Downregulation of Lnc-Spry1 mediates TGF-β-induced epithelial–mesenchymal transition by transcriptional and posttranscriptional regulatory mechanisms

Abstract

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...

ELK1‐activated GPC3‐AS1/GPC3 axis promotes the proliferation and migration of cervical cancer cells

“…Accumulating evidence shows that lncRNA exerts oncogenic or tumor suppressive role with respect to regulating cancerous biological behaviors, such as cell proliferation, migration and EMT . Accordingly, lncRNAs are increasing being identified as crucial regulators in human tumors.…”

“…Accumulating evidence shows that lncRNA exerts oncogenic or tumor suppressive role with respect to regulating cancerous biological behaviors, such as cell proliferation, migration and EMT. [29][30][31][32][33] Accordingly, lncRNAs are increasing being identified as crucial regulators in human tumors. Among these, antisense lncRNA is emerging as a vital participant with respect to affecting various cancerous developments, [34][35][36][37][38] In the present study, five candidates (DICER1-AS1, FAM83H-AS1, GPC3-AS1, DLX6-AS1 and SOX21-AS1) were subjected to qRT-PCR.…”

Knockdown of long non‐coding RNA linc‐ITGB1 inhibits cancer stemness and epithelial‐mesenchymal transition by reducing the expression of Snail in non‐small cell lung cancer

“…7 In addition to the canonical transcriptional programming during EMT, post-transcriptional regulation by microRNAs and non-coding RNAs (lncRNAs) plays an important role in gene regulation during EMT. 8 LncRNAs, a class of non-protein-coding transcripts longer than 200 nucleotides, have emerged as key regulators of a wide range of biological processes, and their abnormal expression is closely associated with tumor proliferation, differentiation, apoptosis and metastasis. 9,10 Several lncRNAs, such as MALAT-1 10,11 and lncRNAH19, 12 are reported to participate in the regulation of EMT.…”

Salvianolic acid B attenuates renal interstitial fibrosis by regulating the HPSE/SDC1 axis

“…TEMT plays an important role in renal interstitial fibrosis. under the stimulation of numerous factors, renal tubular epithelial cells could release cytokines (such as TGF-β1 and FGF-2) into the tubulointerstitial microenvironment, and eventually lead to TEMT (37,38), which is characterized by decreased expression of e-cadherin and increased expression of α-SMa (39). Sal B, as one of the main water-soluble components of Salvia miltiorrhiza Bge, has been shown by previous studies to be able to inhibit TeMT by antioxidation (40) and to decrease α-SMa expression (41).…”