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MicroRNA Specifically Targets Cancer Cells With Common Mutation

by Dr. Meenakshy Varier on October 3, 2016 at 11:53 PM
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MicroRNA Specifically Targets Cancer Cells With Common Mutation

Approximately 20% of all human cancers have mutations in a gene calledáKRAS.áKRAS-mutant cancers are among the most difficult to treat, with poor survival and resistance to chemotherapy.

Researchers at University of California San Diego School of Medicine and Moores Cancer Center used microRNAs Ś small pieces of genetic material Ś to systematically inhibit thousands of other genes to find combinations that are specifically lethal to cancer cells driven by aáKRASámutation.

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The study, published ináCancer Research, provides new information about KRAS-driven cancers and offers a potential therapeutic target for their eradication.

"For decades researchers have tried to directly inhibitáKRASáactivity, but there are no well-defined binding pockets in the protein that we can target with small-molecule drugs," said senior author Tariq Rana, PhD, professor of pediatrics at UC San Diego School of Medicine and Moores Cancer Center. "Instead of trying to deteráKRASáitself, we took the approach of looking for other molecules that, when inhibited, are lethal to cells only whenáKRASáis also mutated."
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To do this, Rana and team used microRNAs, small pieces of genetic material similar to DNA. MicroRNAs do not encode proteins. Instead, microRNAs bind messenger RNAs that do encode proteins, inhibiting their translation or hastening their degradation. Normal cells use microRNAs to help control which genes are turned on or off at different times. MicroRNAs tend to be less active in cancer cells.

In this study, the researchers created a library of more than a thousand human microRNA mimics, each with a different sequence and capable of binding different messenger RNA targets.

First, they tested each microRNA on colorectal cells grown in the lab. Half the cells had aáKRASámutation that made the protein more active, as is the case in many cancers. The other half had normaláKRAS. The microRNA sequences that killed only theáKRAS-mutant cells were then tested again in a panel of lung cancer cell lines with and without KKRASámutations.

From this screen, one microRNA in particular stood out for its ability to suppressáKRAS-dependent cell growth in both colorectal and lung cancer cells: miR-1298. MicroRNA-1298 inhibits two proteins in cancer cells, FAK and LAMB3. When the researchers silenced either of these proteins, they saw the same effect as adding miR-1298 ŚáKRAS-driven cancer cells stopped growing.

In human lung cancer tissue samples, Rana and team discovered that elevated LAMB3 levels were associated with poorer survival for patients witháKRASámutations.

The researchers looked at data from a group of 259 lung cancer patients for whomáKRASástatus and survival outcome were known. Of those, 143 wereáKRAS-positive and 116 wereáKRAS-negative. After about 10 years, survival probability foráKRAS-positive patients with high LAMB3 levels was approximately 20%, compared to approximately 60% foráKRAS-positive patients with low LAMB3.

"This clinical finding suggests LAMB3 could be used as a prognostic biomarker, and underscores LAMB3's potential as a therapeutic target foráKRAS-driven cancers," Rana said. "What's more, it highlights miRNAs as important tools for probing complex biological processes, identifying new therapeutic targets and developing potential new RNA-based therapeutics.



Source: Medindia
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