MicroRNA-218 inhibits glioma invasion, migration, proliferation, and cancer stem-like cell self-renewal by targeting the polycomb group gene Bmi1.
TL;DR: Restoring the expression of miR-218, a microRNA commonly downregulated in glioma, dramatically reduces the migration, invasion, and proliferation ofglioma cells.
Abstract: Malignant gliomas are the most common central nervous system tumors and the molecular mechanism driving their development and recurrence is still largely unknown, limiting the treatment of this disease. Here, we show that restoring the expression of miR-218, a microRNA commonly downregulated in glioma, dramatically reduces the migration, invasion, and proliferation of glioma cells. Quantitative reverse transcription PCR and Western blotting analysis revealed that expression of the stem cell-promoting oncogene Bmi1 was decreased after overexpression of miR-218 in glioma cells. Mechanistic investigations defined Bmi1 as a functional downstream target of miR-218 through which miR-218 ablated cell migration and proliferation. We documented that miR-218 also blocked the self-renewal of glioma stem-like cells, consistent with the suggested role of Bmi1 in stem cell growth. Finally, we showed that miR-218 regulated a broad range of genes involved in glioma cell development, including Wnt pathways that suppress glioma cell stem-like qualities. Taken together, our findings reveal miR-218 as a tumor suppressor that prevents migration, invasion, proliferation, and stem-like qualities in glioma cells.
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TL;DR: It is demonstrated that CCAT1 was upregulated in gallbladder cancer (GBC) tissues and knockeddown impaired the proliferation and invasiveness of GBC cells, at least in part through affecting miRNA-218-5p-mediated regulation of Bmi1.
Abstract: Protein-coding genes account for only ~2% of the human genome, whereas the vast majority of transcripts are non-coding RNAs (ncRNAs) including long ncRNAs (lncRNAs). A growing volume of literature has proposed that lncRNAs are important factors in cancer. Colon cancer-associated transcript-1 (CCAT1), an lncRNA, which was first identified in colon cancer, was previously shown to promote tumor development and be a negative prognostic factor in gastric cancer. However, the mechanism through which CCAT1 exerts its oncogenic activity remains largely unknown. Recently, a novel regulatory mechanism has been proposed in which RNAs can cross-talk with each other via competing shared for microRNAs (miRNAs). The proposed competitive endogenous RNAs could mediate the bioavailability of miRNAs on their targets, thus imposing another level of posttranscriptional regulation. In this study, we demonstrated that CCAT1 was upregulated in gallbladder cancer (GBC) tissues. CCAT1 silencing downregulated, whereas CCAT1 overexpression enhanced the expression of miRNA-218-5p target gene Bmi1 through competitively ‘spongeing' miRNA-218-5p. Our data revealed that CCAT1 knockdown impaired the proliferation and invasiveness of GBC cells, at least in part through affecting miRNA-218-5p-mediated regulation of Bmi1. Moreover, CCAT1 transcript level was correlated with Bmi1 mRNA level in GBC tissues. Together, these results suggest that CCAT1 is a driver of malignancy, which acts in part through ‘spongeing' miRNA-218-5p.
305 citations
TL;DR: An overview of some of the signaling pathways that have been shown to positively and negatively regulate GBM invasion, including, the PI3K/Akt, Wnt, sonic hedgehog-GLI1, and microRNAs are given.
247 citations
TL;DR: As the role of miRNAs in GBM becomes more well understood and novel delivery methods are developed and optimized, miRNA‐based therapies could provide a critical step forward in cancer treatment.
Abstract: Glioblastoma multiforme (GBM) is the most common and lethal cancer of the adult brain, remaining incurable with a median survival time of only 15 months. In an effort to identify new targets for GBM diagnostics and therapeutics, recent studies have focused on molecular phenotyping of GBM subtypes. This has resulted in mounting interest in microRNAs (miRNAs) due to their regulatory capacities in both normal development and in pathological conditions such as cancer. miRNAs have a wide range of targets, allowing them to modulate many pathways critical to cancer progression, including proliferation, cell death, metastasis, angiogenesis, and drug resistance. This review explores our current understanding of miRNAs that are differentially modulated and pathologically involved in GBM as well as the current state of miRNA-based therapeutics. As the role of miRNAs in GBM becomes more well understood and novel delivery methods are developed and optimized, miRNA-based therapies could provide a critical step forward in cancer treatment.
157 citations
TL;DR: In vivo restoration of miR-128 significantly suppressed tumourigenicity of A549 cells in nude mice and inhibited both angiogenesis and lymphangiogenesis of tumour xenografts, and could simultaneously block ERK, AKT and p38 signalling pathways.
149 citations
Cites background from "MicroRNA-218 inhibits glioma invasi..."
...Aberrant expression of miR-128 contributes to the malignant phenotypes of cancer cells, such as proliferation [38], cell motility, invasion [39,40], apoptosis [41] and self-renewal [42,43], but its roles in human NSCLC remain to be elucidated....
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TL;DR: Effective clinical translation of the cellular signalling mechanisms of mTOR offers provocative avenues for new drug development in the nervous system tempered only by the need to elucidate further the intricacies of the mTOR pathway.
Abstract: Neurodegenerative disorders are significantly increasing in incidence as the age of the global population continues to climb with improved life expectancy. At present, more than 30 million individuals throughout the world are impacted by acute and chronic neurodegenerative disorders with limited treatment strategies. The mechanistic target of rapamycin (mTOR), also known as the mammalian target of rapamycin, is a 289 kDa serine/threonine protein kinase that offers exciting possibilities for novel treatment strategies for a host of neurodegenerative diseases that include Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, stroke and trauma. mTOR governs the programmed cell death pathways of apoptosis and autophagy that can determine neuronal stem cell development, precursor cell differentiation, cell senescence, cell survival and ultimate cell fate. Coupled to the cellular biology of mTOR are a number of considerations for the development of novel treatments involving the fine control of mTOR signalling, tumourigenesis, complexity of the apoptosis and autophagy relationship, functional outcome in the nervous system, and the intimately linked pathways of growth factors, phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), AMP activated protein kinase (AMPK), silent mating type information regulation two homologue one (Saccharomyces cerevisiae) (SIRT1) and others. Effective clinical translation of the cellular signalling mechanisms of mTOR offers provocative avenues for new drug development in the nervous system tempered only by the need to elucidate further the intricacies of the mTOR pathway.
134 citations
References
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Journal Article•
TL;DR: I MicroRNAs (miRNAs) are an abundant class of small non-protein-coding RNAs that function as negative gene regulators as discussed by the authors, and have been shown to repress the expression of important cancer-related genes and might prove useful in the diagnosis and treatment of cancer.
Abstract: I MicroRNAs (miRNAs) are an abundant class of small non-protein-coding RNAs that function as negative gene regulators. They regulate diverse biological processes, and bioinformatic data indicates that each miRNA can control hundreds of gene targets, underscoring the potential influence of miRNAs on almost every genetic pathway. Recent evidence has shown that miRNA mutations or mis-expression correlate with various human cancers and indicates that miRNAs can function as tumour suppressors and oncogenes. miRNAs have been shown to repress the expression of important cancer-related genes and might prove useful in the diagnosis and treatment of cancer.
6,064 citations
TL;DR: Evidence has shown that miRNA mutations or mis-expression correlate with various human cancers and indicates that miRNAs can function as tumour suppressors and oncogenes.
Abstract: MicroRNAs (miRNAs) are an abundant class of small non-protein-coding RNAs that function as negative gene regulators They regulate diverse biological processes, and bioinformatic data indicates that each miRNA can control hundreds of gene targets, underscoring the potential influence of miRNAs on almost every genetic pathway Recent evidence has shown that miRNA mutations or mis-expression correlate with various human cancers and indicates that miRNAs can function as tumour suppressors and oncogenes miRNAs have been shown to repress the expression of important cancer-related genes and might prove useful in the diagnosis and treatment of cancer
5,693 citations
"MicroRNA-218 inhibits glioma invasi..." refers background in this paper
...miRNAs downregulate multiple target genes, including oncogenes and tumor suppressor genes, while some miRNAs function as tumor suppressors and others act as oncogenes (6, 7)....
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TL;DR: Current evidence suggests a direct link between miRNAs and disease, and miRNA expression signatures are associated with various types of cancer, and the gain and loss of miRNA target sites appears to be causal to some genetic disorders.
1,999 citations
TL;DR: New insights are discussed into the possible mechanisms by which PcGs regulate cellular identity, and how these functions might be relevant during tumorigenesis are speculated.
Abstract: Polycomb group (PcG) proteins are epigenetic gene silencers that are implicated in neoplastic development. Their oncogenic function might be associated with their well-established role in the maintenance of embryonic and adult stem cells. In this review, we discuss new insights into the possible mechanisms by which PcGs regulate cellular identity, and speculate how these functions might be relevant during tumorigenesis.
1,332 citations
"MicroRNA-218 inhibits glioma invasi..." refers background in this paper
...Bmi1 is a part of the PRC1 complex, which is able to recognize the trimethylated H3K27(H3K27me3), and this interaction could bring neighboring nucleosomes into the proximity of the PRC2 complex (37)....
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TL;DR: How miRNAs influence tumorigenesis by acting as oncogenes and tumour suppressors is discussed.
Abstract: MicroRNAs (miRNAs) are a recently discovered class of approximately 18-24 nucleotide RNA molecules that negatively regulate target mRNAs. All studied multicellular eukaryotes utilise miRNAs to regulate basic cellular functions including proliferation, differentiation, and death. It is now apparent that abnormal miRNA expression is a common feature of human malignancies. In this review, we will discuss how miRNAs influence tumorigenesis by acting as oncogenes and tumour suppressors.
1,226 citations