Downregulation of Spry2 by miR-21 triggers malignancy in human gliomas

Abstract

Gliomas are associated with high mortality because of their exceedingly invasive character. As these tumors acquire their invasiveness from low-grade tumors, it is very important to understand the detailed molecular mechanisms of invasion onset. Recent evidences suggest the significant role of microRNAs in tumor invasion. Thus, we hypothesized that deregulation of microRNAs may be important for the malignant progression of gliomas. We found that the aberrant expression of miR-21 is responsible for glioma invasion by disrupting the negative feedback circuit of Ras/MAPK signaling, which is mediated by Spry2. Upregulation of miR-21 was triggered by tumor microenvironmental factors such as hyaluronan and growth factors in glioma cells lacking functional phosphatase and tensin homolog (PTEN), but not harboring wild-type PTEN. Consistently with these in vitro results, Spry2 protein levels were significantly decreased in 79.7% of invasive WHO grade II-IV human glioma tissues, but not in non-invasive grade I and normal tissues. The Spry2 protein levels were not correlated with their mRNA levels, but inversely correlated with miR-21 levels. Taken together, these results suggest that the posttranscriptional regulation of Spry2 by miR-21 has an essential role on the malignant progression of human gliomas. Thus, Spry2 may be a novel therapeutic target for treating gliomas.

Pilocytic astrocytomas of the optic nerve and their relation to pilocytic astrocytomas elsewhere in the central nervous system

“…This raises the possibility that other alterations in BRAF may drive the activation of p-MAPK1 and CDKN2A in pilocytic astrocytoma of the optic nerve. Alternatively, alterations in negative regulatory factors of the MAPK pathway, such as the Sprouty family of proteins, Raf kinase inhibitor protein, impedes mitogenic signal propagation, and the (7) 10 (16) dual-specificity MAPK phosphatase [29][30][31][32][33][34][35][36] may be found in pilocytic astrocytoma of the optic nerve. Studies are currently under way to test for these possibilities.…”

MiR-21 Upregulation Induced by Promoter Zone Histone Acetylation is Associated with Chemoresistance to Gemcitabine and Enhanced Malignancy of Pancreatic Cancer Cells

“…The expression of miR-21 has been shown to be involved in the progression of several types of cancers (Kwak et al, 2011;Yang et al, 2011), including PDAC (Bloomston et al, 2007;Szafranska et al, 2007;Nagao et al, 2012), and the up-regulation of miR-21 expression has been shown to correlate with a lower cancer survival rate (Dillhoff et al, 2008;Jamieson et al, 2012). Recent studies also demonstrated that miR-21 modulates the chemosensitivity of cancer cells primarily by targeting PTEN or PDCD4 (Moriyama et al, 2009;Ali et al, 2010;Giovannetti et al, 2010;Tomimaru et al, 2010).…”

miRNA-182 and the regulation of the glioblastoma phenotype - toward miRNA-based precision therapeutics

“…miR-21 has oncogenic functions and promotes cell proliferation by targeting the phosphatase and tensin homolog (PTEN), sprouty RTK signaling antagonist 2 (SPRY2) tumor suppressor pathways, and by activating the nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-kB) and rat sarcoma viral oncogene (Ras)-signaling. 26,27 Further molecular analyses revealed that miR-21 promoted cell invasion by targeting the matrix metaloproteinase regulators reversion-inducing cysteine-rich protein with kazal motifs (RECK) and tissue inhibitor of metallopeptidase 3 (TIMP3), 28 and inhibited apoptosis via repression of heterogeneous nuclear ribonucleoprotein K (HNRPK) and programmed cell death 4 (PDCD4). 29 miR-10b and -26a represent additional tumor-promoting miRNAs.…”