Dock1 promotes the mesenchymal transition of glioma and is modulated by MiR‐31

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Excerpt

Gliomas are a group of primary brain tumours that exhibit a spectrum of aberrantly aggressive phenotypes. Despite surgery, radiation therapy and chemotherapy, glioblastoma patients who receive standard treatment show a median survival rate of only 15.6 months 1. Thus, the need to control the invasion of this malignancy by developing novel therapeutic approaches is urgent.
Dock proteins are large polypeptides characterized by the presence of two domains: the dihydrorhodamine 1 (DHR1) domain, which is 200–250 amino acid long and binds phospholipids, and the DHR2 domain, which is 450–550 amino acid long and performs the guanine nucleotide exchange activity 2. Dock proteins are classified into four subgroups based on sequence similarity and domain organization 3. The Dock1/ELMO complex mediates Rac activation in HeLa cells incapable of lamellipodia formation and further promotes cell spreading and migration 4. Dock1 (Dock180) plays an important role in the CXCL12‐mediated chemotaxis and metastasis of breast cancer cells 5. Dock1‐binding ELMO activates Rac downstream of GPCRs of LPA and promotes cell migration 6. However, the effect of Dock1 on the mesenchymal transition (MT) of glioma remains unclear.
MicroRNAs (MiRNAs) are small noncoding RNAs that regulate gene expression at the post‐transcriptional level by degrading or repressing the translation of mRNA targets. Mature miRNAs negatively regulate gene expression through imperfect complementary base‐pairing within the targeted 3’‐untranslated regions (UTRs) of mRNAs 7. Although the biological functions of most miRNAs have not yet been completely revealed, several reports have demonstrated that aberrant expression levels of miRNAs are involved in glioblastoma progression. MiR‐29b and miR‐125a regulate podoplanin and suppress glioblastoma invasion 8. MiR‐410 regulates mesenchymal–epithelial transition (MET) to influence the proliferation and invasion of glioma 9, whereas MiR‐31 functions as a tumour suppressor by regulating cell cycle and epithelial–MT regulatory proteins in liver cancer 10. MiR‐31 also controls G protein alpha‐13 expression and cell invasion in breast cancer cells 11. In addition, human miR‐31 targets radixin and inhibits the migration and invasion of glioma cells by inhibiting protein translation instead of mRNA degradation 12. Overexpression of miR‐31 or loss of KCNMA1 also increases cisplatin resistance in ovarian cancer cells 13. However, the miRNA that can regulate Dock1 expression and can promote glioma cell migration and invasion remains unknown.
This study demonstrated that Dock1 promoted the IL8‐induced chemotaxis and MT of glioma cells through the NF‐κB/Snail signalling pathway. Dock1 was modulated by miR‐31, and miR‐31 downregulation was attributable to the hypermethylation of its promoter region. In addition, the DNA methyltransferase inhibitor 5‐aza‐2’‐deoxycytidine (5‐aza‐dC) restored miR‐31 expression in glioma cells and then inhibited cell invasion.
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