Long non-coding RNAs (lncRNAs) are a class of regulatory genes that participate in a wide range of biological processes, including proliferation, differentiation and development, as well as in a broad spectrum of diseases. Although the role of lncRNAs in TGF-β-induced epithelial-to-mesenchymal transition (EMT) has been well established, little is known about the role of lncRNAs as immediate-early regulators of EMT. Here lnc-Spry1 is identified as an immediate-early regulator of EMT that is downregulated by TGF-β. It is also found that knockdown of lnc-Spry1 promotes a mesenchymal-like phenotype and results in increased cell migration and invasion. In addition, it is shown that lnc-Spry1 depletion preferentially affects the expression of TGF-β-regulated gene targets. Moreover, lnc-Spry1 associates with U2AF65 splicing factor, suggesting a role in alternative splicing. Depletion of lnc-Spry1 induces, as TGF-β, isoform switching of fibroblast growth factor receptors, resulting in FGF-2-sensitive cells. Taken together, these results show that lnc-Spry1 could act as an early mediator of TGF-β signaling and reveal different roles for a lncRNA in modulating transcriptional and posttranscriptional gene expression. Cell Death and Differentiation (2017) 24, 785-797; doi:10.1038/cdd.2017.9; published online 10 February 2017EMT is a basic cellular process in which epithelial cells lose their epithelial characteristics and take on properties of mesenchymal cells. During EMT, epithelial cells lose their cell-cell junctions and the epithelial apical-basal polarity. The actin cytoskeleton is reorganized and cells acquire migratory and invasive properties.1-3 This process is essential in the generation of tissues and organs during embryogenesis, during wound healing and is associated with pathologies, such as fibrosis and cancer. In carcinomas, cancer cells can undergo EMT to escape the primary tumor, invade surrounding tissues and colonize remote sites via blood or lymphatic routes generating metastases.
4-6The EMT program can be activated efficiently and rapidly in epithelial cells in response to soluble factors or cytokines, including epidermal growth factor, fibroblast growth factors (FGFs) and transforming growth factors (TGF-βs). TGF-β may induce EMT through distinct signaling mechanisms causing substantial changes in gene expression. These changes involve three families of transcription factors: the zinc finger Snail, Zeb, and basic helix-loop-helix families.
7Beyond the well-established transcriptional reprogramming during EMT, posttranscriptional mechanisms, such as regulation by alternative pre-mRNA splicing and regulation by noncoding RNA, have an important role and provide an additional layer of complexity on the gene regulation during EMT.
8-12The mammalian genome encodes many thousands of lncRNAs, a class of transcripts 4200 nucleotides with limited protein-coding potential.13 They can act as molecular signals, tethers, decoys, guides or scaffolds at every level of gene regulation in a wide range of biological proc...