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TGF‐β1 activates RSC96 Schwann cells migration and invasion through MMP‐2 and MMP‐9 activities
Author(s) -
Muscella Antonella,
Vetrugno Carla,
Cossa Luca Giulio,
Marsigliante Santo
Publication year - 2020
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14913
Subject(s) - microbiology and biotechnology , extracellular matrix , cell migration , signal transduction , biology , gene knockdown , schwann cell , kinase , matrix metalloproteinase , transforming growth factor , extracellular , cell , biochemistry , apoptosis
Following peripheral nerve injury, remnant Schwann cells adopt a migratory phenotype and remodel the extracellular matrix allowing axonal regrowth. Although much evidence has demonstrated that TGF‐β1 promotes glioma cell motility and induces the expression of extracellular matrix proteins, the effects of TGF‐β1 on Schwann cell migration has not yet been studied. We therefore investigated the cellular effects and the signal transduction pathways evoked by TGF‐β1 in rattus norvegicus neuronal Schwann RSC96 cell. TGF‐β1 significantly increased migration and invasion of Schwann cells assessed by the wound‐healing assay and by cell invasion assay. TGF‐β1‐enhanced migration/invasion was blocked by inhibition of MMP‐2 and MMP‐9. Consistently, by real‐time and western blot analyses, we demonstrated that TGF‐β1 increased MMP‐2 and MMP‐9 mRNA and protein levels. TGF‐β1 also increased MMPs activities in cell growth medium, as shown by gelatin zymography. The selective TGF‐β Type I receptor inhibitor SB431542 completely abrogated any effects by TGF‐β1. Indeed, TGF‐β1 Type I receptor activation provoked the cytosol‐to‐nucleus translocation of SMAD2 and SMAD3. SMAD2 knockdown by siRNA blocked MMP‐2 induction and cell migration/invasion due to TGF‐β1. TGF‐β1 also provoked phosphorylation of MAPKs extracellular regulated kinase 1/2 and JNK1/2. Both MAPKs were upstream to p65/NF‐kB inasmuch as both MAPKs’ inhibitors PD98059 and SP600125 or their down‐regulation by siRNA significantly blocked the TGF‐β1‐induced nuclear translocation of p65/NF‐kB. In addition, p65/NF‐κB siRNA knockdown inhibited the effects of TGF‐β1 on both MMP‐9 and cell migration/invasion. We conclude that TGF‐β1 controls RSC96 Schwann cell migration and invasion through MMP‐2 and MMP‐9 activities. MMP‐2 is controlled by SMAD2 whilst MMP‐9 is controlled via an ERK1/2‐JNK1/2‐NF‐κB dependent pathway.