Altered Expression of RNA-binding Proteins Modulates Tumor Progression by Re-programming Post-transcriptional Gene Regulatory Networks

Abstract

AU-rich elements (AREs) are potent cis-acting determinants of mRNA decay and translational efficiency in mammalian cells. Since ARE-containing transcripts often encode factors that regulate cell division, apoptosis, angiogenesis, and inflammation, alterations in the metabolic fates of these mRNAs can profoundly influence cellular phenotypes associated with oncogenesis. We evaluated changes in the expression of four well characterized ARE-BPs (AUF1, TIA-1, HuR, and TTP) across a variety of human neoplastic syndromes using three principal methods: (i) cDNA arrays comparing expression in 154 tumors from 18 different tissue types versus patient-matched non-transformed tissues, (ii) meta-analyses of gene chip studies comparing expression in normal versus primary and metastatic tumors across diverse tissue types, and (iii) comparing EST and/or SAGE frequency between normal versus cancerous cells derived from many tissue sources. For three ARE-BPs surveyed; AUF1, TIA-1, and HuR, expression was not systematically dysregulated in cancers; however, in selected tissues mRNAs encoding these proteins were frequently up- or down-regulated to a significant extent. Conversely, TTP expression is repressed in many human tumors and in breast cancer correlates with increased expression of an angiogenic factor and is a negative prognostic indicator. In a cultured cancer cell model, restoring TTP expression slows cell proliferation, enhances sensitivity to selected pro-apoptotic stimuli, and decreases expression of vascular endothelial growth factor (VEGF) mRNA by accelerating the decay kinetics of this transcript. Finally, ribonome-wide screens for mRNAs that both associate with TTP and are regulated by TTP have identified a panel of TTP substrate transcripts that may be responsible for linking loss of TTP expression to the exacerbation of tumorigenic phenotypes. Together, these data indicate that the diminution of TTP expression observed in many cancers re-programs a post-transcriptional gene regulatory network, resulting in enhanced expression of several factors that may contribute to tumor aggressiveness.