Abstract
RNA-binding proteins (RBPs) bind to and post-transcriptionally regulate the stability of mRNAs. La-related protein 1 (LARP1) is a conserved RBP that interacts with poly-A-binding protein and is known to regulate 5′-terminal oligopyrimidine tract (TOP) mRNA translation. Here, we show that LARP1 is complexed to 3000 mRNAs enriched for cancer pathways. A prominent member of the LARP1 interactome is mTOR whose mRNA transcript is stabilized by LARP1. At a functional level, we show that LARP1 promotes cell migration, invasion, anchorage-independent growth and in vivo tumorigenesis. Furthermore, we show that LARP1 expression is elevated in epithelial cancers such as cervical and non-small cell lung cancers, where its expression correlates with disease progression and adverse prognosis, respectively. We therefore conclude that, through the post-transcriptional regulation of genes such as mTOR within cancer pathways, LARP1 contributes to cancer progression.
Highlights
RNA-binding proteins (RBPs) regulate the decay kinetics and translational efficiency of mRNA transcripts by accelerating their degradation or prolonging their cytoplasmic half-life.[1]
An elevated expression of Larelated protein 1 (LARP1) has been shown to correlate with clinical outcome in hepatocellular carcinoma,[7] LARP3 protein expression is increased in cervical cancer and higher levels have been shown to correlate with adverse outcome in lung cancer.[8,9]
RBPs contribute to the post-transcriptional regulation of gene expression by binding and regulating the stability of target mRNAs.[29,30]
Summary
RNA-binding proteins (RBPs) regulate the decay kinetics and translational efficiency of mRNA transcripts by accelerating their degradation or prolonging their cytoplasmic half-life.[1]. As RBPs are themselves activated by growth factors and cell signals, this tightly regulated post-transcriptional mechanism enables the cell to rapidly adjust levels of protein expression in response to intrinsic and extracellular signals.[2,3] In addition, RBPs can interact with up to thousands of mRNA transcripts, allowing the coordinated synthesis of multiple proteins involved in a single physiological function (termed an RNA operon).[4] when the expression of an RBP is disrupted, it can potentially disrupt cellular homeostasis and autonomously drive pathological processes by uncoupling the regulation of mRNA stability from cell signaling cues.[5] A protein recently identified as being an RBP is Larelated protein 1 (LARP1).[6] LARP1 belongs to the LARP family, three members of which: LARP1, LARP3 (or genuine La protein) and LARP7 have so far been implicated in cancer. An elevated expression of LARP1 has been shown to correlate with clinical outcome in hepatocellular carcinoma,[7] LARP3 protein expression is increased in cervical cancer and higher levels have been shown to correlate with adverse outcome in lung cancer.[8,9] In contrast, LARP7 is a potential tumor suppressor in gastric and cervical tumors.[10,11]
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