miR-21 and 221 upregulation and miR-181b downregulation in human grade II–IV astrocytic tumors

Conti, Alfredo; Aguennouz, M.; Torre, Domenico La; Tomasello, Chiara; Cardali, Salvatore; Angileri, Filippo Flavio; Maio, Francesca; Cama, Annamaria; Germanò, Antonino; Vita, Giuseppe; Tomasello, Francesco

doi:10.1007/s11060-009-9797-4

Cited by 206 publications

(167 citation statements)

References 53 publications

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“…18 Compared with normal brain tissue, miR-21 relative expression was 7-to 11-folds in low-grade astrocytomas, anaplastic astrocytomas, and GBMs. 34 The present profile data further confirmed increased expression of miR-21 across GBM and astrocytoma cell lines. 24,33 This is particularly interesting as up to 80% of GBMs have a PTEN deficiency, and the prognosis of GBM can be predicted based on the levels of expression of PTEN.…”

Section: Mir-21 Is Overexpressed In Human Gbm Cell Linessupporting

confidence: 80%

Downregulation of miR-21 inhibits EGFR pathway and suppresses the growth of human glioblastoma cells independent of PTEN status

Zhou

Ren

Moore

et al. 2010

Laboratory Investigation

316

247

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MicroRNAs (miRNAs) are a class of endogenous small noncoding RNAs that regulate gene expression after transcription. Aberrant expression of miRNAs has been shown to be involved in tumorigenesis. We showed that miR-21 was one of the most frequently overexpressed miRNA in human glioblastoma (GBM) cell lines. To explore whether miR-21 can serve as a therapeutic target for glioblastoma, we downregulated miR-21 with a specific antisense oligonucleotide and found that apoptosis was induced and cell-cycle progression was inhibited in vitro in U251 (PTEN mutant) and LN229 (PTEN wildtype) GBM cells; xenograft tumors from antisense-treated U251 cells were suppressed in vivo. Antisense-miR-21-treated cells showed a decreased expression of EGFR, activated Akt, cyclin D, and Bcl-2. Although miR-21 is known to regulate PTEN and downregulation of miR-21 led to increased PTEN expression both endogenously and in a reporter gene assay, the GBM suppressor effect of antisense-miR-21 is most likely independent of PTEN regulation because U251 has mutant PTEN. Microarray analysis showed that the knockdown of miR-21 significantly altered expression of 169 genes involved in nine cell-cycle and signaling pathways. Taken together, our studies provide evidence that miR-21 may serve as a novel therapeutic target for malignant gliomas independent of PTEN status. Malignant gliomas are the most common primary brain tumors with high mortality and morbidity. The prognosis for malignant gliomas has not significantly improved in the last four decades. A recent meta-analysis of 12 randomized clinical trials showed that the overall survival rate of highgrade gliomas was 40% at 1 year after surgical removal and only slightly higher, 46%, after combined radiotherapy and chemotherapy. 1 To develop more optimized and effective treatment strategies for malignant gliomas, it is critical to gain deeper understanding of the molecular mechanisms underlying gliomagenesis and to identify targets for therapeutic intervention.The microRNAs (miRNAs) are a class of highly conserved small non-coding RNAs, approximately 22 nucleotides in length, that control gene expression through binding to the seed sequence at the 3 0 -UTR (untranslated region) of target mRNAs, resulting in translational repression or mRNA degradation. 2 This regulatory mechanism was first shown in the developmental processes in worms, flies, and plants. [3][4][5] Subsequently, miRNAs have been shown to have important roles in many physiological processes of mammalian systems by influencing cell apoptosis, proliferation, differentiation, development, and metabolism through regulation of critical signaling molecules including cytokines, growth factors, transcription factors, and pro-apoptotic and anti-apoptotic proteins. [6][7][8] Increasing number of miRNAs have been identified in the human genome and they are collectively called the miRNome. 9 Accumulating evidence shows the potential

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Section: Mir-21 Is Overexpressed In Human Gbm Cell Linessupporting

confidence: 80%

Downregulation of miR-21 inhibits EGFR pathway and suppresses the growth of human glioblastoma cells independent of PTEN status

Zhou

Ren

Moore

et al. 2010

Laboratory Investigation

316

247

View full text Add to dashboard Cite

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“…miRNA has been shown to be critical in the regulation of cancer cell functions in malignant gliomas. For example, miRNA-21 is overexpressed in GBM tumors and functional blockade of this miRNA induces apoptotic cell death (Conti et al, 2009). However, levels of miR-124, miR-137 and miR-451 are significantly reduced in malignant gliomas (both grade III and grade IV) relative to normal brain (Silber et al, 2008;Gal et al, 2008).…”

Section: Regulation Of Glioblastoma Stem Cells By Micro Rnasmentioning

confidence: 99%

Cancer stem cells in glioblastoma—molecular signaling and therapeutic targeting

et al. 2010

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Glioblastomas (GBMs) are highly lethal primary brain tumors. Despite current therapeutic advances in other solid cancers, the treatment of these malignant gliomas remains essentially palliative. GBMs are extremely resistant to conventional radiation and chemotherapies. We and others have demonstrated that a highly tumorigenic subpopulation of cancer cells called GBM stem cells (GSCs) promotes therapeutic resistance. We also found that GSCs stimulate tumor angiogenesis by expressing elevated levels of VEGF and contribute to tumor growth, which has been translated into a useful therapeutic strategy in the treatment of recurrent or progressive GBMs. Furthermore, stem cell-like cancer cells (cancer stem cells) have been shown to promote metastasis. Although GBMs rarely metastasize beyond the central nervous system, these highly infiltrative cancers often invade into normal brain tissues preventing surgical resection, and GSCs display an aggressive invasive phenotype. These studies suggest that targeting GSCs may effectively reduce tumor recurrence and significantly improve GBM treatment. Recent studies indicate that cancer stem cells share core signaling pathways with normal somatic or embryonic stem cells, but also display critical distinctions that provide important clues into useful therapeutic targets. In this review, we summarize the current understanding and advances in glioma stem cell research, and discuss potential targeting strategies for future development of anti-GSC therapies.

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“…The increased signaling results in enhanced glioma invasion by increasing MMP-9 secretion. Figure 1), we were interested in miR-21, which has been reported to be an oncogene that is overexpressed in various tumors, especially in glioblastomas (Chan et al, 2005;Conti et al, 2009;Krichevsky and Gabriely, 2009). Increased expression of miR-21 has been implicated in carcinogenesis, including the inhibition of apoptosis, promotion of cell proliferation and stimulation of tumor growth by targeting PTEN, TPM1, PDCD4 and so on (Krichevsky and Gabriely, 2009).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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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.

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miR-21 and 221 upregulation and miR-181b downregulation in human grade II–IV astrocytic tumors

Cited by 206 publications

References 53 publications

Downregulation of miR-21 inhibits EGFR pathway and suppresses the growth of human glioblastoma cells independent of PTEN status

Downregulation of miR-21 inhibits EGFR pathway and suppresses the growth of human glioblastoma cells independent of PTEN status

Cancer stem cells in glioblastoma—molecular signaling and therapeutic targeting

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

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