Abstract
RNA-RNA and protein-RNA interactions are essential for post-transcriptional regulationin normal development and may be deregulated in cancer initiation and progression. The RNA-binding protein PCBP2, an oncogenic protein in human malignant gliomas, is an essential regulator of mRNA and miRNA biogenesis, stability and activity. Here, we identified Rho GDP dissociation inhibitor α (ARHGDIA) as a target mRNA that binds to PCBP2, and we uncovered the role of ARHGDIA as a putative metastasis suppressor through analyses of in vitro and in vivo models of EMT and metastasis. Furthermore, we demonstrated that ARHGDIA is a potential target of miR-151-5p and miR-16 in gliomas. The interaction between PCBP2 and the 3′UTR of the ARHGDIA mRNA may induce a local change in RNA structure that favors subsequent binding of miR-151-5p and miR-16, thus leading to the suppression of ARHGDIA expression. PCBP2 may facilitate miR-151-5p and miR-16 promotion of glioma cell migration and invasion through mitigating the function of ARHGDIA.
Highlights
The Rho GDP dissociation inhibitor α (RhoGDIα), known as ARHGDIA, RhoGDIA, or RhoGDI1, is thought to be a negative regulator of Rho family G-proteins, namely Rho GTPases [1]
We show that the expression of ARHGDIA is frequently decreased in high-grade malignant gliomas
Total RNA and proteins were extracted from 6 brain tissue samples from donors who were not diagnosed with gliomas and compared with RNA and proteins from 72 glioma tissue samples, which consisted of 12 grade II, 12 grade III and 48 grade IV glioma tissues
Summary
The Rho GDP dissociation inhibitor α (RhoGDIα), known as ARHGDIA, RhoGDIA, or RhoGDI1, is thought to be a negative regulator of Rho family G-proteins, namely Rho GTPases [1]. Three evolutionarily conserved mammalian RhoGDIs have been identified: RhoGDIA (α), RhoGDIB (β) and RhoGDIG (γ). Of the three isoforms of RhoGDI identified to date, ARHGDIA is ubiquitously expressed and interacts with all three key Rho GTPases, including RhoA, Cdc and Rac [2]. RhoGDIs bind to Rho GTPases and maintain them in a biologically inactive state in the cytoplasm, which affects the regulation of actin cytoskeleton processes, including formation of focal adhesions, stress fibers, lamellipodia and filopodia; membrane ruffling and cell motility; and changes in cell morphology [3]. ARHGDIA expression levels are altered in different types of cancers. ARHGDIA expression is increased in colorectal and ovarian cancer [4, 5]
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