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

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.

Figure 1. Affymetrix probes and APA sites in the 3′ UTR of six genes studied in Ref. .

The probes shown in red are used, possibly together with probes located in the coding region, to build the 5′ probeset. The probes shown in green are used to build the 3′ probeset. For DICER1 and FGF2 it is not possible to study the APA site since all probes lie beyond it.

Figure 2. Predictive power of the prognostic score based on ERI in two dataset not used to derive the signature.

(A) the Miller breast cancer dataset and (B) the Shedden lung cancer dataset . Patients are divided into groups using the median score as a cutoff.

Figure 3. 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).