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1.
Recent Results Cancer Res ; 215: 77-88, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31605224

RESUMO

Circulating tumor cells (CTCs) provide valuable information about the molecular evolution of cancers, as they may initially respond and ultimately progress on therapy. As intact tumor cells isolated from the bloodstream, CTCs also enable assessment of heterogeneous subpopulations, and their analysis may include DNA, RNA, and protein biomarkers. New microfluidic cell isolation strategies greatly facilitate the challenge of enriching viable tumor cells from the billions of hematopoietic cells within a standard blood specimen. While counting and characterization of enriched CTCs have primarily relied on immunostaining for tumor cell-specific antigens, new RNA-based analytic platforms are providing new insight into the identity of CTCs and providing new tools for clinical applications. Single-cell RNA sequencing of CTCs reveals a high degree of heterogeneity among cancer cells from a single individual, while new digital RNA-based amplification platforms may now allow high-sensitivity and high-throughput quantitative scoring of CTCs for clinical applications. Here, we focus on transcriptomic analysis of CTCs and its relevance in understanding metastatic cancer progression and in developing diagnostic assays to monitor cancer.


Assuntos
Separação Celular/métodos , Neoplasias/genética , Neoplasias/patologia , Células Neoplásicas Circulantes , RNA Neoplásico/análise , Progressão da Doença , Humanos , Neoplasias/diagnóstico , Células Neoplásicas Circulantes/metabolismo , RNA Neoplásico/genética
2.
Medicine (Baltimore) ; 98(50): e17814, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852062

RESUMO

The purpose of our research was to evaluate diagnostic performance of serum microRNA-135a (miR-135a) in non-small cell lung cancer (NSCLC).Quantitative real time-polymerase chain reaction was employed to detect the expression serum of miR-135a in NSCLC patients and controls. The influence of serum miR-135a level on clinical characteristics of NSCLC patients was explored through the Chi-square test. Serum carcinoembryonic antigen (CEA) level was estimated via enzyme-linked immunosorbent assay. Receiver operating characteristic (ROC) curve was plotted to elucidate diagnostic roles of serum miR-135a and CEA in NSCLC.The expression level of serum miR-135a was significantly lower in NSCLC patients than in healthy controls (0.40 ±â€Š0.29 vs 1.00 ±â€Š0.40, P < .001). Moreover, miR-135a expression was related to lymph node metastasis (P = .021), tumor differentiation (P = .020), and tumor node metastasis stage (P = .031). ROC curve showed serum miR-135a level could discriminate NSCLC patients from healthy controls (P < .0001) with a corresponding cutoff value of 0.665, and a sensitivity and specificity of 81.3% and 83.1%, respectively. The area under the curve was 0.888. In diagnosis analysis on the combination of miR-135a and CEA, when its specificity was maintained at 90%, diagnosis cut-off point reached 0.678.Serum miR-135a level is significantly downregulated in NSCLC and serves as a potential diagnostic biomarker for the disease.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Neoplasias Pulmonares/diagnóstico , MicroRNAs/sangue , Estadiamento de Neoplasias/métodos , Idoso , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Neoplasias Pulmonares/sangue , Masculino , Pessoa de Meia-Idade , RNA Neoplásico/genética , Curva ROC , Reação em Cadeia da Polimerase em Tempo Real
3.
Medicine (Baltimore) ; 98(42): e17601, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31626137

RESUMO

BACKGROUND: Lung adenocarcinoma (LA) is a most common form of non-small cell lung cancer (NSCLC). To date, there are still no effective early diagnosis methods for patients to be cured in time. Noncoding RNA plays an important role in oncogenesis and tumor development. The expression profile of circular RNA (circRNA) in peripheral whole blood (PWB) of LA has not been systematically investigated. In this study, we identified the differentially expressed (DE) circRNAs in PWB of LA by high-throughput sequencing. METHODS: Five paired LA and normal participants PWB samples were chosen to investigate the expression profile of circRNAs by high-throughput sequencing. Twenty LA and 10 normal controls PWB samples were subjected to reverse-transcription polymerase chain reaction (RT-PCR) for validation of circRNAs expression profile. Gene Ontology (GO) functional analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and circRNA-miRNA network analysis was also performed to predict the function of circRNAs in PWB. RESULTS: A total of 10566 circRNAs were identified and annotated, most of the circRNAs were exonic (78.14%). Statistical analysis revealed 4390 DE circRNAs, in which were 3009 upregulated circRNAs and1381downregulated circRNAs in LA. RT-PCR results showed that circRNA expression in LA was higher than that in controls. GO functional analysis, KEGG pathway analysis, and circRNA-miRNA network analysis all showed that circRNAs correlated with tumor development and progression to a certain degree. The current study is the first to systematically characterize and annotate circRNA expression in PWB of LA. Some host genes of the DE circRNAs were involved in tumor signaling pathway and had complicated correlations with tumor related miRNAs, indicating that circRNAs might involve in development and progression of LA. CONCLUSIONS: Our study revealed that circRNAs were abnormally expressed in PWB of LA, which might offer potential targets for the early diagnosis of the disease and new genetic insights into LA.


Assuntos
Adenocarcinoma de Pulmão/genética , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala/métodos , RNA/genética , Adenocarcinoma de Pulmão/sangue , Perfilação da Expressão Gênica/métodos , Humanos , RNA/biossíntese , RNA Neoplásico/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Regulação para Cima
4.
Gene ; 721: 144093, 2019 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-31473323

RESUMO

Previous studies have determined that long non-coding RNA (lncRNA) Fer-1-like protein 4 (FER1L4) is suppressed in osteosarcoma (OS) and inhibits the tumorigenesis in a variety of cancer. However, the precise biological of FER1L4 in OS has not been cleared. The aim of this study is to investigate the roles and potential mechanisms of FER1L4 in apoptosis and epithelial-mesenchymal transition (EMT) in OS. In the present study, the levels of FER1L4 were decreased significantly in OS tissues and cell lines compared with non-tumorous tissues or hFOB1.19. Knockdown of FER1L4 in OS cells decreased the apoptosis rate, but increased the OS cell proliferation, upregulated the expression levels of CD133 and Nanog, as well as promoted Twist1 expression, increased the N-cadherin and Vimentin expression. In turn, the opposite trends were observed upon overexpression of FER1L4. In addition, the expression of PI3K, p-AKT (Ser470) and p-AKT (Thr308) was upregulated by siFER1L4, while decreased upon overexpression of FER1L4. MicroRNA (miRNA) -18a-5p, an osteosarcoma-promoting miRNA which was suggested a target of FER1L4 in osteosarcoma, was identified to be a functional target of FER1L4 on the regulating of cell apoptosis and EMT, presently. The effects of FER1L4 overexpression on the markers of cell apoptosis, proliferation, EMT, and stemness and PI3K/AKT signaling were all reversed by miR-18a-5p upregulation. Furthermore, the suppressor of cytokine signaling 5 (SOCS5) was confirmed a target gene of miR-18a-5p by luciferase gene reporter assay and SOCS5 suppression by miR-18a-5p attenuated the effects of FER1L4 overexpression on the OS cells apoptosis and the expressed levels of PI3K, AKT, Twist1, N-cadherin and Vimentin. In conclusion, our data indicated thatthe overexpression of FER1L4 promoted apoptosis and inhibited the EMT markers expression and PI3K/AKT signaling pathway activation in OS cells via downregulating miR-18a-5p to promote SOCS5.


Assuntos
Apoptose , Neoplasias Ósseas/metabolismo , Transição Epitelial-Mesenquimal , MicroRNAs/metabolismo , Osteossarcoma/metabolismo , RNA Longo não Codificante/metabolismo , RNA Neoplásico/metabolismo , Transdução de Sinais , Proteínas Supressoras da Sinalização de Citocina/biossíntese , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Humanos , MicroRNAs/genética , Osteossarcoma/genética , Osteossarcoma/patologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/genética , RNA Neoplásico/genética , Proteínas Supressoras da Sinalização de Citocina/genética
5.
Cancer Treat Rev ; 80: 101894, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31518831

RESUMO

Despite advances in translating conventional research into multi-modal treatment for colorectal cancer (CRC), therapeutic resistance and relapse remain unresolved in advanced resectable and, particularly, non-resectable disease. Genome and transcriptome sequencing and editing technologies, coupled with interaction mapping and machine learning, are transforming biomedical research, representing the most rational hope to overcome unmet research and clinical challenges. Rapid progress in both bulk and single-cell next-generation sequencing (NGS) analyses in the identification of primary and metastatic intratumor genomic and transcriptional heterogeneity (ITH) and the detection of circulating cell-free DNA (cfDNA) alterations is providing critical insight into the origins and spatiotemporal evolution of genomic clones responsible for early and late therapeutic resistance and relapse. Moreover, DNA and RNA editing pave new avenues towards the discovery of novel drug targets. Breakthrough combinations of sequencing and editing systems with technologies exploring dynamic interaction networks within pioneering studies could delineate how coding and non-coding mutations perturb regulatory networks and gene expression. This review discusses latest data on genomic and transcriptomic landscapes in time and space, as well as early-phase clinical trials on targeted drug combinations, highlighting the transition from research to clinical Colorectal Cancer Precision Medicine, through non-invasive screening, individualized drug response prediction and development of multiple novel drugs. Future studies exploring the potential to target key transcriptional drivers and regulators will contribute to the next-generation pharmaceutical controllability of multi-layered aberrant transcriptional biocircuits.


Assuntos
Neoplasias Colorretais/genética , Animais , DNA de Neoplasias/genética , Genômica/métodos , Humanos , Medicina de Precisão , RNA Neoplásico/genética , Transcrição Genética
6.
Gene ; 721: 144100, 2019 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-31493508

RESUMO

BACKGROUND: Breast cancer (BRCA) is the most prevalent cancer that threatens female health. A growing body of evidence has demonstrated the non-negligible effects of messenger RNAs (mRNAs) on biological processes involved in cancers; however, there is no definite conclusion regarding the role of mRNAs in predicting the prognosis of BRCA patients. MATERIALS AND METHODS: We systematically screened the mRNA expression landscape and clinical data of samples from the Cancer Genome Atlas (TCGA). Univariate Cox analysis and robust likelihood-based survival analysis were conducted to identify key mRNAs associated with BRCA. Furthermore, risk scores based on multivariate Cox analysis divided the training set into high-risk and low-risk groups. ROC analysis determined the optimal cut-off point for patient classification of risk levels. The prognostic model was additionally validated in the testing set and complete dataset. Finally, we plotted the survival curves for the mRNAs used in our model. RESULTS: We obtained the original expression data of 13,617 mRNAs from a total of 1088 samples. After comprehensive survival analysis, the four-mRNA (ACSL1, OTUD3, PKD1L2, and WISP1) prognosis risk assessment model was constructed. Furthermore, the area under cure (AUC) was 0.834, indicating that the model was meaningful and reasonable. In each dataset, analysis based on the four-mRNA signature risk score indicated that the survival status of the group with high risk score was worse than that of the group with low risk scores. Patients with strong mRNA expression of OTUD3, PKD1L2, and WISP1 tended to have good prognosis, whereas patients with high ACSL1 expression tended to have poor prognosis. CONCLUSION: In summary, we constructed a four-mRNA prognosis risk assessment model for BRCA. The newly developed model offers more possibilities for assessing prognosis and guiding the selection of better treatment strategies for BRCA.


Assuntos
Neoplasias da Mama , Bases de Dados de Ácidos Nucleicos , Modelos Biológicos , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Proteínas de Sinalização Intercelular CCN/biossíntese , Proteínas de Sinalização Intercelular CCN/genética , Coenzima A Ligases/biossíntese , Coenzima A Ligases/genética , Intervalo Livre de Doença , Feminino , Humanos , Valor Preditivo dos Testes , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas/genética , RNA Mensageiro/genética , RNA Neoplásico/genética , Receptores Acoplados a Proteínas-G/biossíntese , Receptores Acoplados a Proteínas-G/genética , Taxa de Sobrevida , Proteases Específicas de Ubiquitina/biossíntese , Proteases Específicas de Ubiquitina/genética
7.
Hematol Oncol ; 37(4): 375-382, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31408531

RESUMO

In large B-cell lymphoma (LBCL), MYC translocation and MYC/BCL2 or MYC/BCL6 double hit (DH) are associated with poor prognosis, and there is an unmet need for novel treatment targets in this patient group. Treatments targeting the PD-L1/PD-1 pathway are still poorly elucidated in LBCL. PD-L1 expression might predict response to treatment targeting the PD-L1/PD-1 pathway. We therefore investigated the relationship between PD-L1 protein and mRNA expression levels and MYC and DH translocation in LBCL. We detected MYC, BCL2, and BCL6 translocation by fluorescent in situ hybridization in tissue samples from 130 patients randomly selected from two cohorts of patients with LBCL: 49 patients with MYC translocation of whom 36 had DH and 81 without MYC translocation. PD-L1 protein expression was detected by immunohistochemistry (IHC) in tissue samples from 77 patients and PD-L1 mRNA expression by next-generation RNA sequencing (NGS) in another 77 patients. Twenty-four patients overlapped, ie, were analysed with both IHC and NGS. Nonparametric tests were performed to evaluate intergroup differences. PD-L1 protein expression level was significantly lower in patients with MYC (n = 42, median = 3.3%, interquartile range [IQR] 0.0-10.8) or DH translocations (n = 31, median = 3.3%, IQR 0.0-10.0) compared with patients with no MYC (n = 35, median = 16.7%, IQR 3.3-30.0) or no DH translocations (n = 46, 13.3%, IQR 2.5-30.0), P = .004 and P ≤ .001, respectively. PD-L1 mRNA expression was also significantly lower in patients with MYC or DH translocations, P = .001 and P = .006, respectively. Higher PD-L1 protein and mRNA expression levels were associated with non-germinal centre (GC) type compared with germinal centre B-cell (GCB)-type diffuse LBCL (DLBCL), P = .004 and P = .002, respectively. In conclusion, we report an association between low PD-L1 expression and MYC and DH translocation in patients with LBCL. Our findings may indicate that patients with MYC or DH translocation may benefit less from treatment with PD-L1/PD-1-inhibitors compared with patients without these translocations. This should be evaluated in larger, prospective, consecutive trials.


Assuntos
Antígeno B7-H1/biossíntese , Regulação Neoplásica da Expressão Gênica , Genes myc , Linfoma Difuso de Grandes Células B/metabolismo , Proteínas de Neoplasias/biossíntese , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , Translocação Genética , Adulto , Idoso , Subpopulações de Linfócitos B/metabolismo , Subpopulações de Linfócitos B/patologia , Antígeno B7-H1/genética , Feminino , Perfilação da Expressão Gênica , Genes bcl-2 , Centro Germinativo/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Proteínas Proto-Oncogênicas c-bcl-6/genética , RNA Mensageiro/genética , RNA Neoplásico/genética , Estudos Retrospectivos
8.
Gut ; 68(12): 2129-2141, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31366457

RESUMO

OBJECTIVE: Chronic inflammation is a risk factor in colorectal cancer (CRC) and reactive oxygen species (ROS) released by the inflamed stroma elicit DNA damage in epithelial cells. We sought to identify new drivers of ulcerative colitis (UC) and inflammatory CRC. DESIGN: The study uses samples from patients with UC, mouse models of colitis and CRC and mice deficient for the epithelial-to-mesenchymal transition factor ZEB1 and the DNA repair glycosylase N-methyl-purine glycosylase (MPG). Samples were analysed by immunostaining, qRT-PCR, chromatin immunoprecipitation assays, microbiota next-generation sequencing and ROS determination. RESULTS: ZEB1 was induced in the colonic epithelium of UC and of mouse models of colitis. Compared with wild-type counterparts, Zeb1-deficient mice were partially protected from experimental colitis and, in a model of inflammatory CRC, they developed fewer tumours and exhibited lower levels of DNA damage (8-oxo-dG) and higher expression of MPG. Knockdown of ZEB1 in CRC cells inhibited 8-oxo-dG induction by oxidative stress (H2O2) and inflammatory cytokines (interleukin (IL)1ß). ZEB1 bound directly to the MPG promoter whose expression inhibited. This molecular mechanism was validated at the genetic level and the crossing of Zeb1-deficient and Mpg-deficient mice reverted the reduced inflammation and tumourigenesis in the former. ZEB1 expression in CRC cells induced ROS and IL1ß production by macrophages that, in turn, lowered MPG in CRC cells thus amplifying a positive loop between both cells to promote DNA damage and inhibit DNA repair. CONCLUSIONS: ZEB1 promotes colitis and inflammatory CRC through the inhibition of MPG in epithelial cells, thus offering new therapeutic strategies to modulate inflammation and inflammatory cancer.


Assuntos
Colite Ulcerativa/genética , Neoplasias do Colo/genética , DNA Glicosilases/genética , Células Epiteliais/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Experimentais , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Animais , Biópsia , Células Cultivadas , Colite Ulcerativa/complicações , Colite Ulcerativa/metabolismo , Neoplasias do Colo/etiologia , Neoplasias do Colo/patologia , DNA Glicosilases/metabolismo , Reparo do DNA , Células Epiteliais/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Neoplásico/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Dedos de Zinco
9.
Gene ; 715: 144012, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31357021

RESUMO

Long noncoding RNAs (lncRNAs) have been shown to play an important role in tumor biogenesis and prognosis. The glioma is a grade classified cancer, however, we still lack the knowledge on their function during glioma progression. While previous studies have shown how lncRNAs regulate protein-coding gene epigenetically, it is still unclear how lncRNAs are regulated epigenetically. In this study, we firstly analyzed the RNA-seq data systematically across grades II, IV, and IV of glioma samples. We identified 60 lncRNAs that are significantly differentially expressed over disease progression (DElncRNA), including well-known PVT1, HOTAIR, H19 and rarely studied CARD8-AS, MIR4435-2HG. Secondly, by integrating HM450K methylation microarray data, we demonstrated that some of the lncRNAs are epigenetically regulated by methylation. Thirdly, we developed a DESeq2-GSEA-ceRNA-survival analysis strategy to investigate their functions. Particularly, MIR4435-2HG is highly expressed in high-grade glioma and may have an impact on EMT and TNFα signaling pathway by functioning as a miRNA sponge of miR-125a-5p and miR-125b-5p to increase the expression of CD44. Our results revealed the dynamic expression of lncRNAs in glioma progression and their epigenetic regulation mechanism.


Assuntos
Metilação de DNA , DNA de Neoplasias , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Glioma , MicroRNAs , RNA Longo não Codificante , RNA Neoplásico , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Perfilação da Expressão Gênica , Glioma/genética , Glioma/metabolismo , Glioma/patologia , Humanos , MicroRNAs/biossíntese , MicroRNAs/genética , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , RNA Longo não Codificante/biossíntese , RNA Longo não Codificante/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética
10.
Hematol Oncol ; 37(4): 474-482, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31325181

RESUMO

LncRNAs play critical roles in various pathophysiological and biological processes, such as protein translation, RNA splicing, and epigenetic modification. Indeed, abundant evidences demonstrated that lncRNA act as competing endogenous RNAs (ceRNAs) to participate in tumorigenesis. However, little is known about the underlying function of lncRNA in nonhomologous end joining (NHEJ) pathway 1 (LINP1) in pediatric and adolescent acute myeloid leukemia (AML). The expression of LINP1 was examined in AML patient samples by qRT-PCR. Cell proliferation was examined by CCK-8 and Edu assays. ß-Galactosidase senescence assay, mGlucose uptake assay, lactate production assay, and Gene Ontology (GO) analysis were performed for functional analysis. We found that LINP1 was significantly overexpressed in AML patients at diagnosis, whereas downregulated after complete remission (CR). Furthermore, knockdown of LINP1 expression remarkably suppressed glucose uptake and AML cell maintenance. Mechanistically, LINP1 was found to inhibit the glucose metabolism by suppressing the expression of HNF4a. Both LINP1 and HNF4a knockdown reduced the expression levels of AMPK phosphorylation and WNT5A, indicating for the first time that LINP1 strengthened the HNF4a-AMPK/WNT5A signaling pathway involved in cell glucose metabolism modulation and AML cell survival. Taken together, our results indicated that LINP1 promotes the malignant phenotype of AML cells and stimulates glucose metabolism, which can be regarded as a potential prognostic marker and therapeutic target for AML.


Assuntos
Adenilato Quinase/fisiologia , Fator 4 Nuclear de Hepatócito/fisiologia , Leucemia Mieloide Aguda/genética , RNA Longo não Codificante/fisiologia , RNA Neoplásico/fisiologia , Transdução de Sinais/fisiologia , Proteína Wnt-5a/fisiologia , Adolescente , Animais , Medula Óssea/patologia , Divisão Celular , Criança , Regulação Leucêmica da Expressão Gênica , Técnicas de Silenciamento de Genes , Ontologia Genética , Glucose/metabolismo , Fator 4 Nuclear de Hepatócito/biossíntese , Fator 4 Nuclear de Hepatócito/genética , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Transplante de Neoplasias , Púrpura Trombocitopênica Idiopática/metabolismo , Interferência de RNA , RNA Longo não Codificante/biossíntese , RNA Longo não Codificante/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , RNA Interferente Pequeno/genética , Distribuição Aleatória , Indução de Remissão , Transdução de Sinais/genética , Células THP-1
11.
Nucleic Acids Res ; 47(15): 7753-7766, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31340025

RESUMO

MicroRNAs (miRNAs) are short, noncoding RNAs that regulate gene expression by suppressing mRNA translation and reducing mRNA stability. A miRNA can potentially bind many mRNAs, thereby affecting the expression of oncogenes and tumor suppressor genes as well as the activity of whole pathways. The promise of miRNA therapeutics in cancer is to harness this evolutionarily conserved mechanism for the coordinated regulation of gene expression, and thus restoring a normal cell phenotype. However, the promiscuous binding of miRNAs can provoke unwanted off-target effects, which are usually caused by high-dose single-miRNA treatments. Thus, it is desirable to develop miRNA therapeutics with increased specificity and efficacy. To achieve that, we propose the concept of miRNA cooperativity in order to exert synergistic repression on target genes, thus lowering the required total amount of miRNAs. We first review miRNA therapies in clinical application. Next, we summarize the knowledge on the molecular mechanism and biological function of miRNA cooperativity and discuss its application in cancer therapies. We then propose and discuss a systems biology approach to investigate miRNA cooperativity for the clinical setting. Altogether, we point out the potential of miRNA cooperativity to reduce off-target effects and to complement conventional, targeted, or immune-based therapies for cancer.


Assuntos
Antineoplásicos/uso terapêutico , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias/terapia , RNA Neoplásico/genética , Biologia de Sistemas/métodos , Antagomirs/genética , Antagomirs/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Quimioterapia Adjuvante/métodos , Redes Reguladoras de Genes , Humanos , MicroRNAs/agonistas , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Oligorribonucleotídeos/genética , Oligorribonucleotídeos/metabolismo , Estabilidade de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/agonistas , RNA Neoplásico/antagonistas & inibidores , RNA Neoplásico/metabolismo , Bibliotecas de Moléculas Pequenas/uso terapêutico , Proteínas Supressoras de Tumor/agonistas , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
12.
Cell Physiol Biochem ; 53(1): 258-280, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31313541

RESUMO

BACKGROUND/AIMS: Although neuroblastoma is a heterogeneous cancer, a substantial portion overexpresses CD71 (transferrin receptor 1) and MYCN. This study provides a mechanistically driven rationale for a combination therapy targeting neuroblastomas that doubly overexpress or have amplified CD71 and MYCN. For this subset, CD71 was targeted by its natural ligand, gambogic acid (GA), and MYCN was targeted with an HDAC inhibitor, vorinostat. A combination of GA and vorinostat was then tested for efficacy in cancer and non-cancer cells. METHODS: Microarray analysis of cohorts of neuroblastoma patients indicated a subset of neuroblastomas overexpressing both CD71 and MYCN. The viability with proliferation changes were measured by MTT and colony formation assays in neuroblastoma cells. Transfection with CD71 or MYCN along with quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to detect expression changes. For pathway analysis, gene ontology (GO) and Protein-protein interaction analyses were performed to evaluate the potential mechanisms of GA and vorinostat in treated cells. RESULTS: For both GA and vorinostat, their pathways were explored for specificity and dependence on their targets for efficacy. For GA-treated cells, the viability/proliferation loss due to GA was dependent on the expression of CD71 and involved activation of caspase-3 and degradation of EGFR. It relied on the JNK-IRE1-mTORC1 pathway. The drug vorinostat also reduced cell viability/proliferation in the treated cells and this was dependent on the presence of MYCN as MYCN siRNA transfection led to a blunting of vorinostat efficacy and conversely, MYCN overexpression improved the vorinostat potency in those cells. Vorinostat inhibition of MYCN led to an increase of the pro-apoptotic miR183 levels and this, in turn, reduced the viability/proliferation of these cells. The combination treatment with GA and vorinostat synergistically reduced cell survival in the MYCN and CD71 overexpressing tumor cells. The same treatment had no effect or minimal effect on HEK293 and HEF cells used as models of non-cancer cells. CONCLUSION: A combination therapy with GA and vorinostat may be suitable for MYCN and CD71 overexpressing neuroblastomas.


Assuntos
Antígenos CD , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Sistemas de Liberação de Medicamentos , Proteína Proto-Oncogênica N-Myc , Neuroblastoma , Receptores da Transferrina , Antígenos CD/genética , Antígenos CD/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Células HEK293 , Humanos , MicroRNAs/biossíntese , MicroRNAs/genética , Proteína Proto-Oncogênica N-Myc/antagonistas & inibidores , Proteína Proto-Oncogênica N-Myc/genética , Proteína Proto-Oncogênica N-Myc/metabolismo , Neuroblastoma/tratamento farmacológico , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neuroblastoma/patologia , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Receptores da Transferrina/antagonistas & inibidores , Receptores da Transferrina/genética , Receptores da Transferrina/metabolismo , Vorinostat/farmacologia , Xantonas/farmacologia
13.
Medicine (Baltimore) ; 98(27): e16269, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31277149

RESUMO

Esophageal squamous cell carcinoma (ESCC) is a malignancy that severely threatens human health and carries a high incidence rate and a low 5-year survival rate. MicroRNAs (miRNAs) are commonly accepted as a key regulatory function in human cancer, but the potential regulatory mechanisms of miRNA-mRNA related to ESCC remain poorly understood.The GSE55857, GSE43732, and GSE6188 miRNA microarray datasets and the gene expression microarray datasets GSE70409, GSE29001, and GSE20347 were downloaded from Gene Expression Omnibus databases. The differentially expressed miRNAs (DEMs) and differentially expressed genes (DEGs) were obtained using GEO2R. Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for DEGs were performed by Database for Annotation, Visualization and Integrated Discovery (DAVID). A protein-protein interaction (PPI) network and functional modules were established using the STRING database and were visualized by Cytoscape. Kaplan-Meier analysis was constructed based on The Cancer Genome Atlas (TCGA) database.In total, 26 DEMs and 280 DEGs that consisted of 96 upregulated and 184 downregulated genes were screened out. A functional enrichment analysis showed that the DEGs were mainly enriched in the ECM-receptor interaction and cytochrome P450 metabolic pathways. In addition, MMP9, PCNA, TOP2A, MMP1, AURKA, MCM2, IVL, CYP2E1, SPRR3, FOS, FLG, TGM1, and CYP2C9 were considered to be hub genes owing to high degrees in the PPI network. MiR-183-5p was with the highest connectivity target genes in hub genes. FOS was predicted to be a common target gene of the significant DEMs. Hsa-miR-9-3p, hsa-miR-34c-3p and FOS were related to patient prognosis and higher expression of the transcripts were associated with a poor OS in patients with ESCC.Our study revealed the miRNA-mediated hub genes regulatory network as a model for predicting the molecular mechanism of ESCC. This may provide novel insights for unraveling the pathogenesis of ESCC.


Assuntos
Biologia Computacional/métodos , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , RNA Neoplásico/genética , Bases de Dados Genéticas , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/metabolismo , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Análise em Microsséries
14.
Nature ; 571(7763): 127-131, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31243371

RESUMO

Cancer metastasis is the primary cause of morbidity and mortality, and accounts for up to 95% of cancer-related deaths1. Cancer cells often reprogram their metabolism to efficiently support cell proliferation and survival2,3. However, whether and how those metabolic alterations contribute to the migration of tumour cells remain largely unknown. UDP-glucose 6-dehydrogenase (UGDH) is a key enzyme in the uronic acid pathway, and converts UDP-glucose to UDP-glucuronic acid4. Here we show that, after activation of EGFR, UGDH is phosphorylated at tyrosine 473 in human lung cancer cells. Phosphorylated UGDH interacts with Hu antigen R (HuR) and converts UDP-glucose to UDP-glucuronic acid, which attenuates the UDP-glucose-mediated inhibition of the association of HuR with SNAI1 mRNA and therefore enhances the stability of SNAI1 mRNA. Increased production of SNAIL initiates the epithelial-mesenchymal transition, thus promoting the migration of tumour cells and lung cancer metastasis. In addition, phosphorylation of UGDH at tyrosine 473 correlates with metastatic recurrence and poor prognosis of patients with lung cancer. Our findings reveal a tumour-suppressive role of UDP-glucose in lung cancer metastasis and uncover a mechanism by which UGDH promotes tumour metastasis by increasing the stability of SNAI1 mRNA.


Assuntos
Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Metástase Neoplásica/genética , Metástase Neoplásica/prevenção & controle , Estabilidade de RNA , Fatores de Transcrição da Família Snail/genética , Uridina Difosfato Glucose/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular , Proteína Semelhante a ELAV 1/deficiência , Proteína Semelhante a ELAV 1/genética , Proteína Semelhante a ELAV 1/metabolismo , Transição Epitelial-Mesenquimal , Feminino , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Nus , Fosfotirosina/metabolismo , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Fatores de Transcrição da Família Snail/biossíntese , Uridina Difosfato Glucose Desidrogenase/química , Uridina Difosfato Glucose Desidrogenase/genética , Uridina Difosfato Glucose Desidrogenase/metabolismo , Uridina Difosfato Ácido Glucurônico/metabolismo
15.
BMC Bioinformatics ; 20(1): 339, 2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31208324

RESUMO

BACKGROUND: In the era of precision oncology and publicly available datasets, the amount of information available for each patient case has dramatically increased. From clinical variables and PET-CT radiomics measures to DNA-variant and RNA expression profiles, such a wide variety of data presents a multitude of challenges. Large clinical datasets are subject to sparsely and/or inconsistently populated fields. Corresponding sequencing profiles can suffer from the problem of high-dimensionality, where making useful inferences can be difficult without correspondingly large numbers of instances. In this paper we report a novel deployment of machine learning techniques to handle data sparsity and high dimensionality, while evaluating potential biomarkers in the form of unsupervised transformations of RNA data. We apply preprocessing, MICE imputation, and sparse principal component analysis (SPCA) to improve the usability of more than 500 patient cases from the TCGA-HNSC dataset for enhancing future oncological decision support for Head and Neck Squamous Cell Carcinoma (HNSCC). RESULTS: Imputation was shown to improve prognostic ability of sparse clinical treatment variables. SPCA transformation of RNA expression variables reduced runtime for RNA-based models, though changes to classifier performance were not significant. Gene ontology enrichment analysis of gene sets associated with individual sparse principal components (SPCs) are also reported, showing that both high- and low-importance SPCs were associated with cell death pathways, though the high-importance gene sets were found to be associated with a wider variety of cancer-related biological processes. CONCLUSIONS: MICE imputation allowed us to impute missing values for clinically informative features, improving their overall importance for predicting two-year recurrence-free survival by incorporating variance from other clinical variables. Dimensionality reduction of RNA expression profiles via SPCA reduced both computation cost and model training/evaluation time without affecting classifier performance, allowing researchers to obtain experimental results much more quickly. SPCA simultaneously provided a convenient avenue for consideration of biological context via gene ontology enrichment analysis.


Assuntos
Bases de Dados Genéticas , Aprendizado de Máquina , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Algoritmos , Área Sob a Curva , Ontologia Genética , Humanos , Análise de Componente Principal , RNA Neoplásico/genética , RNA Neoplásico/metabolismo
16.
Hematology ; 24(1): 487-491, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31210592

RESUMO

OBJECTIVES: Acute myeloid leukemia (AML) is a heterogeneous and highly recurrent hematological malignancy. Studies have shown an association between microRNAs and drive genes in AMLs. However, the regulatory roles of miRNAs in AML and how they act on downstream targets and the signaling pathway has been little studied. METHODS: As to understand the mechanism of mRNA-miRNA interaction in the blood malignancy from a large scale of transcriptomic sequencing studies, we applied a comprehensive miRNA-mRNA association, co-expression gene network and ingenuity pathway analysis using TCGA AML datasets. RESULTS: Our results showed that his-mir-335 was a critical regulatory of homeobox A gene family. PBX3, KAT6A, MEIS1, and COMMD3-BMI1 were predicted as top transcription regulators in the regulatory network of the HOXA family. The most significantly enriched functions were cell growth, proliferation, and survival in the mRNA-miRNA network. CONCLUSION: Our work revealed that regulation of the HOXA gene family and its regulation played an important role in the development of AML.


Assuntos
Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Redes Reguladoras de Genes , Leucemia Mieloide Aguda , MicroRNAs , RNA Mensageiro , RNA Neoplásico , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , MicroRNAs/biossíntese , MicroRNAs/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética
17.
Gynecol Oncol ; 154(3): 495-504, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31204077

RESUMO

OBJECTIVE: This study is designed to identify genes and pathways that could promote metastasis to the bowel in high-grade serous ovarian cancer (OC) and evaluate their associations with clinical outcomes. METHODS: We performed RNA sequencing of OC primary tumors (PTs) and their corresponding bowel metastases (n = 21 discovery set; n = 18 replication set). Differentially expressed genes (DEGs) were those expressed at least 2-fold higher in bowel metastases (BMets) than PTs in at least 30% of patients (P < .05) with no increased expression in paired benign bowel tissue and were validated with quantitative reverse transcription PCR. Using an independent OC cohort (n = 333), associations between DEGs in PTs and surgical and clinical outcomes were performed. Immunohistochemistry and mouse xenograft studies were performed to confirm the role of LRRC15 in promoting metastasis. RESULTS: Among 27 DEGs in the discovery set, 21 were confirmed in the replication set: SFRP2, Col11A1, LRRC15, ADAM12, ADAMTS12, MFAP5, LUM, PLPP4, FAP, POSTN, GRP, MMP11, MMP13, C1QTNF3, EPYC, DIO2, KCNA1, NETO1, NTM, MYH13, and PVALB. Higher expression of more than half of the genes in the PT was associated with an increased requirement for bowel resection at primary surgery and an inability to achieve complete cytoreduction. Increased expression of LRRC15 in BMets was confirmed by immunohistochemistry and knockdown of LRRC15 significantly inhibited tumor progression in mice. CONCLUSIONS: We identified 21 genes that are overexpressed in bowel metastases among patients with OC. Our findings will help select potential molecular targets for the prevention and treatment of malignant bowel obstruction in OC.


Assuntos
Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/patologia , Neoplasias Intestinais/genética , Neoplasias Intestinais/secundário , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Animais , Linhagem Celular Tumoral , Estudos de Coortes , Feminino , Técnicas de Silenciamento de Genes , Xenoenxertos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Proteínas de Membrana/genética , Camundongos , Camundongos Nus , RNA Neoplásico/genética , Transcriptoma , Regulação para Cima
18.
Cell Physiol Biochem ; 52(6): 1503-1516, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31112017

RESUMO

BACKGROUND/AIMS: Zinc Finger Protein 281 (ZNF281) was recently identified as a novel oncogene in several human carcinomas. However, the clinical significance of ZNF281 in colorectal cancer (CRC) and the molecular mechanisms by which ZNF281 promotes the growth and metastasis of CRC remain unknown. METHODS: ZNF281 expression in CRC tissues was assessed, and the outcomes were analyzed to determine the clinical importance of ZNF281 expression. Cell Transwell assays and a wound healing assay were performed to assess the effects of ZNF281 on CRC cell migration and invasion in vitro. Western blotting was applied to analyze the potential mechanisms. RESULTS: ZNF281 mRNA and protein levels were significantly increased in CRC tissues compared with normal colon tissues, and high ZNF281 expression was associated with advanced T stage, N stage, TNM stage and differentiation. Therefore, ZNF281 expression might be an independent prognostic indicator in CRC patients. Moreover, knockdown of ZNF281 expression suppressed cell proliferation, migration and invasion by inhibiting the Wnt/ß-catenin pathway. CONCLUSION: Our study indicates that ZNF281 plays a critical role in the progression and metastasis of CRC and could represent a potential therapeutic target for CRC.


Assuntos
Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Transativadores/metabolismo , Idoso , Linhagem Celular Tumoral , Movimento Celular/genética , Movimento Celular/fisiologia , Proliferação de Células/genética , Proliferação de Células/fisiologia , Neoplasias Colorretais/genética , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Células HT29 , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Invasividade Neoplásica/fisiopatologia , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , RNA Interferente Pequeno/genética , Transativadores/antagonistas & inibidores , Transativadores/genética , Regulação para Cima , Via de Sinalização Wnt , beta Catenina/metabolismo
19.
Hematol Oncol ; 37(4): 409-417, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31102419

RESUMO

Accumulating studies have focused on circulating microRNAs, which might be potential biomarkers for different malignancies. The aim of this study was to investigate the potential of serum exosomal microRNAs to be novel serum biomarkers for smouldering myeloma (SMM) or even multiple myeloma (MM). The levels of serum exosomal microRNAs and serum circulating microRNAs were measured in healthy individuals and patients with SMM (n = 20) or MM (n = 20). Serum exosomal microRNAs and serum circulating microRNAs were extracted from serum, and the expression levels of selected microRNAs were quantified by real-time polymerase chain reaction (PCR). The levels of serum exosome-derived miR-20a-5p, miR-103a-3p, and miR-4505 were significantly different among patients with MM, patients with SMM, and healthy individuals, while there were differences in the levels of let-7c-5p, miR-185-5p, and miR-4741 in patients with MM relative to those in SMM patients or healthy controls. Additionally, a significant correlation was rarely found between the levels of serum and exosomal microRNAs. This study shows that serum exosomal microRNAs can be used independently as novel serum biomarkers for MM.


Assuntos
Exossomos/química , MicroRNAs/sangue , Mieloma Múltiplo/sangue , RNA Neoplásico/sangue , Adulto , Idoso , Doenças Assintomáticas , Biomarcadores Tumorais/sangue , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , MicroRNAs/biossíntese , MicroRNAs/genética , Pessoa de Meia-Idade , Gamopatia Monoclonal de Significância Indeterminada/sangue , RNA Neoplásico/biossíntese , RNA Neoplásico/genética
20.
Mol Cell Biochem ; 459(1-2): 131-139, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31114934

RESUMO

To investigate the expression status of FAM98A and its potential involvement in endometrial carcinoma, the relative expression of FAM98A in clinical endometrial carcinoma tissues was analyzed by immunohistochemistry and real-time polymerase chain reaction. Endogenous FAM98A protein was determined by Western blotting. The overall survival was calculated by the Kaplan-Meier's analysis. Cell growth/viability/proliferation was evaluated by cell counting, 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide assay, and clonogenic assay, respectively. Cell apoptosis was determined by the Annexin V/7-AAD double-staining methods followed by flow cytometry analysis. The regulatory effect of miR-142-3p on FAM98A was interrogated by luciferase reporter assay. Aberrant overexpression of FAM98A was found in endometrial carcinoma both in vitro and in vivo. Furthermore, high level of FMA98A was associated with poor prognosis. FAM98A deficiency in Ishikawa and RL95-2 cells significantly inhibited cell growth, cell viability, and cell proliferation. In addition, FAM98A-knockdown stimulated remarkable cell apoptosis, which might be mediated by down-regulation of BCL2 and up-regulation of BAX. Mechanistically, it was demonstrated that miR-142-3p directly targeted FAM98A, and modulated its expression. In conclusion, we unraveled the oncogenic properties of FAM98A in endometrial carcinoma and highlighted the miR-142-3p-FAM98A signaling in this disease.


Assuntos
Proliferação de Células , Neoplasias do Endométrio/metabolismo , Proteínas/metabolismo , Apoptose , Linhagem Celular Tumoral , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas/genética , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/genética , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Proteína X Associada a bcl-2/biossíntese , Proteína X Associada a bcl-2/genética
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