are regulated by the microRNAs? We now have several important ones we’re focusing on and are trying to elucidate the pathways they are regulating so we can understand how these phenotypes arise.
 
Does this have therapeutic potential? The companies that are looking at microRNAs frequently talk about silencing a microRNA to treat a condition, but this is activation.
 
I do think that there is therapeutic potential. Obviously, I’ll say that we’re very early in this, and many technical obstacles have to be overcome — namely delivery. But we believe that if we can deliver microRNAs to cancer cells, then there could be profound effects on the tumors.
 
One thing that is encouraging in this regard is that there has been a lot of effort by companies and laboratories to develop methods to deliver siRNAs for therapies. Those technologies can be directly applied to deliver microRNAs [since the two] are functionally equivalent in the cell. They have different targets but they interact with the same protein machinery in the cell and they function in the same way.
 
We’re hopeful there will be methods to deliver [microRNA] and we do think there is some therapeutic potential that we’re interested in exploring.

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