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When oxygen is short, EGFR prevents maturation of cancer-fighting miRNAs
Date:5/23/2013

p>In many cancers, EGFR is overexpressed or dysfunctional, constantly sending signals to cells to divide. Hung and colleagues found that EGFR also fuels cancer progression by stifling tumor-suppressing miRNAs.

As a tumor grows, large portions of its interior can become starved for oxygen (hypoxia) for lack of adequate blood vessels. This stress suffocates many tumor cells, but the few that endure become highly malignant, resist treatment and are most likely to spread, Hung said.

Anti-angiogenesis drugs designed to kill tumors by blocking their ability to spin webs of supportive blood vessels often succeed at first, Hung said, but then fail against the more malignant cells that survive hypoxia.

When hypoxia hits, EGFR gets active and gets eaten

Low-oxygen conditions cause EGFR overexpression. EGFR also is pulled into the cell interior, captured in cavities called vesicles and eventually fed into lysosomes, a membrane-enclosed organelle loaded with enzymes to dissolve proteins.

It was known that EGFR continues to signal even while caught in the vesicles, which actually prolongs its activation. Hung and colleagues found that EGFR signals to a key protein in miRNA processing called argonaute 2, or AGO2.

AGO2 connects with two other proteins called Dicer and TRBP to form a complex that processes microRNA precursors into mature miRNAs, which regulate gene expression after messenger RNA has been expressed but before it's translated into a protein.

Oncoprotein-regulating miRNAs don't grow up

The scientists found that EGFR attaches phosphate groups to AGO2, which in turn weakens AGO2's ability to connect with Dicer to produce mature microRNAs. EGFR's effect is stronger during oxygen starvation than under normal conditions.

The team identified a number of specific miRNAs affected by EGFR, most of which have been reported to have tumor suppressor characteristics. The miRNAs regula
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Contact: Scott Merville
smerville@mdanderson.org
713-792-0661
University of Texas M. D. Anderson Cancer Center
Source:Eurekalert

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