MicroRNA expression profiles classify human cancers

Lü, Jun; Getz, Gad; Miska, Eric A.; Alvarez-Saavedra, Ezequiel; Lamb, Justin; Peck, Donald J.; Sweet‐Cordero, Alejandro; Ebert, Benjamin L.; Mak, Raymond H.; Ferrando, Adolfo A.; Downing, James R.; Jacks, Tyler; Horvitz, H. Robert; Golub, Todd R.

doi:10.1038/nature03702

Cited by 8,643 publications

(7,127 citation statements)

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“…The function of miRNAs may be deregulated in cancer in several manners, including miRNA gene mutation, deletion or promoter hypermethylation, but also as a consequence of mutations in their target sequences (Esquela‐Kerscher and Slack, 2006; Nana‐Sinkam and Croce, 2011; Palmero et al., 2011). Although attenuated expression of the miRNA transcriptome is frequently observed (Kumar et al., 2007; Lu et al., 2005), various miRNAs are overexpressed in specific tumors compared to their healthy tissue of origin (Ma et al., 2010a,b; Volinia et al., 2006), and thus are termed “oncomiRs”. Furthermore, the predicted targets for several cancer‐associated miRNAs include protein‐coding tumor suppressors and oncogenes, supporting a role for miRNAs in cancer pathogenesis (Esquela‐Kerscher and Slack, 2006; Nana‐Sinkam and Croce, 2011; Palmero et al., 2011).…”

Section: Addressing Tumor Heterogeneity and Complexitymentioning

confidence: 99%

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

2012

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It is a time of great promise and expectation for the applications of knowledge about mechanisms of cancer toward more effective and enduring therapies for human disease. Conceptualizations such as the hallmarks of cancer are providing an organizing principle with which to distill and rationalize the abject complexities of cancer phenotypes and genotypes across the spectrum of the human disease. A countervailing reality, however, involves the variable and often transitory responses to most mechanism‐based targeted therapies, returning full circle to the complexity, arguing that the unique biology and genetics of a patient's tumor will in the future necessarily need to be incorporated into the decisions about optimal treatment strategies, the frontier of personalized cancer medicine. This perspective highlights considerations, metrics, and methods that may prove instrumental in charting the landscape of evaluating individual tumors so to better inform diagnosis, prognosis, and therapy. Integral to the consideration is remarkable heterogeneity and variability, evidently embedded in cancer cells, but likely also in the cell types composing the supportive and interactive stroma of the tumor microenvironment (e.g., leukocytes and fibroblasts), whose diversity in form, regulation, function, and abundance may prove to rival that of the cancer cells themselves. By comprehensively interrogating both parenchyma and stroma of patients' cancers with a suite of parametric tools, the promise of mechanism‐based therapy may truly be realized.

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Section: Addressing Tumor Heterogeneity and Complexitymentioning

confidence: 99%

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

2012

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“…Research in a Caenorhabditis elegans model system revealed changes in miRNA expression in relation to lifespan and longevity (Boehm & Slack, 2005; Ibáñez‐Ventoso et al ., 2006; Pincus et al ., 2011). In humans, highly specific miRNA expression patterns are correlated with many age‐related diseases including cardiovascular disease (Small & Olson, 2011; Huan et al ., 2015c) and cancer (Lu et al ., 2005; Hayes et al ., 2014). Recent studies have examined differentially expressed miRNAs in relation to age in whole blood (ElSharawy et al ., 2012), peripheral blood mononuclear cells (PBMC) (Noren Hooten et al ., 2010), and serum (Noren Hooten et al ., 2013; Zhang et al ., 2014).…”

Section: Introductionmentioning

confidence: 99%

Age‐associated microRNA expression in human peripheral blood is associated with all‐cause mortality and age‐related traits

et al. 2017

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SummaryRecent studies provide evidence of correlations of DNA methylation and expression of protein‐coding genes with human aging. The relations of microRNA expression with age and age‐related clinical outcomes have not been characterized thoroughly. We explored associations of age with whole‐blood microRNA expression in 5221 adults and identified 127 microRNAs that were differentially expressed by age at P < 3.3 × 10−4 (Bonferroni‐corrected). Most microRNAs were underexpressed in older individuals. Integrative analysis of microRNA and mRNA expression revealed changes in age‐associated mRNA expression possibly driven by age‐associated microRNAs in pathways that involve RNA processing, translation, and immune function. We fitted a linear model to predict ‘microRNA age’ that incorporated expression levels of 80 microRNAs. MicroRNA age correlated modestly with predicted age from DNA methylation (r = 0.3) and mRNA expression (r = 0.2), suggesting that microRNA age may complement mRNA and epigenetic age prediction models. We used the difference between microRNA age and chronological age as a biomarker of accelerated aging (Δage) and found that Δage was associated with all‐cause mortality (hazards ratio 1.1 per year difference, P = 4.2 × 10−5 adjusted for sex and chronological age). Additionally, Δage was associated with coronary heart disease, hypertension, blood pressure, and glucose levels. In conclusion, we constructed a microRNA age prediction model based on whole‐blood microRNA expression profiling. Age‐associated microRNAs and their targets have potential utility to detect accelerated aging and to predict risks for age‐related diseases.

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“…Therefore, it is possible that upregulation of DICER1 may in part mediate metformin's antitumorigenic effects. In general with few exceptions, cancer cells have decreased global miRNA expression (Lu et al ., 2005; Kumar et al ., 2007), leading to the hypothesis that upregulation of DICER1 may lead to increased miRNA expression, which would then contribute to lowering tumorigenic activity. Consistent with this idea, DICER1 expression is decreased in several types of human cancers (Bahubeshi et al ., 2011; Foulkes et al ., 2014).…”

Section: Introductionmentioning

confidence: 99%

Metformin‐mediated increase in DICER1 regulates microRNA expression and cellular senescence

et al. 2016

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SummaryMetformin, an oral hypoglycemic agent, has been used for decades to treat type 2 diabetes mellitus. Recent studies indicate that mice treated with metformin live longer and have fewer manifestations of age‐related chronic disease. However, the molecular mechanisms underlying this phenotype are unknown. Here, we show that metformin treatment increases the levels of the microRNA‐processing protein DICER1 in mice and in humans with diabetes mellitus. Our results indicate that metformin upregulates DICER1 through a post‐transcriptional mechanism involving the RNA‐binding protein AUF1. Treatment with metformin altered the subcellular localization of AUF1, disrupting its interaction with DICER1 mRNA and rendering DICER1 mRNA stable, allowing DICER1 to accumulate. Consistent with the role of DICER1 in the biogenesis of microRNAs, we found differential patterns of microRNA expression in mice treated with metformin or caloric restriction, two proven life‐extending interventions. Interestingly, several microRNAs previously associated with senescence and aging, including miR‐20a, miR‐34a, miR‐130a, miR‐106b, miR‐125, and let‐7c, were found elevated. In agreement with these findings, treatment with metformin decreased cellular senescence in several senescence models in a DICER1‐dependent manner. Metformin lowered p16 and p21 protein levels and the abundance of inflammatory cytokines and oncogenes that are hallmarks of the senescence‐associated secretory phenotype (SASP). These data lead us to hypothesize that changes in DICER1 levels may be important for organismal aging and to propose that interventions that upregulate DICER1 expression (e.g., metformin) may offer new pharmacotherapeutic approaches for age‐related disease.

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MicroRNA expression profiles classify human cancers

Cited by 8,643 publications

References 29 publications

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

Age‐associated microRNA expression in human peripheral blood is associated with all‐cause mortality and age‐related traits

Metformin‐mediated increase in DICER1 regulates microRNA expression and cellular senescence

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