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1.
BMC Bioinformatics ; 21(Suppl 8): 199, 2020 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938402

RESUMO

BACKGROUND: Non-coding RNAs include different classes of molecules with regulatory functions. The most studied are microRNAs (miRNAs) that act directly inhibiting mRNA expression or protein translation through the interaction with a miRNAs-response element. Other RNA molecules participate in the complex network of gene regulation. They behave as competitive endogenous RNA (ceRNA), acting as natural miRNA sponges to inhibit miRNA functions and modulate the expression of RNA messenger (mRNA). It became evident that understanding the ceRNA-miRNA-mRNA crosstalk would increase the functional information across the transcriptome, contributing to identify new potential biomarkers for translational medicine. RESULTS: We present miRTissue ce, an improvement of our original miRTissue web service. By introducing a novel computational pipeline, miRTissue ce provides an easy way to search for ceRNA interactions in several cancer tissue types. Moreover it extends the functionalities of previous miRTissue release about miRNA-target interaction in order to provide a complete insight about miRNA mediated regulation processes. miRTissue ce is freely available at http://tblab.pa.icar.cnr.it/mirtissue.html . CONCLUSIONS: The study of ceRNA networks and its dynamics in cancer tissue could be applied in many fields of translational biology, as the investigation of new cancer biomarker, both diagnostic and prognostic, and also in the investigation of new therapeutic strategies of intervention. In this scenario, miRTissue ce can offer a powerful instrument for the analysis and characterization of ceRNA-ceRNA interactions in different tissue types, representing a fundamental step in order to understand more complex regulation mechanisms.


Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Redes Reguladoras de Genes/genética , MicroRNAs/genética , RNA Neoplásico/genética , Humanos , Prognóstico
2.
Ann Hematol ; 99(11): 2611-2617, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32980888

RESUMO

EP300-ZNF384 fusion is a rare recurrent cytogenetic abnormality associated with B cell acute lymphoblastic leukemia (B-ALL), which was rarely studied in Chinese patient cohort. Here, we used a customized RNA fusion gene panel to investigate gene fusions in 56 selected acute leukemia patients without conventional genetic abnormalities. Two EP300-ZNF384 fusion forms were detected in ten cases, which were in-frame fusions of EP300 exon 6 fused with exon 3 or 2 of ZNF384. The fusions led to the lack of most functional domains of EP300. We firstly reported EP300-ZNF384 fusion in a mixed-phenotype acute leukemia (MPAL) patient whose CD33 and CD13 were negative. The rest nine B-ALL patients with EP300-ZNF384 fusion expressed CD33 and/or CD13. Fifty-six percent of B-ALL patients (5/9) with EP300-ZNF384 fusion were positive with CD10. After the diagnosis of EP300-ZNF384 fusion, 70% of the patients achieved remission after chemotherapy. Our observations indicated that EP300-ZNF384 fusion consists of a distinct subgroup of B-ALL with a characteristic immunophenotype. These patients are sensitive to current chemotherapy regimen and have an excellent outcome.


Assuntos
Proteína p300 Associada a E1A , Proteínas de Fusão Oncogênica , Leucemia-Linfoma Linfoblástico de Células Precursoras , RNA Neoplásico , Análise de Sequência de RNA , Transativadores , Adulto , Estudos de Coortes , Proteína p300 Associada a E1A/genética , Proteína p300 Associada a E1A/metabolismo , Feminino , Humanos , Masculino , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Transativadores/genética , Transativadores/metabolismo
3.
PLoS One ; 15(9): e0238420, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32931492

RESUMO

BACKGROUND: Patients diagnosed with Oral Floor Squamous Cell Carcinoma (OFSCC) face considerable challenges in physiology and psychology. This study explored prognostic signatures to predict prognosis in OFSCC through a detailed transcriptomic analysis. METHOD: We built an interactive competing endogenous RNA (ceRNA) network that included lncRNAs, miRNAs and mRNAs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to predict the gene functions and regulatory pathways of mRNAs. Least absolute shrinkage and selection operator algorithm (LASSO) analysis and Cox regression analysis were used to screen prognosis factors. The Kaplan-Meier method was used to analyze the survival rate of prognosis factors. Risk score was used to assess the reliability of the prediction model. RESULTS: A specific ceRNA network consisting of 56 mRNAs, 16 miRNAs and 31 lncRNAs was established. Three key genes (HOXC13, TGFBR3, KLHL40) and 4 clinical factors (age, gender, TNM, and clinical stage) were identified and effectively predicted the for survival time. The expression of a gene signature was validated in two external validation cohorts. The signature (areas under the curve of 3 and 5 years were 0.977 and 0.982, respectively) showed high prognostic accuracy in the complete TCGA cohort. CONCLUSIONS: Our study successfully developed an extensive ceRNA network for OFSCC and further identified a 3-mRNA and 4-clinical-factor signature, which may serve as a biomarker.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Neoplasias Bucais/genética , RNA Neoplásico/genética , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/mortalidade , Bases de Dados de Ácidos Nucleicos , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Proteínas de Homeodomínio/genética , Humanos , Estimativa de Kaplan-Meier , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Soalho Bucal , Neoplasias Bucais/mortalidade , Proteínas Musculares/genética , Prognóstico , Proteoglicanas/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Fatores de Risco
4.
Life Sci ; 259: 118157, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32735888

RESUMO

AIMS: Previous studies have demonstrated that circular RNAs play significant roles in several tumors, including lung adenocarcinoma; however, specific biological functions and molecular mechanisms underlying this process remain unclear. MATERIALS AND METHODS: Here, we conducted real-time quantitative PCR (qRT-PCR) to measure hsa_circ_0001588 expression levels in 60 paired lung adenocarcinoma tissues and cell lines. Furthermore, the association between hsa_circ_0001588 and clinical features of lung adenocarcinoma was analyzed. Functional experiments were conducted to assess the influence of hsa_circ_0001588 on proliferation, migration, and invasion in lung adenocarcinoma cells. We detected possible downstream targets of hsa_circ_0001588 using bioinformatics analysis. Luciferase reporter assays, qRT-PCR, and western blotting assays were performed to verify the molecular mechanism underlying hsa_circ_0001588 functions. KEY FINDINGS: We found that hsa_circ_0001588 was prominently upregulated in lung adenocarcinoma tissues and cell lines; elevated expression of hsa_circ_0001588 was positively correlated with poor clinicopathological features of lung adenocarcinoma. Functional experiments revealed that hsa_circ_0001588 acts as an oncogene to promote the proliferation, migration, and invasion of lung adenocarcinoma in vitro. Mechanistically, hsa_circ_0001588 promoted the proliferation, migration, and metastasis of lung adenocarcinoma by binding to miR-524-3p to promote nucleus accumbens-associated protein 1(NACC1) expression. SIGNIFICANCE: Together, our results revealed that hsa_circ_0001588 upregulated the expression of NACC1 by combining with miR-524-3p to promote the proliferation, migration, and invasion of lung adenocarcinoma cells, suggesting that hsa_circ_0001588 may be an underlying therapeutic target for lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , MicroRNAs/genética , Proteínas de Neoplasias/genética , RNA Circular/genética , RNA Neoplásico/genética , Proteínas Repressoras/genética , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Biologia Computacional , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Invasividade Neoplásica/genética , Reação em Cadeia da Polimerase , Prognóstico , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Nature ; 585(7823): 107-112, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32728218

RESUMO

Treating patients who have cancer with vaccines that stimulate a targeted immune response is conceptually appealing, but cancer vaccine trials have not been successful in late-stage patients with treatment-refractory tumours1,2. We are testing melanoma FixVac (BNT111)-an intravenously administered liposomal RNA (RNA-LPX) vaccine, which targets four non-mutated, tumour-associated antigens that are prevalent in melanoma-in an ongoing, first-in-human, dose-escalation phase I trial in patients with advanced melanoma (Lipo-MERIT trial, ClinicalTrials.gov identifier NCT02410733). We report here data from an exploratory interim analysis that show that melanoma FixVac, alone or in combination with blockade of the checkpoint inhibitor PD1, mediates durable objective responses in checkpoint-inhibitor (CPI)-experienced patients with unresectable melanoma. Clinical responses are accompanied by the induction of strong CD4+ and CD8+ T cell immunity against the vaccine antigens. The antigen-specific cytotoxic T-cell responses in some responders reach magnitudes typically reported for adoptive T-cell therapy, and are durable. Our findings indicate that RNA-LPX vaccination is a potent immunotherapy in patients with CPI-experienced melanoma, and suggest the general utility of non-mutant shared tumour antigens as targets for cancer vaccination.


Assuntos
Antineoplásicos/uso terapêutico , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Melanoma/imunologia , Melanoma/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , RNA Neoplásico/genética , Linfócitos T/imunologia , Antígenos de Neoplasias/imunologia , Antineoplásicos/farmacologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/efeitos adversos , Terapia Combinada , Humanos , Melanoma/tratamento farmacológico , Melanoma/patologia , Estadiamento de Neoplasias , Linfócitos T/citologia , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/imunologia , Vacinação
6.
Ann Hematol ; 99(10): 2231-2242, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32621182

RESUMO

Long non-coding RNAs (lncRNAs) have an established role in cell biology. Among their functions is the regulation of hematopoiesis. They characterize the different stages of hematopoiesis in a more lineage-restricted expression pattern than coding mRNAs. They affect hematopoietic stem cell renewal, proliferation, and differentiation of committed progenitors by interacting with master regulators transcription factors. Among these transcription factors, MYC has a prominent role. Similar to MYC's transcriptional activation/amplification of protein coding genes, MYC also regulates lncRNAs' expression profile, while it is also regulated by lncRNAs. Both myeloid and lymphoid malignancies are prone to the association of MYC with lncRNAs. Such interaction inhibits apoptosis, enhances cell proliferation, deregulates metabolism, and promotes genomic instability and resistance to treatment. In this review, we discuss the recent findings that encompass the crosstalk between lncRNAs and describe the pathways that very probably have a pathogenetic role in both acute and chronic hematologic malignancies.


Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Hematológicas/genética , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogênicas c-myc/fisiologia , RNA Longo não Codificante/genética , RNA Neoplásico/genética , Autorrenovação Celular/genética , Genes myc , Hematopoese/genética , Humanos , Leucemia/genética , Linfócitos/metabolismo , Linfócitos/patologia , Linfoma/genética , Mieloma Múltiplo/genética , Células Mieloides/metabolismo , Células Mieloides/patologia , Nicho de Células-Tronco
7.
Nucleic Acids Res ; 48(14): e80, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32496547

RESUMO

Small RNAs are important regulators of gene expression and are involved in human development and disease. Next generation sequencing (NGS) allows for scalable, genome-wide studies of small RNA; however, current methods are challenged by low sensitivity and high bias, limiting their ability to capture an accurate representation of the cellular small RNA population. Several studies have shown that this bias primarily arises during the ligation of single-strand adapters during library preparation, and that this ligation bias is magnified by 2'-O-methyl modifications (2'OMe) on the 3' terminal nucleotide. In this study, we developed a novel library preparation process using randomized splint ligation with a cleavable adapter, a design which resolves previous challenges associated with this ligation strategy. We show that a randomized splint ligation based workflow can reduce bias and increase the sensitivity of small RNA sequencing for a wide variety of small RNAs, including microRNA (miRNA) and tRNA fragments as well as 2'OMe modified RNA, including Piwi-interacting RNA and plant miRNA. Finally, we demonstrate that this workflow detects more differentially expressed miRNA between tumorous and matched normal tissues. Overall, this library preparation process allows for highly accurate small RNA sequencing and will enable studies of 2'OMe modified RNA with new levels of detail.


Assuntos
Biblioteca Gênica , Pequeno RNA não Traduzido/isolamento & purificação , Análise de Sequência de RNA/métodos , Eletroforese Capilar , Feminino , Humanos , Masculino , Metilação , MicroRNAs/química , MicroRNAs/genética , MicroRNAs/isolamento & purificação , Hibridização de Ácido Nucleico , Oligorribonucleotídeos/química , RNA Neoplásico/química , RNA Neoplásico/genética , RNA Neoplásico/isolamento & purificação , RNA de Plantas/química , RNA de Plantas/genética , RNA de Plantas/isolamento & purificação , Pequeno RNA não Traduzido/química , Pequeno RNA não Traduzido/genética , RNA de Transferência/química , RNA de Transferência/isolamento & purificação , Distribuição Aleatória , Sensibilidade e Especificidade , Alinhamento de Sequência
8.
PLoS Pathog ; 16(6): e1008624, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32555725

RESUMO

Human papillomaviruses (HPV) are a major cause of malignancy worldwide. They are the aetiological agents of almost all cervical cancers as well as a sub-set of other anogenital and head and neck cancers. Hijacking of host cellular pathways is essential for virus pathogenesis; however, a major challenge remains to identify key host targets and to define their contribution to HPV-driven malignancy. The Hippo pathway regulates epithelial homeostasis by down-regulating the function of the transcription factor YAP. Increased YAP expression has been observed in cervical cancer but the mechanisms driving this increase remain unclear. We found significant down-regulation of the master Hippo regulatory kinase STK4 (also termed MST1) in cervical disease samples and cervical cancer cell lines compared with healthy controls. Re-introduction of STK4 inhibited the proliferation of HPV positive cervical cells and this corresponded with decreased YAP nuclear localization and decreased YAP-dependent gene expression. The HPV E6 and E7 oncoproteins maintained low STK4 expression in cervical cancer cells by upregulating the oncomiR miR-18a, which directly targeted the STK4 mRNA 3'UTR. Interestingly, miR-18a knockdown increased STK4 expression and activated the Hippo pathway, significantly reducing cervical cancer cell proliferation. Our results identify STK4 as a key cervical cancer tumour suppressor, which is targeted via miR-18a in HPV positive tumours. Our study indicates that activation of the Hippo pathway may offer a therapeutically beneficial option for cervical cancer treatment.


Assuntos
Transformação Celular Viral , MicroRNAs/metabolismo , Papillomaviridae/metabolismo , Infecções por Papillomavirus/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , RNA Neoplásico/metabolismo , Transdução de Sinais , Proteínas Supressoras de Tumor/metabolismo , Neoplasias do Colo do Útero/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/metabolismo , Papillomaviridae/genética , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Proteínas Serina-Treonina Quinases/genética , RNA Neoplásico/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia
9.
PLoS One ; 15(5): e0233187, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32396572

RESUMO

Breast cancer is the most commonly diagnosed malignancy in women, and has the second highest mortality rate. Over 90% of all cancer-related deaths are due to metastasis, which is the spread of malignant cells from the primary tumor to a secondary site in the body. It is hypothesized that one cause of metastasis involves epithelial-mesenchymal transition (EMT). When epithelial cells undergo EMT and transition into mesenchymal cells, they display increased levels of cell proliferation and invasion, resulting in a more aggressive phenotype. While many factors regulate EMT, microRNAs have been implicated in driving this process. MicroRNAs are short noncoding RNAs that suppress protein production, therefore loss of microRNAs may promote the overexpression of specific target proteins important for EMT. The goal of this study was to investigate the role of miR-96 and miR-183 in EMT in breast cancer. Both miR-96 and miR-183 were found to be downregulated in post-EMT breast cancer cells. When microRNA mimics were transfected into these cells, there was a significant decrease in cell viability and migration, and a shift from a mesenchymal to an epithelial morphology (mesenchymal-epithelial transition or MET). These MET-related changes may be facilitated in part by the regulation of ZEB1 and vimentin, as both of these proteins were downregulated when miR-96 and miR-183 were overexpressed in post-EMT cells. These findings indicate that the loss of miR-96 and miR-183 may help facilitate EMT and contribute to the maintenance of a mesenchymal phenotype. Understanding the role of microRNAs in regulating EMT is significant in order to not only further elucidate the pathways that facilitate metastasis, but also identify potential therapeutic options for preventing or reversing this process.


Assuntos
Neoplasias da Mama/metabolismo , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , MicroRNAs/biossíntese , Modelos Biológicos , RNA Neoplásico/biossíntese , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Transição Epitelial-Mesenquimal , Feminino , Humanos , Células MCF-7 , MicroRNAs/genética , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , RNA Neoplásico/genética
10.
Gene ; 753: 144781, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32428698

RESUMO

Circular RNAs (circRNAs) act as essential regulators in the tumorigenesis of renal cell carcinoma. Our study aims to investigate the underlying function and the molecular mechanisms of circ_0001368 in renal cell carcinoma. The qRT-PCR results indicate that the circ_0001368 expression level was downregulated in the carcinoma cells and tissues of the renal cell. circ_0001368 weakened cell proliferation and invasion in the ACHN and 786-O cells. The luciferase reporter assay showed that circ_0001368 functioned as an endogenous sponge for miR-492. The transwell and CCK8 assays showed that circ_0001368 suppressed cell proliferation and invasion in the ACHN and 786-O cells. Large tumor suppressor kinase 2 (LATS2) was confirmed by Targetscan as a target gene of miR-492. The overexpression of LATS2 repressed the growth and invasion of ACHN and 786-O cells. circ_0001368 upregulated the LATS2 expression and suppressed ACHN and 786-O cell growth and invasion by sponging miR-492. circ_0001368 suppressed the proliferation ability of 786-O in vivo. In conclusion, circ_0001368 was identified in this study as a novel anti-tumor RNA in renal cell carcinoma and can function as a potential therapeutic target for renal cell carcinoma treatment.


Assuntos
Carcinoma de Células Renais/genética , Neoplasias Renais/genética , MicroRNAs/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , RNA Circular/genética , Proteínas Supressoras de Tumor/metabolismo , Carcinogênese , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , MicroRNAs/genética , Invasividade Neoplásica , Proteínas Serina-Treonina Quinases/genética , RNA Circular/metabolismo , RNA Neoplásico/genética , Proteínas Supressoras de Tumor/genética
11.
Gene ; 753: 144796, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32450203

RESUMO

Colorectal cancer (CRC) is one of the most common types of cancer which affects the colon and the rectum. Approximately one third of annual CRC mortality occurs due to the late detection of this type of cancer. Therefore, there is an urgent need for more powerful diagnostic and prognostic tools for identification and treatment of colorectal tumorigenesis. Non-coding RNAs (ncRNAs) have been implicated in the pathology of CRC and also linked to metastasis, proliferation, differentiation, migration, angiogenesis and apoptosis in numerous cancers. Recently, attention has turned towards ncRNAs as specific targets for diagnosis, prognosis and treatment of various types of cancers, including CRC. In this review, we have tried to outline the roles of ncRNAs, and their involvement in signaling pathways responsible for the progression of CRC.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Apoptose/genética , Carcinogênese/genética , Transformação Celular Neoplásica/genética , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/genética , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Prognóstico , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Neoplásico/genética , RNA não Traduzido , Transdução de Sinais/genética
12.
World Neurosurg ; 138: 425-435, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32251831

RESUMO

Glioblastoma multiforme (GBM) is the most common and aggressive primary malignancy of the central nervous system. The standard used to monitor disease progression and therapeutic response has been magnetic resonance imaging, which is usually obtained preoperatively and postoperatively. Patients with GBM are monitored every 2-3 months and scans are repeated until progression is detected. Sometimes there is an inability to detect tumor progression or difficulty in differentiating tumor progression from pseudoprogression. With the difficulty of distinguishing disease progression, as well as the cost of imaging, there may be a need for the existence of a noninvasive liquid biopsy. There is no reliable biomarker for GBM that can be used for liquid biopsy, but if one could be detected in serum or cerebrospinal fluid and vary with tumor burden, then, it could be developed into one. MicroRNAs (miRNAs) are short, single-stranded, noncoding RNAs that posttranscriptionally control gene expression. They play vital roles in tumor progression, migration, invasion, and stemness. Because miRNAs are secreted in stable forms in bodily fluid, either via extracellular vesicles or in cell-free form, they have great potential as biomarkers that can be used for liquid biopsy. Various miRNAs that are dysregulated in GBM have been identified in tissue, cerebrospinal fluid, and serum samples. There needs to be standardization of sample collection and quantification for both cell-free and exosomal-derived samples. Further studies need to be performed on larger cohorts to evaluate the sensitivity and specificity of not just miRNAs but most potential biomarkers.


Assuntos
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/patologia , MicroRNA Circulante/biossíntese , Glioblastoma/diagnóstico , Glioblastoma/patologia , Biópsia Líquida/métodos , RNA Neoplásico/biossíntese , Neoplasias Encefálicas/cirurgia , MicroRNA Circulante/genética , Glioblastoma/cirurgia , Humanos , RNA Neoplásico/genética
14.
Life Sci ; 248: 117473, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32114007

RESUMO

MicroRNAs (miRNAs) are a group of tiny molecules of 18-22 nucleotide long noncoding RNA that regulate the post-transcriptional gene expression through translational inhibition and/or mRNA destabilization. Because of their involvement in important developmental processes, it is highly likely that the altered expression of miRNAs could be associated with abnormal conditions like suboptimal growth or diseases. Thus, the expression of miRNAs can be used as biomarkers in pathophysiological conditions. Recently, a handful of miRNAs are detected in cell-free conditions including biofluids and cell culture media and they exhibit specific expression patterns that are associated with altered physiological conditions. Extracellular miRNAs are not only extremely stable outside cells in a variety of biofluids but also they are easy to acquire. These characteristics led to the idea of using extracellular miRNAs as a potential biomarker for the onset and prognosis of cancer. Although miRNAs have been proposed as a potential diagnostic tool for cancer detection, their application in the routine clinical investigation is yet to come. First, this review will provide an insight into the extracellular miRNAs, particularly, their release mechanisms and characteristics, and the potential of extracellular miRNAs as a biomarker in cancer detection. Finally, it will discuss the potential of using extracellular miRNAs in different cancer diagnoses and challenges associated with the clinical application of extracellular miRNAs as noninvasive biomarkers.


Assuntos
Biomarcadores Tumorais/genética , MicroRNA Circulante/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias/diagnóstico , Neoplasias/genética , RNA Neoplásico/genética , Biomarcadores Tumorais/sangue , MicroRNA Circulante/sangue , Detecção Precoce de Câncer/métodos , Exossomos/química , Feminino , Humanos , Masculino , Neoplasias/sangue , Neoplasias/patologia , Especificidade de Órgãos , Prognóstico , RNA Neoplásico/sangue
15.
Exp Hematol ; 82: 8-23, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32007479

RESUMO

Establishing an in vitro "red blood cell matrix" that would allow uninterrupted access to a stable, homogeneous reticulocyte population would facilitate the establishment of continuous, long-term in vitro Plasmodium vivax blood stage cultures. In this study, we have explored the suitability of the erythroleukemia K562 cell line as a continuous source of such reticulocytes and have investigated regulatory factors behind the terminal differentiation (and enucleation, in particular) of this cell line that can be used to drive the reticulocyte production process. The Duffy blood group antigen receptor (Fy), essential for P. vivax invasion, was stably introduced into K562 cells by lentiviral gene transfer. miRNA-26a-5p and miRNA-30a-5p were downregulated to promote erythroid differentiation and enucleation, resulting in a tenfold increase in the production of reticulocytes after stimulation with an induction cocktail compared with controls. Our results suggest an interplay in the mechanisms of action of miRNA-26a-5p and miRNA-30a-5p, which makes it necessary to downregulate both miRNAs to achieve a stable enucleation rate and Fy receptor expression. In the context of establishing P. vivax-permissive, stable, and reproducible reticulocytes, a higher enucleation rate may be desirable, which may be achieved by the targeting of further regulatory mechanisms in Fy-K562 cells; promoting the shift in hemoglobin production from fetal to adult may also be necessary. Despite the fact that K562 erythroleukemia cell lines are of neoplastic origin, this cell line offers a versatile model system to research the regulatory mechanisms underlying erythropoiesis.


Assuntos
Leucemia Eritroblástica Aguda , Plasmodium vivax/crescimento & desenvolvimento , Reticulócitos , Diferenciação Celular , Sistema do Grupo Sanguíneo Duffy/biossíntese , Sistema do Grupo Sanguíneo Duffy/genética , Regulação Leucêmica da Expressão Gênica , Humanos , Células K562 , Leucemia Eritroblástica Aguda/genética , Leucemia Eritroblástica Aguda/metabolismo , Leucemia Eritroblástica Aguda/parasitologia , Leucemia Eritroblástica Aguda/patologia , MicroRNAs/biossíntese , MicroRNAs/genética , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Receptores de Superfície Celular/biossíntese , Receptores de Superfície Celular/genética , Reticulócitos/metabolismo , Reticulócitos/parasitologia , Reticulócitos/patologia
16.
Mol Cell Biochem ; 466(1-2): 103-115, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32006291

RESUMO

Increasing evidence confirmed that the Warburg effect plays an important role involved in the progression of malignant tumors. Resibufogenin (RES) has been proved to have a therapeutic effect in multiple malignant tumors. However, the mechanism of whether RES exerted an antitumor effect on breast cancer through regulating the Warburg effect is largely unknown. The effect of RES on glycolysis was determined by glucose consumption, lactate production, ATP generation, extracellular acidification rate and oxygen consumption rate in breast cancer cells. The total RNA and protein levels were respectively measured by RT-qPCR and western blot. Cell proliferation and apoptosis were examined using the CCK-8 assay, colony formation assay, and flow cytometry, respectively. The interaction between miR-143-3p and HK2 was verified by dual-luciferase reporter gene assay. We also evaluated the influence of RES on the tumor growth and Warburg effect in vivo. RES treatment significantly decreased glycolysis, cell proliferation and induced apoptosis of both MDA-MB-453 and MCF-7 cells. Simultaneously, the expression of HK2 was decreased in breast cancer cells treated with RES, which was positively associated with tumor size and glycolysis. Moreover, HK2 was a direct target gene of miR-143-3p. Mechanistically, upregulation of miR-143-3p by RES treatment inhibited tumor growth by downregulating HK2-mediated Warburg effect in breast cancer. Our findings suggested that RES exerted anti-tumorigenesis and anti-glycolysis activities in breast cancer through upregulating the inhibitory effect of miR-143-3p on HK2 expression, which provided a new potential strategy for breast cancer clinical treatment.


Assuntos
Neoplasias da Mama , Bufanolídeos/farmacologia , Glicólise/efeitos dos fármacos , Hexoquinase/metabolismo , MicroRNAs/metabolismo , Proteínas de Neoplasias/metabolismo , RNA Neoplásico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Glicólise/genética , Hexoquinase/genética , Humanos , Células MCF-7 , MicroRNAs/genética , Proteínas de Neoplasias/genética , RNA Neoplásico/genética , Transdução de Sinais/genética
17.
Cancer Genet ; 242: 1-7, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32036224

RESUMO

Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality in the world, in which colon adenocarcinoma (COAD) is the most common histological subtype of CRC. In this study, our aim is to identify gene modules and representative candidate biomarkers for clinical prognosis of patients with COAD, and help to predict prognosis and reveal the mechanisms of cancer progression. Weighted gene co-expression network analysis (WGCNA) was performed to construct a co-expression network and identify gene modules correlated with TNM clinical staging of COAD patients. The Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed with the module gene. Protein-protein interaction (PPI) network and hub gene identification were explored with Cytoscape software. Finally, the hub gene mRNA level was validated in Oncomine database. Five gene modules, related with the pathological TNM stage, were constructed, and the gene module was enriched in cell proliferation, invasion and migration related GO terms and metabolic related KEGG pathways. A total of top 10 hub genes was identified, and in which six of the hub genes show a significant up-regulation in COAD as compared to normal tissue, including IVL, KRT16, KRT6C, KRT6A, KRT78 and SBSN. In conclusion, we identified five gene modules and six candidate biomarkers correlated with the TNM staging of COAD patients. These findings may help us to understand the tumor progression of COAD and provide prognostic biomarkers as well as therapeutic targets.


Assuntos
Adenocarcinoma/genética , Neoplasias do Colo/genética , Redes Reguladoras de Genes , Genes Neoplásicos , Adenocarcinoma/patologia , Biomarcadores Tumorais/genética , Neoplasias do Colo/patologia , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Predisposição Genética para Doença , Humanos , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , RNA Neoplásico/genética
18.
Life Sci ; 245: 117363, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32001271

RESUMO

AIMS: CircRNAs are emerging as a novel class of non-coding RNAs that play crucial roles in malignant cancer. However, the expression profile and potential mechanism of circRNAs in gliomas remain uncharacterized. In this study, we aim to investigate abnormally expressed circRNAs during glioma pathogenesis and find out potential therapeutic targets for treatment. MAIN METHODS: The glioma cell lines (U251 and SHG-44), 32 pairs of glioma tissue samples and adjacent control samples were used in this study. Microarray and bioinformatics tools were performed to identify circRNAs expression in glioma. QRT-PCR experiment was used to confirm gene expression. CCK-8 and transwell assay were conducted to measure cell viability and invasion. Dual-luciferase reporter experiment was performed to identify target bindings between RNAs. KEY FINDINGS: The circRNA circ_0037655 was highly expressed in both glioma tissues and cell lines (U251 and SHG-44) compared to control. Inhibition of circ_0037655 could suppress the viability and invasion of glioma cells. Circ_0037655 acts as a sponge of miR-214 and inhibition of miR-214 could reverse cell viability and invasion ability induced by si-circ_0037655. Over-expression of miR-214 could reduce the expression of p-Akt (PI3K pathway indicator). SIGNIFICANCE: This study identified circRNAs expression profile in gliomas and revealed that circ_0037655 could promote glioma progression by regulating miR-214/PI3K signaling, which may provide new therapeutic approach for gliomas.


Assuntos
Glioma/metabolismo , MicroRNAs/metabolismo , Proteína Oncogênica v-akt/metabolismo , RNA Circular/metabolismo , RNA Neoplásico/metabolismo , Transdução de Sinais , Animais , Linhagem Celular Tumoral , Glioma/genética , Humanos , Camundongos Nus , Transplante de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos , RNA Circular/genética , RNA Neoplásico/genética , Reação em Cadeia da Polimerase em Tempo Real , Transcriptoma
19.
Ann Hematol ; 99(4): 753-763, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32016577

RESUMO

The main challenges in treating acute promyelocytic leukemia (APL) are currently early mortality, relapse, refractory disease after induction therapy, and drug resistance to ATRA and ATO. In this study, a computational chemogenomics approach was used to identify new molecular targets and drugs for APL treatment. The transcriptional profiles induced by APL were compared with those induced by genetic or chemical perturbations. The genes that can reverse the transcriptional profiles induced by APL when perturbed were considered to be potential therapeutic targets for APL. Drugs targeting these genes or proteins are predicted to be able to treat APL if they can reverse the APL-induced transcriptional profiles. To improve the target identification accuracy of the above correlation method, we plotted the functional protein association networks of the predicted targets by STRING. The results determined PML, RARA, SPI1, HDAC3, CEBPA, NPM1, ABL1, BCR, PTEN, FOS, PDGFRB, FGFR1, NUP98, AFF1, and MEIS1 to be top candidates. Interestingly, the functions of PML, RARA, HDAC3, CEBPA, NPM1, ABL, and BCR in APL have been previously reported in the literature. This is the first chemogenomics analysis predicting potential APL drug targets, and the findings could be used to guide the design of new drugs targeting refractory and recurrent APL.


Assuntos
Antineoplásicos/farmacologia , Quimioinformática , Desenvolvimento de Medicamentos , Leucemia Promielocítica Aguda/tratamento farmacológico , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Conjuntos de Dados como Assunto , Desenho de Fármacos , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica/efeitos da radiação , Marcação de Genes , Genes Neoplásicos , Humanos , Proteínas de Neoplasias/genética , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Proteínas de Fusão Oncogênica/genética , Mapeamento de Interação de Proteínas , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Transcriptoma
20.
Ann Hematol ; 99(4): 765-772, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32062741

RESUMO

Bone marrow WT1 mRNA levels assessed by the ELN method are useful to establish prognostic correlations in myeloid malignancies treated with chemotherapy or hematopoietic stem cell transplantation (HCT). Those patients with WT1 levels below ten copies have a good outcome. However, some of these patients relapse. To further characterize this group of cases, we applied a new and sensitive digital (ddPCR) WT1 method. A consecutive series of 49 patients with treated myeloid malignancies and with an ELN WT1 quantitation of < 10 copies were included in the study. All cases (47 AML and 2 MDS) have received intensive chemotherapy or HCT. One to four micrograms of total RNA were retrotranscribed to obtain ≥ 10,000 ABL1 copies using the ELN protocol. Only those cases with a good quality cDNA were used in the ddPCR WT1 test. The ddPCR Gene Expression WT1 Assay of Bio-Rad© was used to perform the PCR amplification, and the microdroplets were quantified in the Bio-Rad's QX200 droplet reader. Eighteen patients showed a negative WT1 ddPCR assay (0 copies/µl), whereas 31 cases were positive (results ranged from 1 to 15.2 copies/µl). Survival analysis showed statistically significant differences in terms of OS between both groups, 83 ± 8% vs. 46 ± 9% (p = 0.024). A statistically significant correlation was also found between ddPCRWT1 results and CD123+ cell number detected by flow cytometry (p = 0.024). Larger series of patients tested with the current ddPCRWT1 method will solve whether it could be used to stratify patients with myeloid malignancies achieving deep WT1 molecular response (< 10 copies).


Assuntos
Genes do Tumor de Wilms , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/genética , Reação em Cadeia da Polimerase/métodos , Adulto , Idoso , DNA Complementar/genética , Feminino , Citometria de Fluxo , Dosagem de Genes , Humanos , Imunofenotipagem , Lactente , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , RNA Neoplásico/genética , Reação em Cadeia da Polimerase em Tempo Real , Adulto Jovem
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