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1.
Genes Dev ; 30(15): 1704-17, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27516533

RESUMO

Autophagy degrades and is thought to recycle proteins, other macromolecules, and organelles. In genetically engineered mouse models (GEMMs) for Kras-driven lung cancer, autophagy prevents the accumulation of defective mitochondria and promotes malignancy. Autophagy-deficient tumor-derived cell lines are respiration-impaired and starvation-sensitive. However, to what extent their sensitivity to starvation arises from defective mitochondria or an impaired supply of metabolic substrates remains unclear. Here, we sequenced the mitochondrial genomes of wild-type or autophagy-deficient (Atg7(-/-)) Kras-driven lung tumors. Although Atg7 deletion resulted in increased mitochondrial mutations, there were too few nonsynonymous mutations to cause generalized mitochondrial dysfunction. In contrast, pulse-chase studies with isotope-labeled nutrients revealed impaired mitochondrial substrate supply during starvation of the autophagy-deficient cells. This was associated with increased reactive oxygen species (ROS), lower energy charge, and a dramatic drop in total nucleotide pools. While starvation survival of the autophagy-deficient cells was not rescued by the general antioxidant N-acetyl-cysteine, it was fully rescued by glutamine or glutamate (both amino acids that feed the TCA cycle and nucleotide synthesis) or nucleosides. Thus, maintenance of nucleotide pools is a critical challenge for starving Kras-driven tumor cells. By providing bioenergetic and biosynthetic substrates, autophagy supports nucleotide pools and thereby starvation survival.


Assuntos
Autofagia , Neoplasias Pulmonares/metabolismo , Nucleotídeos/metabolismo , Proteínas ras/metabolismo , Animais , Proteína 7 Relacionada à Autofagia/genética , Proteína 7 Relacionada à Autofagia/metabolismo , Linhagem Celular Tumoral , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/genética , Deleção de Genes , Variação Genética , Genoma Mitocondrial/genética , Glutamina/farmacologia , Neoplasias Pulmonares/fisiopatologia , Camundongos , Mitocôndrias/metabolismo , Nucleosídeos/farmacologia , Oxirredução
2.
Hum Mutat ; 32(6): E2226-45, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21618345

RESUMO

microRNAs are a recently discovered and well studied class of small noncoding functional RNAs. The regulatory role of microRNAs (miRNAs) has been well studied in a wide variety of biological processes but there have been no systematic effort to understand and analyze the genetic variations in miRNA loci and study its functional consequences. We have comprehensively curated genetic variations in miRNA loci in the human genome and established a computational pipeline to assess potential functional consequences of these variants along with methods for systematic curation and reporting of variations in these loci. The data is made available on the Leiden Open (source) Variation Database (LOVD) platform at http://genome.igib.res.in/mirlovd to provide ease of aggregation and analysis and is open for community curation efforts.


Assuntos
Bases de Dados de Ácidos Nucleicos , Variação Genética , Genoma Humano , MicroRNAs/genética , Genômica , Humanos , Internet
3.
Nat Cancer ; 1(9): 923-934, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-34476408

RESUMO

Macroautophagy (hereafter autophagy) degrades and recycles intracellular components to sustain metabolism and survival during starvation. Host autophagy promotes tumor growth by providing essential tumor nutrients. Autophagy also regulates immune cell homeostasis and function and suppresses inflammation. Although host autophagy does not promote a T-cell anti-tumor immune response in tumors with low tumor mutational burden (TMB), whether this was the case in tumors with high TMB was not known. Here we show that autophagy, especially in the liver, promotes tumor immune tolerance by enabling regulatory T-cell function and limiting stimulator of interferon genes, T-cell response and interferon-γ, which enables growth of high-TMB tumors. We have designated this as hepatic autophagy immune tolerance. Autophagy thereby promotes tumor growth through both metabolic and immune mechanisms depending on mutational load and autophagy inhibition is an effective means to promote an antitumor T-cell response in high-TMB tumors.


Assuntos
Autofagia , Neoplasias , Autofagia/genética , Homeostase , Humanos , Imunidade Celular , Mutação , Neoplasias/genética
4.
Cancer Res ; 79(17): 4339-4347, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31300474

RESUMO

Lung carcinoids (LC) are rare and slow growing primary lung neuroendocrine tumors. We performed targeted exome sequencing, mRNA sequencing, and DNA methylation array analysis on macro-dissected LCs. Recurrent mutations were enriched for genes involved in covalent histone modification/chromatin remodeling (34.5%; MEN1, ARID1A, KMT2C, and KMT2A) as well as DNA repair (17.2%) pathways. Unsupervised clustering and principle component analysis on gene expression and DNA methylation profiles showed three robust molecular subtypes (LC1, LC2, LC3) with distinct clinical features. MEN1 gene mutations were found to be exclusively enriched in the LC2 subtype. LC1 and LC3 subtypes were predominately found at peripheral and endobronchial lung, respectively. The LC3 subtype was diagnosed at a younger age than LC1 and LC2 subtypes. IHC staining of two biomarkers, ASCL1 and S100, sufficiently stratified the three subtypes. This molecular classification of LCs into three subtypes may facilitate understanding of their molecular mechanisms and improve diagnosis and clinical management. SIGNIFICANCE: Integrative genomic analysis of lung carcinoids identifies three novel molecular subtypes with distinct clinical features and provides insight into their distinctive molecular signatures of tumorigenesis, diagnosis, and prognosis.


Assuntos
Tumor Carcinoide/genética , Tumor Carcinoide/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Ciclo Celular/genética , Estudos de Coortes , Metilação de DNA , Epigênese Genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Mutação , Proteínas Proto-Oncogênicas/genética , RNA Mensageiro/genética , Reprodutibilidade dos Testes , Proteínas S100/metabolismo
5.
Nat Commun ; 9(1): 4158, 2018 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-30315258

RESUMO

The commonly mutated genes in pancreatic neuroendocrine tumors (PanNETs) are ATRX, DAXX, and MEN1. We genotyped 64 PanNETs and found 58% carry ATRX, DAXX, and MEN1 mutations (A-D-M mutant PanNETs) and this correlates with a worse clinical outcome than tumors carrying the wild-type alleles of all three genes (A-D-M WT PanNETs). We performed RNA sequencing and DNA-methylation analysis to reveal two distinct subgroups with one consisting entirely of A-D-M mutant PanNETs. Two genes differentiating A-D-M mutant from A-D-M WT PanNETs were high ARX and low PDX1 gene expression with PDX1 promoter hyper-methylation in the A-D-M mutant PanNETs. Moreover, A-D-M mutant PanNETs had a gene expression signature related to that of alpha-cells (FDR q-value < 0.009) of pancreatic islets including increased expression of HNF1A and its transcriptional target genes. This gene expression profile suggests that A-D-M mutant PanNETs originate from or transdifferentiate into a distinct cell type similar to alpha cells.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Tumores Neuroendócrinos/genética , Proteínas Nucleares/genética , Proteínas Proto-Oncogênicas/genética , Proteína Nuclear Ligada ao X/genética , Proteínas Correpressoras , Metilação de DNA/genética , Metilação de DNA/fisiologia , Humanos , Imuno-Histoquímica , Chaperonas Moleculares , Regiões Promotoras Genéticas/genética , Estudos Prospectivos , Estudos Retrospectivos
6.
Sci Rep ; 7(1): 2466, 2017 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-28550310

RESUMO

Editing in microRNAs, particularly in seed can significantly alter the choice of their target genes. We show that out of 13 different human tissues, different regions of brain showed higher adenosine to inosine (A-to-I) editing in mature miRNAs. These events were enriched in seed sequence (73.33%), which was not observed for cytosine to uracil (17.86%) editing. More than half of the edited miRNAs showed increased stability, 72.7% of which had ΔΔG values less than -6.0 Kcal/mole and for all of them the edited adenosines mis-paired with cytosines on the pre-miRNA structure. A seed-editing event in hsa-miR-411 (with A - C mismatch) lead to increased expression of the mature form compared to the unedited version in cell culture experiments. Further, small RNA sequencing of GBM patients identified significant miRNA hypoediting which correlated with downregulation of ADAR2 both in metadata and qRT-PCR based validation. Twenty-two significant (11 novel) A-to-I hypoediting events were identified in GBM samples. This study highlights the importance of specific sequence and structural requirements of pre-miRNA for editing along with a suggestive crucial role for ADAR2. Enrichment of A-to-I editing in seed sequence highlights this as an important layer for genomic regulation in health and disease, especially in human brain.


Assuntos
Adenosina Desaminase/genética , Neoplasias Encefálicas/genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , MicroRNAs/genética , Edição de RNA , Proteínas de Ligação a RNA/genética , Adenosina/metabolismo , Adenosina Desaminase/metabolismo , Autopsia , Pareamento de Bases , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Estudos de Casos e Controles , Corpo Caloso/metabolismo , Corpo Caloso/patologia , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Biblioteca Gênica , Glioblastoma/metabolismo , Glioblastoma/patologia , Substância Cinzenta/metabolismo , Substância Cinzenta/patologia , Células HEK293 , Humanos , Inosina/metabolismo , MicroRNAs/classificação , MicroRNAs/metabolismo , Conformação de Ácido Nucleico , Estabilidade de RNA , Proteínas de Ligação a RNA/metabolismo , Termodinâmica , Substância Branca/metabolismo , Substância Branca/patologia
7.
Target Oncol ; 12(4): 449-462, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28589491

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) represents one of the most lethal cancers worldwide due to therapy resistance and disease recurrence. Tumor relapse following treatment could be driven by the persistence of liver cancer stem-like cells (CSCs). The protein BMI1 is a member of the polycomb epigenetic factors governing cellular self-renewal, proliferation, and stemness maintenance. BMI1 expression also correlates with poor patient survival in various cancer types. OBJECTIVE: We aimed to elucidate the extent to which BMI1 can be used as a potential therapeutic target for CSC eradication in HCC. METHODS: We have recently participated in characterizing the first known pharmacological small molecule inhibitor of BMI1. Here, we synthesized a panel of novel BMI1 inhibitors and examined their ability to alter cellular growth and eliminate cancer progenitor/stem-like cells in HCC with different p53 backgrounds. RESULTS: Among various molecules examined, RU-A1 particularly downregulated BMI1 expression, impaired cell viability, reduced cell migration, and sensitized HCC cells to 5-fluorouracil (5-FU) in vitro. Notably, long-term analysis of HCC survival showed that, unlike chemotherapy, RU-A1 effectively reduced CSC content, even as monotherapy. BMI1 inhibition with RU-A1 diminished the number of stem-like cells in vitro more efficiently than the model compound C-209, as demonstrated by clonogenic assays and impairment of CSC marker expression. Furthermore, xenograft assays in zebrafish showed that RU-A1 abrogated tumor growth in vivo. CONCLUSIONS: This study demonstrates the ability to identify agents with the propensity for targeting CSCs in HCC that could be explored as novel treatments in the clinical setting.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Complexo Repressor Polycomb 1/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Antineoplásicos/química , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Células HEK293 , Células Hep G2 , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Complexo Repressor Polycomb 1/biossíntese , Complexo Repressor Polycomb 1/genética , Bibliotecas de Moléculas Pequenas/química , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
8.
Oncotarget ; 7(8): 8783-96, 2016 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-26840028

RESUMO

The tumor suppressor p53 plays a central role in tumor prevention. The E3 ubiquitin ligase MDM2 is the most critical negative regulator of p53, which binds to p53 and degrades p53 through ubiquitation. MDM2 itself is a transcriptional target of p53, and therefore, MDM2 forms a negative feedback loop with p53 to tightly regulate p53 levels and function. microRNAs (miRNAs) play a key role in regulation of gene expression. miRNA dysregulation plays an important role in tumorigenesis. In this study, we found that miRNA miR-1827 is a novel miRNA that targets MDM2 through binding to the 3'-UTR of MDM2 mRNA. miR-1827 negatively regulates MDM2, which in turn increases p53 protein levels to increase transcriptional activity of p53 and enhance p53-mediated stress responses, including apoptosis and senescence. Overexpression of miR-1827 suppresses the growth of xenograft colorectal tumors, whereas the miR-1827 inhibitor promotes tumor growth in mice in a largely p53-dependent manner. miR-1827 is frequently down-regulated in human colorectal cancer. Decreased miR-1827 expression is associated with high MDM2 expression and poor prognosis in colorectal cancer. In summary, our results reveal that miR-1827 is a novel miRNA that regulates p53 through targeting MDM2, and highlight an important role and the underlying mechanism of miR-1827 in tumor suppression.


Assuntos
Transformação Celular Neoplásica/patologia , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Regiões 3' não Traduzidas , Animais , Apoptose , Western Blotting , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Humanos , Técnicas Imunoenzimáticas , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estadiamento de Neoplasias , Prognóstico , Proteínas Proto-Oncogênicas c-mdm2/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Análise Serial de Tecidos , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/genética , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Mol Cancer Res ; 12(4): 485-90, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24478461

RESUMO

UNLABELLED: Evidence suggests that the catabolic process of macroautophagy (autophagy hereafter) can either suppress or promote cancer. The essential autophagy gene ATG6/BECN1 encoding the Beclin1 protein has been implicated as a haploinsufficient tumor suppressor in breast, ovarian, and prostate cancers. The proximity of BECN1 to the known breast and ovarian tumor suppressor breast cancer 1, early onset, BRCA1, on chromosome 17q21, has made this determination equivocal. Here, the mutational status of BECN1 was assessed in human tumor sequencing data from The Cancer Genome Atlas (TCGA) and other databases. Large deletions encompassing both BRCA1 and BECN1, and deletions of only BRCA1 but not BECN1, were found in breast and ovarian cancers, consistent with BRCA1 loss being a primary driver mutation in these cancers. Furthermore, there was no evidence for BECN1 mutation or loss in any other cancer, casting doubt on whether BECN1 is a tumor suppressor in most human cancers. IMPLICATIONS: Contrary to previous reports, BECN1 is not significantly mutated in human cancer and not a tumor-suppressor gene, as originally thought. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/early/2014/04/01/1541-7786.MCR-13-0614/F1.large.jpg.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Autofagia/genética , Proteínas de Membrana/genética , Neoplasias/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Proteína Beclina-1 , Expressão Gênica , Genes Supressores de Tumor , Mutação em Linhagem Germinativa , Humanos , Proteínas de Membrana/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia
11.
Oncotarget ; 5(19): 9106-17, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-25193859

RESUMO

Tumor suppressor p53 plays a central role in tumor suppression. To ensure its proper function, the levels and activity of p53 are under a tight regulation in cells. MicroRNAs are short non-coding RNAs that play an important role in regulation of gene expression. Recently, microRNA-339-5p has been reported to be frequently down-regulated in colorectal cancer, and furthermore, its down-regulation is associated with poor prognosis in cancer patients, which strongly suggests a tumor suppressive function of microRNA-339-5p in colorectal cancer. In this study, we found that microRNA-339-5p directly represses the expression of MDM2, a key negative regulator of p53, through binding to MDM2 3'-UTR in colorectal cancer cells. Through the down-regulation of MDM2, microRNA-339-5p increases p53 protein levels and functions, including p53 transcriptional activity and p53-mediated apoptosis and senescence in response to stress. Furthermore, microRNA-339-5p inhibits the migration and invasion of colorectal cancer cells and the growth of colorectal xenograft tumors in a largely p53-dependent manner. Our results highlighted an important role of microRNA-339-5p in suppression of colorectal tumorigenesis, and also revealed that regulating the p53 function is an important mechanism for microRNA-339-5p in tumor suppression.


Assuntos
Transformação Celular Neoplásica/genética , Neoplasias Colorretais/patologia , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-mdm2/biossíntese , Proteína Supressora de Tumor p53/metabolismo , Regiões 3' não Traduzidas/genética , Animais , Apoptose/genética , Sítios de Ligação/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Senescência Celular/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Proteínas de Ligação a DNA/genética , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Células HCT116 , Humanos , Células MCF-7 , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/farmacologia , Invasividade Neoplásica/genética , Transplante de Neoplasias , Prognóstico , Proteínas Proto-Oncogênicas c-mdm2/genética , Transplante Heterólogo , Proteína Supressora de Tumor p53/biossíntese , Proteína Supressora de Tumor p53/genética
12.
Cancer Discov ; 4(8): 914-27, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24875857

RESUMO

UNLABELLED: Macroautophagy (autophagy hereafter) recycles intracellular components to sustain mitochondrial metabolism that promotes the growth, stress tolerance, and malignancy of lung cancers, suggesting that autophagy inhibition may have antitumor activity. To assess the functional significance of autophagy in both normal and tumor tissue, we conditionally deleted the essential autophagy gene, autophagy related 7 (Atg7), throughout adult mice. Here, we report that systemic ATG7 ablation caused susceptibility to infection and neurodegeneration that limited survival to 2 to 3 months. Moreover, upon fasting, autophagy-deficient mice suffered fatal hypoglycemia. Prior autophagy ablation did not alter the efficiency of non-small cell lung cancer (NSCLC) initiation by activation of oncogenic Kras(G12D) and deletion of the Trp53 tumor suppressor. Acute autophagy ablation in mice with preexisting NSCLC, however, blocked tumor growth, promoted tumor cell death, and generated more benign disease (oncocytomas). This antitumor activity occurred before destruction of normal tissues, suggesting that acute autophagy inhibition may be therapeutically beneficial in cancer. SIGNIFICANCE: We systemically ablated cellular self-cannibalization by autophagy in adult mice and determined that it is dispensable for short-term survival, but required to prevent fatal hypoglycemia and cachexia during fasting, delineating a new role for autophagy in metabolism. Importantly, acute, systemic autophagy ablation was selectively destructive to established tumors compared with normal tissues, thereby providing the preclinical evidence that strategies to inhibit autophagy may be therapeutically advantageous for RAS-driven cancers.


Assuntos
Autofagia/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Glucose/metabolismo , Neoplasias Pulmonares/genética , Animais , Proteína 7 Relacionada à Autofagia , Caquexia/genética , Caquexia/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Homeostase , Humanos , Hipoglicemia/genética , Hipoglicemia/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Supressora de Tumor p53/genética
13.
Database (Oxford) ; 2014: bau011, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24578356

RESUMO

A large repertoire of gene-centric data has been generated in the field of zebrafish biology. Although the bulk of these data are available in the public domain, most of them are not readily accessible or available in nonstandard formats. One major challenge is to unify and integrate these widely scattered data sources. We tested the hypothesis that active community participation could be a viable option to address this challenge. We present here our approach to create standards for assimilation and sharing of information and a system of open standards for database intercommunication. We have attempted to address this challenge by creating a community-centric solution for zebrafish gene annotation. The Zebrafish GenomeWiki is a 'wiki'-based resource, which aims to provide an altruistic shared environment for collective annotation of the zebrafish genes. The Zebrafish GenomeWiki has features that enable users to comment, annotate, edit and rate this gene-centric information. The credits for contributions can be tracked through a transparent microattribution system. In contrast to other wikis, the Zebrafish GenomeWiki is a 'structured wiki' or rather a 'semantic wiki'. The Zebrafish GenomeWiki implements a semantically linked data structure, which in the future would be amenable to semantic search. Database URL: http://genome.igib.res.in/twiki.


Assuntos
Crowdsourcing/métodos , Genoma/genética , Internet , Anotação de Sequência Molecular/métodos , Peixe-Zebra/genética , Animais , Bases de Dados Genéticas
14.
Biol Direct ; 8: 10, 2013 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-23618224

RESUMO

BACKGROUND: MicroRNAs (miRNAs) are non-uniformly distributed in genomes and ~30% of the miRNAs in the human genome are clustered. In this study we have focused on the imprinted miRNA cluster miR-379/miR-656 on 14q32.31 (hereafter C14) to test their coordinated function. We have analyzed expression profile of >1000 human miRNAs in >1400 samples representing seven different human tissue types obtained from cancer patients along with matched and unmatched controls. RESULTS: We found 68% of the miRNAs in this cluster to be significantly downregulated in glioblastoma multiforme (GBM), 61% downregulated in kidney renal clear cell carcinoma (KIRC), 46% in breast invasive carcinoma (BRCA) and 14% in ovarian serous cystadenocarcinoma (OV). On a genome-wide scale C14 miRNAs accounted for 12-30% of the total downregulated miRNAs in different cancers. Pathway enrichment for the predicted targets of C14 miRNA was significant for cancer pathways, especially Glioma (p< 3.77x10⁻6, FDR<0.005). The observed downregulation was confirmed in GBM patients by real-time PCR, where 79% of C14 miRNAs (34/43) showed downregulation. In GBM samples, hypermethylation at C14 locus (p<0.003) and downregulation of MEF2, a crucial transcription factor for the cluster was observed which likely contribute to the observed downregulation of the entire miRNA cluster. CONCLUSION: We provide compelling evidence that the entire C14 miRNA cluster is a tumor suppressor locus involved in multiple cancers, especially in GBM, and points toward a general mechanism of coordinated function for clustered miRNAs.


Assuntos
Regulação Neoplásica da Expressão Gênica/fisiologia , MicroRNAs/genética , Neoplasias/genética , Neoplasias da Mama/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Glioma/genética , Humanos , Técnicas In Vitro , Masculino , Neoplasias Ovarianas/genética , Reação em Cadeia da Polimerase em Tempo Real
15.
Zebrafish ; 7(2): 179-80, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20528264

RESUMO

The advancements in genomics technologies and the amenability to large-scale computational analysis have contributed immensely to the understanding of the zebrafish genome, its organization, and its functional correlates. Translating genomics information into biological meaning would require integration and amenability of data and tools. FishMap is a community resource for genomic datasets on zebrafish created with a vision to provide relevant and readily available information to zebrafish researchers. The present update of FishMap has kept up with the availability of the latest zebrafish genome assembly (Zv8). In this update, particular emphasis has been given to noncoding RNAs and noncoding RNA-mediated regulation in addition to genomic regulatory motifs, which are emerging areas of vertebrate biology. FishMap Zv8 update also features a sequence mapping and analysis server. Consistent with its commitment to make the information freely available to the community, FishMap features options to share data between compatible resources in addition to making it amenable to programmatic access. FishMap Zv8 update is available at http://fishmap2.igib.res.in.


Assuntos
Biologia Computacional/métodos , Bases de Dados Genéticas , Redes Reguladoras de Genes/genética , Genômica/métodos , Internet , Software , Peixe-Zebra/genética , Animais
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