Abstract
Heterogeneous nuclear ribonucleoproteins (hnRNPs) control gene expression by acting at multiple levels and are often deregulated in epithelial tumors; however, their roles in the fine regulation of cellular reprogramming, specifically in epithelial–mesenchymal transition (EMT), remain largely unknown. Here, we focused on the hnRNP-Q (also known as SYNCRIP), showing by molecular analysis that in hepatocytes it acts as a “mesenchymal” gene, being induced by TGFβ and modulating the EMT. SYNCRIP silencing limits the induction of the mesenchymal program and maintains the epithelial phenotype. Notably, in HCC invasive cells, SYNCRIP knockdown induces a mesenchymal–epithelial transition (MET), negatively regulating their mesenchymal phenotype and significantly impairing their migratory capacity. In exploring possible molecular mechanisms underlying these observations, we identified a set of miRNAs (i.e., miR-181-a1-3p, miR-181-b1-3p, miR-122-5p, miR-200a-5p, and miR-let7g-5p), previously shown to exert pro- or anti-EMT activities, significantly impacted by SYNCRIP interference during EMT/MET dynamics and gathered insights, suggesting the possible involvement of this RNA binding protein in their transcriptional regulation.
Highlights
Synaptotagmin-binding Cytoplasmic RNA-Interacting Protein (SYNCRIP) Is Involved in TGFβ-Induced epithelial–mesenchymal transition (EMT) of Hepatocytes
Hepatocytes were stably infected with retroviral vectors expressing different shRNAs against SYNCRIP and a scrambled sequence as a control
QRT-PCR (Figure 1F) and WB (Figure 1G) analysis showed that while the SYNCRIPknockdown did not interfere with the TGFβ-mediated upregulation of the EMT-TF Zeb2, it significantly prevented the induction of Snail protein and the downregulation of its main epithelial target genes (E-cadherin and HNF1α). These findings indicate that SYNCRIP can act as a mesenchymal gene, positively regulated in TGFβ-induced EMT, and provide evidence of a functional role for this Heterogeneous nuclear ribonucleoproteins (hnRNPs) in the transdifferentiation of the hepatocytes by contributing to the modulation of
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Epithelial–mesenchymal transition (EMT) is a cellular reprogramming mechanism that allows epithelial cells to acquire mesenchymal properties. This transdifferentiation process has a key role in physiology and pathology, being required in the embryo for gastrulation and morphogenesis, in the adult for wound healing, and in epithelial tumors for several functions, such as stemness, resistance to therapy and, mainly, malignant progression. Transitional cells, can migrate and disseminate, allowing carcinoma cells to metastasize. Mesenchymal cells can reacquire an epithelial phenotype by undergoing mesenchymal–epithelial transition (MET), which is regulated by tumor niche (reviewed in [1])
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