Journal Article•
Oncomirs : microRNAs with a role in cancer
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.
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TL;DR: This review summarizes the potential role of miRNAs as molecular markers for cancer classification, prognostic stratification and drug-response prediction and also summarizes their potential as circulating markers and cancer-predisposing genes.
Abstract: Molecular diagnostics in cancer should provide the highest specificity and sensitivity in classification, prognostic stratification and early detection. miRNAs could contribute to hitting the mark, or at least to come nearer, by virtue of their cancer-specific expression and stability. Indeed, different to other RNA classes, miRNAs can be detected and quantified not only in frozen tissues, but also in formalin-fixed paraffin-embedded tissues, as well as serum/plasma samples. Thus, miRNA studies have quickly moved from research on the molecular basis of cancer to areas of clinical application. This review summarizes the potential role of miRNAs as molecular markers for cancer classification, prognostic stratification and drug-response prediction. It also summarizes their potential as circulating markers and cancer-predisposing genes. If we consider that studies on miRNAs in cancer therapy have already given important contributions, miRNAs have an impact in all cancer areas. Whether this will translate into...
251 citations
TL;DR: The miRNA profile of Epstein-Barr virus-positive nasopharyngeal carcinoma (NPC) tissue samples characterized by cloning and sequencing is reported and it is found that the tumor suppressor BRCA-1 is a target of miR-15a as well asmiR-16, suggesting a miRNA role in NPC pathogenesis.
Abstract: MicroRNAs (miRNAs) represent a conserved class of small noncoding RNAs that are found in all higher eukaryotes as well as some DNA viruses. miRNAs are 20 to 25 nucleotides in length and have important regulatory functions in biological processes such as embryonic development, cell differentiation, hormone secretion, and metabolism. Furthermore, miRNAs have been implicated in the pathology of various diseases, including cancer. miRNA expression profiles not only classify different types of cancer but also may even help to characterize distinct tumor stages, therefore constituting a valuable tool for prognosis. Here we report the miRNA profile of Epstein-Barr virus (EBV)-positive nasopharyngeal carcinoma (NPC) tissue samples characterized by cloning and sequencing. We found that all EBV miRNAs from the BART region are expressed in NPC tissues, whereas EBV miRNAs from the BHRF1 region are not found. Moreover, we identified two novel EBV miRNA genes originating from the BART region that have not been found in other tissues or cell lines before. We also identified three new human miRNAs which might be specific for nasopharyngeal tissues. We further show that a number of different cellular miRNAs, including miR-15a and miR-16, are up- or downregulated in NPC tissues compared to control tissues. We found that the tumor suppressor BRCA-1 is a target of miR-15a as well as miR-16, suggesting a miRNA role in NPC pathogenesis.
251 citations
TL;DR: It is suggested that circulating miR-125b expression is associated with chemotherapeutic resistance of breast cancer, which has important implications in the development of targeted therapeutics for overcoming chemotherAPEutic resistance in novel anti-cancer strategies.
Abstract: Background
Chemotherapy is an important component in the treatment paradigm for breast cancers However, the resistance of cancer cells to chemotherapeutic agents frequently results in the subsequent recurrence and metastasis Identification of molecular markers to predict treatment outcome is therefore warranted The aim of the present study was to evaluate whether expression of circulating microRNAs (miRNAs) can predict clinical outcome in breast cancer patients treated with adjuvant chemotherapy
Methodology/Principal Findings
Circulating miRNAs in blood serum prior to treatment were determined by quantitative Real-Time PCR in 56 breast cancer patients with invasive ductal carcinoma and pre-operative neoadjuvant chemotherapy Proliferating cell nuclear antigen (PCNA) immunostaining and TUNEL were performed in surgical samples to determine the effects of chemotherapy on cancer cell proliferation and apoptosis, respectively Among the miRNAs tested, only miR-125b was significantly associated with therapeutic response, exhibiting higher expression level in non-responsive patients (n = 26, 46%; p = 0008) In addition, breast cancers with high miR-125b expression had higher percentage of proliferating cells and lower percentage of apoptotic cells in the corresponding surgical specimens obtained after neoadjuvant chemotherapy Increased resistance to anticancer drug was observed in vitro in breast cancer cells with ectopic miR-125b expression; conversely, reducing miR-125b level sensitized breast cancer cells to chemotherapy Moreover, we demonstrated that the E2F3 was a direct target of miR-125b in breast cancer cells
Conclusions/Significance
These data suggest that circulating miR-125b expression is associated with chemotherapeutic resistance of breast cancer This finding has important implications in the development of targeted therapeutics for overcoming chemotherapeutic resistance in novel anti-cancer strategies
250 citations
TL;DR: The literature surrounding the identification of metastatic miRNA in breast cancer patients is reviewed, highlighting key areas where miRNA biomarker discovery could be beneficial, identifying key concepts, recognizing critical areas requiring further research and discussing potential problems.
Abstract: Breast cancer affects approximately 12 % women worldwide and results in 14 % of all cancer-related fatalities. Breast cancer is commonly categorized into one of four main subtypes (luminal A, luminal B, human epidermal growth factor receptor 2 (HER2) positive and basal), indicating molecular characteristics and informing treatment regimes. The most severe form of breast cancer is metastasis, when the tumour spreads from the breast tissue to other parts of the body. Significantly, the primary tumour subtype affects rates and sites of metastasis. Currently, up to 5 % of patients present with incurable metastasis, with an additional 10–15 % of patients going on to develop metastasis within 3 years of diagnosis. MicroRNAs (miRNAs) are short 21–25 long nucleotides that have been shown to significantly affect gene expression. Currently, >2000 miRNAs have been identified and significantly, specific miRNAs have been found associated with diseases states. Importantly, miRNAs are found circulating in the blood, presenting an opportunity to use these circulating disease-related miRNAs as biomarkers. Clearly, the identification of circulating miRNA specific to metastatic breast cancer presents a unique opportunity for early disease identification and for monitoring disease burden. Currently however, few groups have identified miRNA associated with metastatic breast cancer. Here, we review the literature surrounding the identification of metastatic miRNA in breast cancer patients, highlighting key areas where miRNA biomarker discovery could be beneficial, identifying key concepts, recognizing critical areas requiring further research and discussing potential problems.
250 citations
TL;DR: The effects of age as a factor in breast cancer diagnosis and treatment relating it to factors such as genetic status, breast cancer subtype, hormone factors and nodal status are examined and the observed correlations are examined.
Abstract: Currently, breast cancer affects approximately 12% of women worldwide. While the incidence of breast cancer rises with age, a younger age at diagnosis is linked to increased mortality. We discuss age related factors affecting breast cancer diagnosis, management and treatment, exploring key concepts and identifying critical areas requiring further research. We examine age as a factor in breast cancer diagnosis and treatment relating it to factors such as genetic status, breast cancer subtype, hormone factors and nodal status. We examine the effects of age as seen through the adoption of population wide breast cancer screening programs. Assessing the incidence rates of each breast cancer subtype, in the context of age, we examine the observed correlations. We explore how age affects patient's prognosis, exploring the effects of age on stage and subtype incidence. Finally we discuss the future of breast cancer diagnosis and treatment, examining the potential of emerging tests and technologies (such as microRNA) and how novel research findings are being translated into clinically relevant practices.
247 citations
References
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TL;DR: Although they escaped notice until relatively recently, miRNAs comprise one of the more abundant classes of gene regulatory molecules in multicellular organisms and likely influence the output of many protein-coding genes.
32,946 citations
TL;DR: Two small lin-4 transcripts of approximately 22 and 61 nt were identified in C. elegans and found to contain sequences complementary to a repeated sequence element in the 3' untranslated region (UTR) of lin-14 mRNA, suggesting that lin- 4 regulates lin- 14 translation via an antisense RNA-RNA interaction.
11,932 citations
TL;DR: A new, bead-based flow cytometric miRNA expression profiling method is used to present a systematic expression analysis of 217 mammalian miRNAs from 334 samples, including multiple human cancers, and finds the miRNA profiles are surprisingly informative, reflecting the developmental lineage and differentiation state of the tumours.
Abstract: Recent work has revealed the existence of a class of small non-coding RNA species, known as microRNAs (miRNAs), which have critical functions across various biological processes. Here we use a new, bead-based flow cytometric miRNA expression profiling method to present a systematic expression analysis of 217 mammalian miRNAs from 334 samples, including multiple human cancers. The miRNA profiles are surprisingly informative, reflecting the developmental lineage and differentiation state of the tumours. We observe a general downregulation of miRNAs in tumours compared with normal tissues. Furthermore, we were able to successfully classify poorly differentiated tumours using miRNA expression profiles, whereas messenger RNA profiles were highly inaccurate when applied to the same samples. These findings highlight the potential of miRNA profiling in cancer diagnosis.
9,470 citations
TL;DR: The predicted regulatory targets of mammalian miRNAs were enriched for genes involved in transcriptional regulation but also encompassed an unexpectedly broad range of other functions.
5,246 citations
TL;DR: The two RNase III proteins, Drosha and Dicer, may collaborate in the stepwise processing of miRNAs, and have key roles in miRNA-mediated gene regulation in processes such as development and differentiation.
Abstract: Hundreds of small RNAs of approximately 22 nucleotides, collectively named microRNAs (miRNAs), have been discovered recently in animals and plants. Although their functions are being unravelled, their mechanism of biogenesis remains poorly understood. miRNAs are transcribed as long primary transcripts (pri-miRNAs) whose maturation occurs through sequential processing events: the nuclear processing of the pri-miRNAs into stem-loop precursors of approximately 70 nucleotides (pre-miRNAs), and the cytoplasmic processing of pre-miRNAs into mature miRNAs. Dicer, a member of the RNase III superfamily of bidentate nucleases, mediates the latter step, whereas the processing enzyme for the former step is unknown. Here we identify another RNase III, human Drosha, as the core nuclease that executes the initiation step of miRNA processing in the nucleus. Immunopurified Drosha cleaved pri-miRNA to release pre-miRNA in vitro. Furthermore, RNA interference of Drosha resulted in the strong accumulation of pri-miRNA and the reduction of pre-miRNA and mature miRNA in vivo. Thus, the two RNase III proteins, Drosha and Dicer, may collaborate in the stepwise processing of miRNAs, and have key roles in miRNA-mediated gene regulation in processes such as development and differentiation.
5,191 citations