Emerging roles of competing endogenous RNAs in cancer: insights from the regulation of PTEN

Abstract

The capacity of noncoding RNA to regulate gene expression in health and disease is epitomized by the microRNAs, small ∼22-nucleotide RNAs that target mRNAs to repress their translation into protein. Recently a previously unrecognized gene regulatory layer has emerged, characterized by the ability of a wide range of RNA transcripts to vie for microRNA binding and alleviate the repressive effect of microRNAs on their mRNA targets. Termed competing endogenous RNAs (ceRNAs), these participate in a microRNA-dependent cross talk, producing robust networks that when perturbed may lead to cancer. To date, the tumor suppressor PTEN has been most extensively validated as competing with a variety of ceRNAs in different cancers: reducing these ceRNAs appears to reduce PTEN levels, tipping cells toward cancer progression. In this review we look at ceRNA networks in cancer, their characteristics, and constituent parts, focusing on the insights that can be gained from the studies conducted on PTEN. We also explore the conditions that facilitate ceRNA cross talk, proposing that the disruption of these conditions may represent a general phenomenon in carcinogenesis.

Fig 1

Various transcript categories may bind miRNAs to alleviate repression of mRNA targets. (A) Without competing transcripts, microRNAs effect translational repression and/or enhance the degradation of mRNAs. (B) Upregulating ceRNAs that share miRNA response elements (MREs) can sequester microRNAs, derepressing their mRNA targets.

Fig 2

The degree of cross talk between transcripts should be determined by certain molecular conditions. (A) The relative abundance of the miRNA pool and targeted ceRNA transcripts, with cross talk maximized at approximately equimolar concentrations. Adapted with permission from reference . (B) As more MREs are shared between competing transcripts, cross talk between them will also increase. (C) Strength of miRNA binding to targets contributes to on-off rates and will determine the rate at which miRNAs are released to bind alternate targets.

Fig 3

PTEN ceRNAs. Various coexpressed transcripts sharing MREs with the PTEN mRNA have been shown to relieve repression of PTEN. In cancer, decreased expression of these ceRNAs can increase the repression of PTEN to facilitate tumorigenesis.