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Shortening of 3'UTRs correlates with poor prognosis in breast and lung cancer.

Lembo A, Di Cunto F, Provero P - PLoS ONE (2012)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Biology and Biochemistry and Molecular Biotechnology Center, University of Turin, Turin, Italy.

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.

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Related in: MedlinePlus

Schematic representation of two possible mechanisms leading to higher ERI in poor-prognosis tumors.(A) Differential synthesis: the shorter isoform is synthesized in a higher proportion in the poor-prognosis tumors, leading to less degradation by microRNAs. (B) Differential degradation: the isoforms are produced in the same proportion in the two cases, but a microRNA expressed exclusively in the poor-prognosis tumors selectively degrades the long isoform. In both cases we expect a higher ERI (relative prevalence of short form) in the poor-prognosis group. However in case (A) the overall expression of the two isoforms is expected to be higher in the poor-prognosis case, while the opposite is expected in case (B).
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pone-0031129-g003: Schematic representation of two possible mechanisms leading to higher ERI in poor-prognosis tumors.(A) Differential synthesis: the shorter isoform is synthesized in a higher proportion in the poor-prognosis tumors, leading to less degradation by microRNAs. (B) Differential degradation: the isoforms are produced in the same proportion in the two cases, but a microRNA expressed exclusively in the poor-prognosis tumors selectively degrades the long isoform. In both cases we expect a higher ERI (relative prevalence of short form) in the poor-prognosis group. However in case (A) the overall expression of the two isoforms is expected to be higher in the poor-prognosis case, while the opposite is expected in case (B).

Mentions: The observed higher ERI in poor-outcome tumors could be due either to altered ratios in the synthesis of the two isoforms, or to altered degradation rates. As an example of the latter mechanism, assume a microRNA, able to bind the long isoform of a transcript but not the short one, is expressed at higher levels in poor-outcome tumors. Then even if the two isoforms are synthesized at the same rate, the long one will be degraded faster in the poor-outcome tumors, leading to higher ERI. At least in the simplest case in which only one of the two mechanisms is at work it is possible to distinguish between them by looking at the differences in the total expression of the transcript between poor- and good-outcome cases (Figure 3).


Shortening of 3'UTRs correlates with poor prognosis in breast and lung cancer.

Lembo A, Di Cunto F, Provero P - PLoS ONE (2012)

Schematic representation of two possible mechanisms leading to higher ERI in poor-prognosis tumors.(A) Differential synthesis: the shorter isoform is synthesized in a higher proportion in the poor-prognosis tumors, leading to less degradation by microRNAs. (B) Differential degradation: the isoforms are produced in the same proportion in the two cases, but a microRNA expressed exclusively in the poor-prognosis tumors selectively degrades the long isoform. In both cases we expect a higher ERI (relative prevalence of short form) in the poor-prognosis group. However in case (A) the overall expression of the two isoforms is expected to be higher in the poor-prognosis case, while the opposite is expected in case (B).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3275581&req=5

pone-0031129-g003: Schematic representation of two possible mechanisms leading to higher ERI in poor-prognosis tumors.(A) Differential synthesis: the shorter isoform is synthesized in a higher proportion in the poor-prognosis tumors, leading to less degradation by microRNAs. (B) Differential degradation: the isoforms are produced in the same proportion in the two cases, but a microRNA expressed exclusively in the poor-prognosis tumors selectively degrades the long isoform. In both cases we expect a higher ERI (relative prevalence of short form) in the poor-prognosis group. However in case (A) the overall expression of the two isoforms is expected to be higher in the poor-prognosis case, while the opposite is expected in case (B).
Mentions: The observed higher ERI in poor-outcome tumors could be due either to altered ratios in the synthesis of the two isoforms, or to altered degradation rates. As an example of the latter mechanism, assume a microRNA, able to bind the long isoform of a transcript but not the short one, is expressed at higher levels in poor-outcome tumors. Then even if the two isoforms are synthesized at the same rate, the long one will be degraded faster in the poor-outcome tumors, leading to higher ERI. At least in the simplest case in which only one of the two mechanisms is at work it is possible to distinguish between them by looking at the differences in the total expression of the transcript between poor- and good-outcome cases (Figure 3).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Biology and Biochemistry and Molecular Biotechnology Center, University of Turin, Turin, Italy.

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.

Show MeSH
Related in: MedlinePlus