1,721,269 research outputs found
The genetic network of microRNAs in cancer
No full textThe microRNAs, or miRNAs, control global protein output, by regulating translation of protein coding genes. During the last five years many groups, including ours, have been actively involved in the discovery of miRNA deregulation in cancer cells. Now much of the effort is focused on the elucidation of functional miRNA pathways and therefore on the identification of key miRNA targets.
miRNA can be either regulating, or regulated by, cancer genes: in fact protein targets have been revealed for some cancer miRNAs (i.e. miR-17/92, miR-21) and in other instances miRNAs have been positioned downstream of pivotal tumor proteins (i.e. miR-34 and p53). Typically, each miRNA has been studied for its single contribution to differential expression or to predictive molecular signatures. But the effects of microRNAs are likely to be complex for two reasons: 1) the action of miRNA activity is exerted in a one-to-many fashion, i.e. each miRNA can control translation of tens or even hundreds of different coding messenger RNAs; 2) conversely, each single protein-coding mRNA can be controlled by more than one non-coding miRNA.
Therefore, we propose a paradigm shift to the study of miRNAs role in cancer by applying a “whole cell” systems biology approach. We will build a miRNA gene network by using both public and a large body of unpublished expression datasets.
In primis, we will infer a network reflecting the miRNome of normal cells and tissues. Preliminary results demonstrating the feasibility and information content of such a network are included in this grant application. The complete miRNA network in normal tissues will be the first goal of our project and will become our reference. To date no such genetic network is known, thus our work is of absolute novelty.
In parallel, we will build miRNA networks relative to different oncologic conditions. By comparing the reference normal network to the cancer networks we will reach the second goal of our work: the identification of the variations in miRNA networks relating to cancer
states. We will infer networks for each step in cancer progression: from benign tumors to overtly metastatic states.
Third, we will revise and assay the miRNA re-programming events identified during the project in cancer and leukemia by using both bioinformatics and molecular/cellular techniques. Cellular assays will test the true extent of these miRNAs’ function, cooperation and target genes.
The aim of our proposal is in fact that of unravelling the critical and coordinated steps in the miRNA program required to express the full pathological potential of cancer cells
Progetto Telethon: Estrazione dati per l'analisi dei microarrays a DNA
No full textLe due applicazioni della nuova tecnologia dei microarrays a DNA, profili d'espressione ed array CGH, permettono la generazione di enormi quantita' di dati genetici relativi a malattie ereditarie umane. L'effettiva e completa comprensione di tali moli di dati richiede l'impiego di calcolatori elettronici e programmi adatti per estrarre i dati ed interpretarne il significato. Inoltre e' particolarmente impegnativa anche la gestione dei dati . A tal fine sono necessarie banche dati specializzate, che consentano anche il trasferimento dei dati in formati standard da e verso programmi di analisi. Inoltre nonostante molti pacchetti applicativi di analisi siano stati messi a punto recentemente, vi sono ancora ampi spazi inesplorati. Il nostro servizio fornisce ai ricercatori che compiono esperimenti di DNA microarrays tutto il supporto necessario per giungere ad un pieno utilizzo delle informazioni contenute negli esperimenti. Inoltre il ricercatore puo' utilizzare ilservizio anche per il mantenimento dei dati su supporto digitale e per la pubblicazione via WWW. Infine, abbiamo messo a punto un software proprietario che permette ai ricercatori di mettere in relazione i risultati dei microarrays alle funzioni della cellula coinvolte nelle malattie ereditarie, con le relative valutazioni statistiche. E un altro pacchetto applicativo consente al ricercatore di capire dove sulla mappa del genoma umano siano localizzate le funzioni effettivamente alterate. In tal modo viene accelerata la fase di scoperta di nuovi geni responsabili per malattie ereditarie umane.
Durata: 3 anni
TT Number: GTF0301
Unexpected findings of variability in microRNAs suggest roles in human genetics
Full text linkShort RNA molecules were considered to be junk for decades, but in recent years they have been shown to have important functional roles. MicroRNAs (miRNAs) in particular have attracted much attention. They have been assumed to be highly conserved in humans and other species; however, a recent study published in Genome Medicine reveals an unexpected level of variability in human miRNAs, including variations within the seed region. This challenges the current view of miRNAs, and may explain previous reports of pathogenic mutations in miRNAs.See research article http://genomemedicine.com/content/4/8/62/abstract. © 2012 BioMed Central Ltd
Progetto Telethon: Identification of ATM binding proteins
No full textAtaxia-telangiectasia (AT) is an autosomal recessive disorder charaeterized by cerebellar ataxia,telangiectases, immune defects, and a predisposition to matignancy. Chromosomal breakage is a feature. At least 4 complemention groups (A, C, D, and E) map to chromosome 11q23 and are Associated with mutations in the ATM gene. The nature of the basic defect is a mystery but is believed to involve one or more of the enzymes concerned with DNA repair or processing. Zakian (1995) provided a dendrogram indicating the relationship between ATM and the various ATM-like genes homologous to the phosphatidylinositol 3-kinase family. She pointed out that'whether or not these ATM-like genes are ATM homologs, continued inquiry in genetically tractable model organisms like yeast and Drosophila will surely provide valuable insight into the functions of this family of proteins’Hawley and friend (1996) commented upon the current state of ATM research and concluded that ATM must play crucial roles in normally developing or undamaged cells, as well as the studied role in irradiated cells, in order to explain the neurologic, immune, and reproductive problems observd in AT patients. They also proposed that ATM may be intimately associated with both p53 and the molecular machinery required for chromosomal exchange, perhaps as componente of the recombination nodules. We are going to investigate on the cellular partners of the ATM protein. Finding these molecules of the molecular mechanisms involved in the pathology of AT, and thus will enable the design of compounds capable of modulating these interactions. The techniques used in this study will be biochemical and molecular, and will allow the identification, purification, and characterization of ATM associated proteins.
TT Number: E.088
Prognostic microRNA/mRNA signature from the integrated analysis of patients with invasive breast cancer.
No full textThe optimal management of breast cancer (BC) presents challenges due to the heterogeneous molecular classification of the disease. We performed survival analysis on a cohort of 466 patients with primary invasive ductal carcinoma (IDC), the most frequent type of BC, by integrating mRNA, microRNA (miRNA), and DNA methylation next-generation sequencing data from The Cancer Genome Atlas (TCGA). Expression data from eight other BC cohorts were used for validation. The prognostic value of the resulting miRNA/mRNA signature was compared with that of other prognostic BC signatures. Thirty mRNAs and seven miRNAs were associated with overall survival across different clinical and molecular subclasses of a 466-patient IDC cohort from TCGA. The prognostic RNAs included PIK3CA, one of the two most frequently mutated genes in IDC, and miRNAs such as hsa-miR-328, hsa-miR-484, and hsa-miR-874. The area under the curve of the receiver-operator characteristic for the IDC risk predictor in the TCGA cohort was 0.74 at 60 mo of overall survival (P < 0.001). Most relevant for clinical application, the integrated signature had the highest prognostic value in early stage I and II tumors (receiver-operator characteristic area under the curve = 0.77, P value < 0.001). The genes in the RNA risk predictor had an independent prognostic value compared with the clinical covariates, as shown by multivariate analysis. The integrated RNA signature was successfully validated on eight BC cohorts, comprising a total of 2,399 patients, and it had superior performance for risk stratification with respect to other RNA predictors, including the mRNAs used in MammaPrint and Oncotype DX assays
EARLY DIAGNOSIS AND EXPRESSION PROFILING CLASSIFICATION OF COLORECTAL AND LIVER TUMORS. AIRC Regional Grant.
No full textCancer was expected to be one of the human health problems that could benefit from the
completion of the human genome information. To address the expectation, this project brings
together clinicians and molecular biologists to investigate health problems associated with
colorectal and liver cancer. The best known and, so far, most effective instrument to generate
genome-wide information has been the use of microarrays for gene expression profiling that,
together with the bioinformatic strategies for analyzing microarray data, have allowed to put
expression aberrations into a global perspective and allowed to compare pathologic versus
normal profiles. Cancer has been analyzed using this technology to define tumor molecular
classifications, discover diagnostic methods for the prediction of cancer susceptibility and
prediction to drug response. Here, we intend to use this technology for the study colorectal and
liver cancer features. In addition, aberrant DNA methylation has proven to be a tumor marker
that can be detected with high sensitivity and specificity. Here, we intend to identify a panel of
highly informative methylation markers and use them as screening tools for the early diagnosis
of colorectal and hepatocellular carcinoma.
The project is organized in four interlaced Tasks, each one leaded by one of the
participating groups. Each task is defined by specific objectives. The first two tasks involve the
oncogenomic classification of colorectal and liver cancer through the use of EST and microRNA
microarrays. Their specific objectives are: (i) discovery of gene expression signatures with
prognostic significance in colorectal cancer; (ii) integration of EST and micro RNA microarrays,
microsatellite and DNA methylation data into a molecular classification of colorectal carcinomas;
(iii) identification of gene expression signatures predicting response to preoperative
chemoradiation therapy in rectal carcinomas; (iv) identification of expression signatures
differentiating cirrhotic liver associated or not associated with hepatocellular carcinoma, with the
aim of identifying molecular markers predicting cancer risk in liver cirrhosis; (v) apply the newly
discovered markers of cancer risk for the screening of serum of liver cirrhotic patients for the
early detection of HCC. The third task involves the use of DNA methylation markers for the early
diagnosis of colorectal and liver carcinomas, whose specific objectives are: (i) discovery of new
methylation markers; (ii) use of an optimized panel of DNA methylation markers for the follow-up
of colorectal and hepatocellular cancer patients; (iii) use of an optimized panel of DNA
methylation markers for the screening of colorectal cancer patients’ first-grade relatives and
patients with liver cirrhosis. The entire project is supported by a bioinformatic infrastructure
(Task 4) for data management, mining and validation of microarray results to define molecular
signatures in cancer, whose specific objectives are: (i) storage and management of microarray
experiments; (ii) mining of microarray profiles: data normalization, quality control and validation
of gene signatures; (iii) communication with clinical data.
Through the identification of molecular markers that are able to predict the clinical course
of colorectal and liver cancer and the response to preoperative therapeutic regimens in rectal
cancer, a significant improvement on patients’ clinical management can be achieved. In addition,
by defining the most useful DNA methylation markers and the most effective approaches for their
identification in body fluids of colorectal and hepatocellular cancer patients, the project can
provide highly sensitive and specific screening instruments, whose application could potentially
improve long-term clinical outcome
MicroRNA Expression Signatures in Solid Malignancies
No full textABSTRACT: An ongoing challenge in cancer research is represented by the identification of new specific clinical molecular markers and pharmacological targets. During the last 10 years, microRNAs (miRNAs) have become one of the hottest subjects in the area of cancer genomics. MicroRNAs are single-stranded RNAs of 19 to 24 nucleotides in length generated through a complex maturation process. Recent studies have demonstrated that microRNAs can have an oncogene or tumor suppressor role by regulating the expression of target genes. Therefore, microRNAs are highly related to cancer processes, including initiation, growth, apoptosis, invasion, and metastasis. In this panorama, several high-through put technologies studies have revealed miRNA roles in classifying tumors and predicting patient outcome with high accuracy. We provide a review highlighting recent progress on the understanding of the cellular function of human microRNAs and their expression in solid tumors
Hepatocyte growth factor activates phosphoinositide 3-kinase C2 beta in renal brush-border plasma membranes
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Non-coding RNAs: a key to future personalized molecular therapy?
Full text linkContinual discoveries on non-coding RNA (ncRNA) have changed the landscape of human genetics and molecular biology. Over the past ten years it has become clear that ncRNAs are involved in many physiological cellular processes and contribute to molecular alterations in pathological conditions. Several classes of ncRNAs, such as small interfering RNAs, microRNAs, PIWI-associated RNAs, small nucleolar RNAs and transcribed ultra-conserved regions, are implicated in cancer, heart diseases, immune disorders, and neurodegenerative and metabolic diseases. ncRNAs have a fundamental role in gene regulation and, given their molecular nature, they are thus both emerging therapeutic targets and innovative intervention tools. Next-generation sequencing technologies (for example SOLiD or Genome Analyzer) are having a substantial role in the high-throughput detection of ncRNAs. Tools for non-invasive diagnostics now include monitoring body fluid concentrations of ncRNAs, and new clinical opportunities include silencing and inhibition of ncRNAs or their replacement and re-activation. Here we review recent progress on our understanding of the biological functions of human ncRNAs and their clinical potential
Mitochondria dysfunction in circulating tumor cells
No full textCirculating tumor cells (CTCs) represent a subset of heterogeneous cells, which, once released from a tumor site, have the potential to give rise to metastasis in secondary sites. Recent research focused on the attempt to detect and characterize these rare cells in the circulation, and advancements in defining their molecular profile have been reported in diverse tumor species, with potential implications for clinical applications. Of note, metabolic alterations, involving mitochondria, have been implicated in the metastatic process, as key determinants in the transition of tumor cells to a mesenchymal or stemness-like phenotype, in drug resistance, and in induction of apoptosis. This review aimed to briefly analyse the most recent knowledge relative to mitochondria dysfunction in CTCs, and to envision implications of altered mitochondria in CTCs for a potential utility in clinics
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