Abstract
A major part of the post-transcriptional regulation of gene expression is affected by trans-acting elements, such as microRNAs, binding the 3′ untraslated region (UTR) of their target mRNAs. Proliferating cells partly escape this type of negative regulation by expressing shorter 3′ UTRs, depleted of microRNA binding sites, compared to non-proliferating cells. Using large-scale gene expression datasets, we show that a similar phenomenon takes place in breast and lung cancer: tumors expressing shorter 3′ UTRs tend to be more aggressive and to result in shorter patient survival. Moreover, we show that a gene expression signature based only on the expression ratio of alternative 3′ UTRs is a strong predictor of survival in both tumors. Genes undergoing 3′UTR shortening in aggressive tumors of the two tissues significantly overlap, and several of them are known to be involved in tumor progression. However the pattern of 3′ UTR shortening in aggressive tumors in vivo is clearly distinct from analogous patterns involved in proliferation and transformation.
Highlights
MicroRNAs and other trans-acting factors that bind mRNA regulate protein levels by preventing mRNA translation and inducing its degradation
We have shown that 39UTR shortening in specific mRNAs correlates with poor prognosis in both breast and lung cancer, and that a significant part of this phenomenon is attributable to differential synthesis of alternative isoforms rather than to their differential degradation
Several genes involved in tumor progression and resistance to therapy express shortened 39 untraslated region (UTR) in aggressive tumors, supporting the notion that tumor cells gain an evolutionary advantage by removing these genes from the control of trans-acting regulators acting on the 39 UTR
Summary
MicroRNAs and other trans-acting factors that bind mRNA regulate protein levels by preventing mRNA translation and inducing its degradation. Many individual microRNAs have been shown to be aberrantly expressed in several types of cancer [2]. A picture emerges in which microRNAs keep cells from inappropriately proliferating and invading the surrounding tissues [3,4] by repressing the expression of their targets. In a heterogeneous cell population, selection will favor the cells that are able to escape such control. This can be done either by suppressing the expression of the individual microRNAs or, perhaps more efficiently, by interfering globally with the mechanism of regulation by microRNAs, for example by decreasing expression of genes involved in the microRNA pathway such as DICER1 [5,6] or TARBP2 [7]
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