RESUMO
BACKGROUND: Pancreatic and peri-pancreatic neoplasms encompass a variety of histotypes characterized by a heterogeneous prognostic impact. miRNAs are considered efficient candidate biomarkers due to their high stability in tissues and body fluids. We applied Nanostring profiling of circulating exosomal miRNAs to distinct pancreatic lesions in order to establish a source for biomarker development. METHODS: A series of 140 plasma samples obtained from patients affected by pancreatic ductal adenocarcinoma (PDAC, n = 58), pancreatic neuroendocrine tumors (PanNET, n = 42), intraductal papillary mucinous neoplasms (IPMN, n = 20), and ampulla of Vater carcinomas (AVC, n = 20) were analyzed. Comprehensive miRNA profiling was performed on plasma-derived exosomes. Relevant miRNAs were validated by qRT-PCR and in situ hybridization (ISH). RESULTS: Lesion specific miRNAs were identified through multiple disease comparisons. Selected miRNAs were validated in the plasma by qRT-PCR and at tissue level by ISH. We leveraged the presence of clinical subtypes with each disease cohort to identify miRNAs that are differentially enriched in aggressive phenotypes. CONCLUSIONS: This study shows that pancreatic lesions are characterized by specific exosomal-miRNA signatures. We also provide the basis for further explorations in order to better understand the relevance of these signatures in pancreatic neoplasms.
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Carcinoma Ductal Pancreático/genética , Exossomos/genética , MicroRNAs/sangue , Tumores Neuroendócrinos/genética , Neoplasias Pancreáticas/genética , Idoso , Ampola Hepatopancreática/patologia , Biomarcadores Tumorais/genética , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Pâncreas/patologia , Prognóstico , Neoplasias PancreáticasRESUMO
Cells in non-invasive breast lesions are widely believed to possess molecular alterations that render them either susceptible or refractory to the acquisition of invasive capability. One such alteration could be the ectopic expression of the ß2 isoform of phosphoinositide-dependent phospholipase C (PLC-ß2), known to counteract the effects of hypoxia in low-invasive breast tumor-derived cells. Here, we studied the correlation between PLC-ß2 levels and the propensity of non-invasive breast tumor cells to acquire malignant features. Using archival FFPE samples and DCIS-derived cells, we demonstrate that PLC-ß2 is up-regulated in DCIS and that its forced down-modulation induces an epithelial-to-mesenchymal shift, expression of the cancer stem cell marker CD133, and the acquisition of invasive properties. The ectopic expression of PLC-ß2 in non-transformed and DCIS-derived cells is, to some extent, dependent on the de-regulation of miR-146a, a tumor suppressor miRNA in invasive breast cancer. Interestingly, an inverse relationship between the two molecules, indicative of a role of miR-146a in targeting PLC-ß2, was not detected in primary DCIS from patients who developed a second invasive breast neoplasia. This suggests that alterations of the PLC-ß2/miR-146a relationship in DCIS may constitute a molecular risk factor for the appearance of new breast lesions. Since neither traditional classification systems nor molecular characterizations are able to predict the malignant potential of DCIS, as is possible for invasive ductal carcinoma (IDC), we propose that the assessment of the PLC-ß2/miR-146a levels at diagnosis could be beneficial for identifying whether DCIS patients may have either a low or high propensity for invasive recurrence.
Assuntos
Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Intraductal não Infiltrante/patologia , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Células-Tronco Neoplásicas/patologia , Fosfolipase C beta/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/metabolismo , Carcinoma Intraductal não Infiltrante/genética , Carcinoma Intraductal não Infiltrante/metabolismo , Proliferação de Células , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Células-Tronco Neoplásicas/metabolismo , Fosfolipase C beta/genética , Prognóstico , Células Tumorais CultivadasRESUMO
Spinal cord paralysis is relatively common after surgical repair of thoraco-abdominal aortic aneurysm (TAAA) and its etiology is unknown. The present study was designed to examine the histopathology of the disease and investigate whether miR-155 ablation would reduce spinal cord ischemic damage and delayed hindlimb paralysis induced by aortic cross-clamping (ACC) in our mouse model. The loss of locomotor function in ACC-paralyzed mice correlated with the presence of extensive gray matter damage and central cord edema, with minimal white matter histopathology. qRTPCR and Western blotting showed that the spinal cords of wild-type ACC mice that escaped paralysis showed lower miR-155 expression and higher levels of transcripts encoding Mfsd2a, which is implicated in the maintenance of blood-brain barrier integrity. In situ based testing demonstrated that increased miR-155 detection in neurons was highly correlated with the gray matter damage and the loss of one of its targets, Mfsd2a, could serve as a good biomarker of the endothelial cell damage. In vitro, we demonstrated that miR-155 targeted Mfsd2a in endothelial cells and motoneurons and increased endothelial cell permeability. Finally, miR-155 ablation slowed the progression of central cord edema, and reduced the incidence of paralysis by 40%. In sum, the surgical pathology findings clearly indicated that the epicenter of the ischemic-induced paralysis was the gray matter and that endothelial cell damage correlated to Mfsd2a loss is a good biomarker of the disease. MiR-155 targeting therefore offers new therapeutic opportunity for edema caused by traumatic spinal cord injury and diagnostic pathologists, by using immunohistochemistry, can clarify if this mechanism also is important in other ischemic diseases of the CNS, including stroke.
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Isquemia/metabolismo , Proteínas de Membrana Transportadoras/genética , MicroRNAs/genética , Traumatismos da Medula Espinal/genética , Animais , Modelos Animais de Doenças , Imuno-Histoquímica/métodos , Isquemia/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/metabolismo , Doenças do Sistema Nervoso/genética , Neurônios/metabolismo , Medula Espinal/patologia , Traumatismos da Medula Espinal/fisiopatologia , Simportadores , Proteínas Supressoras de Tumor/genéticaRESUMO
RNAi is a powerful tool for the regulation of gene expression. It is widely and successfully employed in functional studies and is now emerging as a promising therapeutic approach. Several RNAi-based clinical trials suggest encouraging results in the treatment of a variety of diseases, including cancer. Here we present miR-Synth, a computational resource for the design of synthetic microRNAs able to target multiple genes in multiple sites. The proposed strategy constitutes a valid alternative to the use of siRNA, allowing the employment of a fewer number of molecules for the inhibition of multiple targets. This may represent a great advantage in designing therapies for diseases caused by crucial cellular pathways altered by multiple dysregulated genes. The system has been successfully validated on two of the most prominent genes associated to lung cancer, c-MET and Epidermal Growth Factor Receptor (EGFR). (See http://microrna.osumc.edu/mir-synth).
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Técnicas de Silenciamento de Genes , MicroRNAs/genética , Software , Regiões 3' não Traduzidas , Sequência de Bases , Receptores ErbB/biossíntese , Receptores ErbB/genética , Expressão Gênica , Genes Reporter , Células HEK293 , Células HeLa , Humanos , Luciferases de Renilla/biossíntese , Luciferases de Renilla/genética , Proteínas Proto-Oncogênicas c-met/biossíntese , Proteínas Proto-Oncogênicas c-met/genética , Interferência de RNAAssuntos
Crise Blástica/genética , Células Dendríticas/metabolismo , Neoplasias Hematológicas/genética , MicroRNAs/metabolismo , Plasmocitoma/genética , Sarcoma Mieloide/genética , Crise Blástica/metabolismo , Neoplasias Hematológicas/patologia , Humanos , Plasmocitoma/metabolismo , Sarcoma Mieloide/mortalidade , Análise de SobrevidaRESUMO
HMGA2 gene amplification and overexpression in human prolactinomas and the development of pituitary adenomas in HMGA2 transgenic mice showed that HMGA2 plays a crucial role in pituitary tumorigenesis. We have explored the pRB/E2F1 pathway to investigate the mechanism by which HMGA2 acts. Here we show that HMGA2 interacts with pRB and induces E2F1 activity in mouse pituitary adenomas by displacing HDAC1 from the pRB/E2F1 complex-a process that results in E2F1 acetylation. We found that loss of E2F1 function (obtained by mating HMGA2 and E2F1(-/-) mice) suppressed pituitary tumorigenesis in HMGA2 mice. Thus, HMGA2-mediated E2F1 activation is a crucial event in the onset of these tumors in transgenic mice and probably also in human prolactinomas.
Assuntos
Fator de Transcrição E2F1/fisiologia , Proteína HMGA2/fisiologia , Neoplasias Hipofisárias/metabolismo , Acetilação , Animais , Linhagem Celular , Proliferação de Células , Transformação Celular Neoplásica , DNA/metabolismo , Fator de Transcrição E2F1/genética , Ativação Enzimática , Proteína HMGA2/biossíntese , Proteína HMGA2/genética , Histona Desacetilase 1 , Histona Desacetilases/metabolismo , Histonas/metabolismo , Humanos , Camundongos , Camundongos Knockout , Camundongos Mutantes , Camundongos Transgênicos , Neoplasias Hipofisárias/patologia , Regiões Promotoras Genéticas , Ligação Proteica , Elementos de Resposta , Proteína do Retinoblastoma/metabolismo , Transdução de SinaisRESUMO
We showed that Emicro-MiR-155 transgenic mice develop acute lymphoblastic leukemia/high-grade lymphoma. Most of these leukemias start at approximately 9 months irrespective of the mouse strain. They are preceded by a polyclonal pre-B-cell proliferation, have variable clinical presentation, are transplantable, and develop oligo/monoclonal expansion. In this study, we show that in these transgenic mice the B-cell precursors have the highest MiR-155 transgene expression and are at the origin of the leukemias. We determine that Src homology 2 domain-containing inositol-5-phosphatase (SHIP) and CCAAT enhancer-binding protein beta (C/EBPbeta), 2 important regulators of the interleukin-6 signaling pathway, are direct targets of MiR-155 and become gradually more down-regulated in the leukemic than in the preleukemic mice. We hypothesize that miR-155, by down-modulating Ship and C/EBPbeta, initiates a chain of events that leads to the accumulation of large pre-B cells and acute lymphoblastic leukemia/high-grade lymphoma.
Assuntos
Proteína beta Intensificadora de Ligação a CCAAT/biossíntese , Transformação Celular Neoplásica/metabolismo , MicroRNAs/biossíntese , Monoéster Fosfórico Hidrolases/biossíntese , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Células Precursoras de Linfócitos B/metabolismo , Animais , Proteína beta Intensificadora de Ligação a CCAAT/genética , Transformação Celular Neoplásica/genética , Regulação para Baixo/genética , Regulação Leucêmica da Expressão Gênica/genética , Inositol Polifosfato 5-Fosfatases , Interleucina-6/metabolismo , Linfoma de Células B/genética , Linfoma de Células B/metabolismo , Camundongos , Camundongos Transgênicos , MicroRNAs/genética , Monoéster Fosfórico Hidrolases/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Transdução de Sinais/genéticaRESUMO
Four hundred and eighty-one ultraconserved sequences (UCRs) longer than 200 bases were discovered in the genomes of human, mouse and rat. These are DNA sequences showing 100% identity among the three species. UCRs are frequently located at genomic regions involved in cancer, differentially expressed in human leukemias and carcinomas and in some instances regulated by microRNAs (miRNAs). Here we present UCbase & miRfunc, the first database which provides ultraconserved sequences data and shows miRNA function. Also, it links UCRs and miRNAs with the related human disorders and genomic properties. The current release contains over 2000 sequences from three species (human, mouse and rat). As a web application, UCbase & miRfunc is platform independent and it is accessible at http://microrna.osu.edu/.UCbase4.
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Sequência Conservada , DNA/química , Bases de Dados de Ácidos Nucleicos , MicroRNAs/metabolismo , Animais , Sequência de Bases , Humanos , Camundongos , MicroRNAs/química , Ratos , Interface Usuário-ComputadorRESUMO
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive hematologic malignancy originating from plasmacytoid dendritic cells (pDCs). The microRNA expression profile of BPDCN was compared to that of normal pDCs and the impact of miRNA dysregulation on the BPDCN transcriptional program was assessed. MiRNA and gene expression profiling data were integrated to obtain the BPDCN miRNA-regulatory network. The biological process mainly dysregulated by this network was predicted to be neurogenesis, a phenomenon raising growing interest in solid tumors. Neurogenesis was explored in BPDCN by querying different molecular sources (RNA sequencing, Chromatin immunoprecipitation-sequencing, and immunohistochemistry). It was shown that BPDCN cells upregulated neural mitogen genes possibly critical for tumor dissemination, expressed neuronal progenitor markers involved in cell migration, exchanged acetylcholine neurotransmitter, and overexpressed multiple neural receptors that may stimulate tumor proliferation, migration and cross-talk with the nervous system. Most neural genes upregulated in BPDCN are currently investigated as therapeutic targets.
RESUMO
Altered expression of microRNAs (miRNAs) has been detected in cancer, suggesting that these small non-coding RNAs can act as oncogenes or tumor suppressor genes. In the present study, we investigated the expression of miRNA-17-5p, miRNA-18a, miRNA-20a, miRNA-92a, miRNA-146a, miRNA-146b and miRNA-155 by real-time quantitative RT-PCR in a panel of melanocyte cultures and melanoma cell lines and explored the possible role of miRNA-155 in melanoma cell proliferation and survival. The analyzed miRNAs were selected on the basis of previous studies strongly supporting their involvement in cancer development and/or progression. We found that miRNA-17-5p, miRNA-18a, miRNA-20a, and miRNA-92a were overexpressed, whereas miRNA-146a, miRNA-146b and miRNA-155 were down-regulated in the majority of melanoma cell lines with respect to melanocytes. Ectopic expression of miRNA-155 significantly inhibited proliferation in 12 of 13 melanoma cell lines with reduced levels of this miRNA and induced apoptosis in 4 out of 4 cell lines analyzed. In conclusion, our data further support the finding of altered miRNA expression in melanoma cells and establish for the first time that miRNA-155 is a negative regulator of melanoma cell proliferation and survival.
Assuntos
Melanoma/genética , Melanoma/patologia , MicroRNAs/genética , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Humanos , MicroRNAs/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
MicroRNAs (miRNAs) are short non-coding RNAs involved in post-transcriptional regulation of gene expression. Since the discovery of the first miRNA gene lin-4 in C. elegans, over 500 miRNAs have been identified in humans and the list is growing. Their biological importance, initially demonstrated in cancer, was also more recently discovered in many other pathologies like Alzheimer's disease, Parkinson's disease, viral infections, diabetes, and myopathies. In the present review we will summarize miRNA profiling studies in human diseases and discuss the newly discovered link between microRNAs and drug response. An understanding of how microRNAs influence the body's response to certain drugs and how these affect the expression of microRNAs, will be of key importance in developing drugs with greater safety and efficacy.
Assuntos
Doença/genética , MicroRNAs/genética , MicroRNAs/fisiologia , Animais , Humanos , Neoplasias/genética , Processamento de Proteína Pós-Traducional/genética , Processamento Pós-Transcricional do RNA/fisiologiaRESUMO
miR-224 has recently emerged as a driver oncomiR in sporadic colorectal carcinogenesis, but its pathogenetic role is still controversial. A large phenotypical and molecularly characterized series of preinvasive and invasive colorectal lesions was investigated for miR-224 expression by qRT-PCR and in situ hybridization. The caspase-3 and caspase-7 status was also assessed and correlated to miR-224 dysregulation. miR-224 was significantly upregulated during the adenoma-carcinoma sequence and in the context of inflammatory bowel disease dysplastic lesions, whereas its expression was significantly downregulated among BRAF-mutated tumors and in the presence of a DNA mismatch repair deficiency. miR-224 targets caspase-3 and caspase-7 in colorectal cancer, and this inverse relation was already evident from the earliest phases of transformation in intestinal mucosa. The miR-224/caspases axis may represent an interesting field of study for innovative biomarkers/therapeutics for BRAF-mutated/DNA mismatch repair-deficient tumors.
RESUMO
PURPOSE: Non-small cell lung cancer (NSCLC) has heterogeneous histopathologic classification and clinical behavior and very low survival rate. WWOX (WW domain-containing oxidoreductase) is a tumor suppressor gene, and its expression is altered in several cancers. The purpose of this study is to better define the role of WWOX in NSCLC tumorigenesis and progression by determining its pathogenetic and prognostic significance. EXPERIMENTAL DESIGN: WWOX protein expression was evaluated by immunohistochemistry in 170 patients with NSCLC (101 squamous cell carcinomas, 66 adenocarcinomas, 3 large cell carcinomas) and was correlated with histopathologic (histotype, subtype, grade, tumor-node-metastasis, stage, index of cell proliferation Ki67/MIB1) and clinical (age, gender, local recurrences, distant metastases, overall survival, and disease-free survival) characteristics. RESULTS: WWOX expression was absent/reduced in 84.9% of NSCLCs, whereas it was normal in 80.5% of adjacent normal lung tissues. WWOX expression was strongly associated with tumor histology (P=1.1x10(-5)) and histologic grade (P=0.0081): the percentage of cases with absent/strongly reduced WWOX expression was higher in squamous cell carcinomas and in poorly differentiated tumors. Regarding adenocarcinoma, bronchioloalveolar pattern showed normal WWOX expression in 62.5% of the cases, whereas in solid and acinar patterns, a prevalence of cases with absent/very low WWOX expression was observed (79.2% and 50%, respectively). Finally, weak WWOX staining intensity was related to the high index of cell proliferation (P=0.0012). CONCLUSIONS: Our results suggest that the loss of WWOX expression plays different roles in tumorigenesis of distinct histotypes and subtypes of NSCLC and is related to high aggressiveness (G3; high proliferating activity) of tumors.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/metabolismo , Oxirredutases/biossíntese , Proteínas Supressoras de Tumor/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Oxirredutases/química , Prognóstico , Fatores de Tempo , Proteínas Supressoras de Tumor/química , Oxidorredutase com Domínios WWRESUMO
Cancer initiation and progression can involve microRNAs (miRNA), which are small noncoding RNAs that can regulate gene expression. Their expression profiles can be used for the classification, diagnosis, and prognosis of human malignancies. Loss or amplification of miRNA genes has been reported in a variety of cancers, and altered patterns of miRNA expression may affect cell cycle and survival programs. Germ-line and somatic mutations in miRNAs or polymorphisms in the mRNAs targeted by miRNAs may also contribute to cancer predisposition and progression. We propose that alterations in miRNA genes play a critical role in the pathophysiology of many, perhaps all, human cancers.
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MicroRNAs/genética , Neoplasias/genética , Animais , Predisposição Genética para Doença , Humanos , Mutação , Mapeamento de NucleotídeosRESUMO
First line drug treatment of follicular lymphoma (FL) patients is followed by a highly variable disease-free time before relapse in about one third of patients. No molecular marker is able to predict efficiently the risk of relapse. We investigated the expression profile of microRNAs (miRNAs) by microarrays and of the tumor microenvironment by immunohistochemistry in 26 FLs and 12 reactive lymph nodes (rLN) as reference. Twenty-nine miRNAs were differentially expressed in FLs compared to rLNs and some of them discriminated grade 1 from 3a FLs. Both FLs and rLNs displayed molecular heterogeneity. FLs grouped into two clusters mostly driven by the tumor T-cell content. Among 21 drug-treated FL patients with an average follow-up of 13.5 years, eight cases relapsed. Twenty-six miRNAs discriminated between relapsed and non-relapsed FLs. Ten miRNAs also correlated with Foxp3+ cells number. Notably, Foxp3+ cells were significantly less in relapsed patients and lower Foxp3+ cell number associated with shorter time-to-relapse. Foxp3+ cells did not co-expressed follicular helper T-cell markers and were therefore classified as regulatory T cells rather than follicular regulatory T-cells. These findings introduce new knowledge about the relationship between miRNA alterations and infiltrating immune cells and show that Foxp3+ cells might be predictive of disease relapse.
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In order to investigate the role of microRNAs in the pathogenesis of different B-cell lymhoma subtypes, we have applied an array-based assay to a series of 76 mixed non-Hodgkin B-cell lymphomas, including Burkitt's lymphoma (BL), diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, mantle cell lymphoma (MCL) and follicular lymphoma. Lymphomas clustered according to histological subtypes, driven by two miRNA clusters (the miR-29 family and the miR-17-92 cluster). Since the two miRNA clusters are known to be MYC-regulated, we investigated whether this would be supported in MYC-driven experimental models, and found that this signature separated BL cell lines and a MYC-translocated MCL cell lines from normal germinal center B-cells and other B-cell populations. Similar results were also reproduced in tissue samples comparing BL and reactive lymph node samples. The same series was then quantitatively analyzed for MYC expression by immunohistochemistry and MYC protein levels were compared with corresponding miRNA signatures. A specific metric was developed to summarize the levels of MYC-related microRNAs and the corresponding protein levels. We found that MYC-related signatures are directly related to MYC protein expression across the whole spectrum of B-cells and B-cell lymphoma, suggesting that the MYC-responsive machinery shows predominantly quantitative, rather than qualitative, modifications in B-cell lymphoma. Novel MYC-related miRNAs were also discovered by this approach. Finally, network analysis found that in BL MYC-related differentially expressed miRNAs could control, either positively or negatively, a limited number of hub proteins, including BCL2, CDK6, MYB, ZEB1, CTNNB1, BAX and XBP1.
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A substantial number of ductal carcinoma in situ (DCIS) detected by mammography never progress to invasive ductal carcinoma (IDC) and current approaches fail to identify low-risk patients not at need of adjuvant therapies. We aimed to identify the key miRNAs protecting DCIS from malignant evolution, that may constitute markers for non-invasive lesions. We studied 100 archived DCIS samples, including pure DCIS, DCIS with adjacent IDC and pure DCIS from patients with subsequent IDC in contralateral breast or no recurrence. A DCIS derived cell line was used for molecular and cellular studies. A genome wide study revealed that pure DCIS has higher miR-126 and miR-218 expression than DCIS with adjacent IDC lesions or than IDC. The down-regulation of miR-126 and miR-218 promoted invasiveness in vitro and, in patients with pure DCIS, was associated with later onset of IDC. Survival studies of independent cohorts indicated that both miRNAs play a protective role in IDC. The clinical findings are in agreement with the miRNAs' roles in cell adhesion, differentiation and proliferation. We propose that miR-126 and miR-218 have a protective role in DCIS and represent novel biomarkers for the risk assessment in women with early detection of breast cancer.
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We have recently reported that MicroRNAs (miR)-221 and miR-222 were up-regulated in human thyroid papillary carcinomas in comparison with the normal thyroid tissue. Bioinformatic analysis proposed the p27(Kip1) protein, a key regulator of cell cycle, as a candidate target for the miR-221/222 cluster. Here, we report that the enforced expression of miR-221 and miR-222 was able to reduce p27(Kip1) protein levels in thyroid carcinoma and HeLa cells in the absence of significant changes in specific p27(Kip1) mRNA levels. This effect is direct as miR-221 and miR-222 negatively regulate the expression of the 3'-untranslated region-based reporter construct from the p27(Kip1) gene, and is dependent on two target sites in this region. Consistent with these results, an enforced expression of the miR-221 and miR-222 induced the thyroid papillary carcinoma cell line (TPC-1) to progress to the S phase of the cell cycle. It is likely that the negative regulation of p27(Kip1) by miR-221 and miR-222 might also have a role in vivo since we report an inverse correlation between miR-221 and miR-222 up-regulation and down-regulation of the p27(Kip1) protein levels in human thyroid papillary carcinomas. Therefore, the data reported here demonstrate that miR-221 and miR-222 are endogenous regulators of p27(Kip1) protein expression, and thereby, the cell cycle.
Assuntos
Carcinoma Papilar/genética , Ciclo Celular/genética , Regulação Neoplásica da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/genética , MicroRNAs/genética , MicroRNAs/fisiologia , Neoplasias da Glândula Tireoide/genética , Sequência de Bases , Inibidor de Quinase Dependente de Ciclina p27 , Regulação para Baixo , Células HeLa , Humanos , Células Tumorais CultivadasRESUMO
Alterations in miRNA genes play a critical role in the pathophysiology of many, perhaps all, human cancers: cancer initiation and progression can involve alterations of microRNA genes (miRNAs) encoding small noncoding RNAs that can regulate gene expression. The main mechanism of microRNoma (defined as the full complement of microRNAs present in a genome) alteration in cancer cell seems to result in aberrant gene expression characterized by abnormal levels of expression for mature and/or precursor miRNA sequences in comparison with the corresponding normal tissues. Loss or amplification of miRNA genes has been reported in a variety of cancers, and altered patterns of miRNA expression may affect cell cycle and survival programs. The causes of the widespread differential expression of miRNA genes between malignant and normal cells can be explained by the genomic location of these genes in cancer-associated genomic regions, by epigenetic mechanisms as well as by alterations of members of the processing machinery. Germline and somatic mutations in miRNAs or polymorphisms in the mRNAs targeted by miRNAs may also contribute to cancer predisposition and progression. miRNAs expression profiling has been exploited to identify miRNAs potentially involved in the pathogenesis of human cancers and has allowed the identification of signatures associated with diagnosis, staging, progression, prognosis, and response to treatment of human tumors. Here we present a flowchart of principal steps to produce, analyze, and understand the biological significance of miRNA microarray data.