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1.
PLoS One ; 15(9): e0239462, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32956413

RESUMO

This study was performed to determine the clinical significance of adenomatous polyposis coli (APC)-binding protein end-binding 1 (EB1) in hepatocellular carcinoma (HCC) and to characterize its biochemical role in comparison with previous reports. We performed immunohistochemical staining to detect EB1 expression in tissues from 235 patients with HCC and investigated its correlations with clinicopathological features and prognosis. We also investigated the roles of EB1 in cell proliferation, migration, and tumorigenesis in vitro and in vivo by siRNA- and CRISPR/Cas9-mediated modulation of EB1 expression in human HCC cell lines. The results showed that EB1 expression was significantly correlated with several important factors associated with tumor malignancy, including histological differentiation, portal vein invasion status, and intrahepatic metastasis. Patients with high EB1 expression in HCC tissue had poorer overall survival and higher recurrence rates than patients with low EB1 expression. EB1 knockdown and knockout in HCC cells reduced cell proliferation, migration, and invasion in vitro and inhibited tumor growth in vivo. Further, genes encoding Dlk1, HAMP, and SLCO1B3 that were differentially expressed in association with EB1 were identified using RNA microarray analysis. In conclusion, elevated expression of EB1 promotes tumor growth and metastasis of HCC. EB1 may serve as a new biomarker for HCC, and genes coexpressed with EB1 may represent potential targets for therapy.


Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Proteínas Associadas aos Microtúbulos/fisiologia , Proteínas de Neoplasias/fisiologia , Adulto , Idoso , Animais , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/genética , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Inativação de Genes , Genes APC , Hepatite Viral Humana/complicações , Xenoenxertos , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/genética , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Associadas aos Microtúbulos/antagonistas & inibidores , Proteínas Associadas aos Microtúbulos/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Veia Porta/patologia , Prognóstico , Interferência de RNA , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , RNA Interferente Pequeno/genética , Proteínas Recombinantes/metabolismo , Recidiva , Taxa de Sobrevida , Análise Serial de Tecidos
2.
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
3.
Sci Rep ; 10(1): 5212, 2020 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-32251338

RESUMO

Organotypic cultures of tissue slices have been successfully established in lung, prostate, colon, gastric and breast cancer among other malignancies, but until now an ex vivo model based on tissue slices has not been established for uterine leiomyoma. In the present study, we describe a method for culturing tumour slides onto an alginate scaffold. Morphological integrity of tissue slices was maintained for up to 7 days of culture, with cells expressing desmin, estrogen and progesterone receptors. Driver mutations were present in the ex vivo slices at all-time points analyzed. Cultivated tumour slices responded to ovarian hormones stimulation upregulating the expression of genes involved in leiomyoma pathogenesis. This tissue model preserves extracellular matrix, cellular diversity and genetic background simulating more in-vivo-like situations. As a novelty, this platform allows encapsulation of microspheres containing drugs that can be tested on the ex vivo tumour slices. After optimizing drug release rates, microspheres would then be directly tested in animal models through local injection.


Assuntos
Estradiol , Leiomioma/patologia , Progesterona , Técnicas de Cultura de Tecidos , Neoplasias Uterinas/patologia , Alginatos , Animais , Antineoplásicos/farmacologia , Análise Mutacional de DNA , Composição de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Estradiol/farmacologia , Éxons/genética , Matriz Extracelular , Feminino , Leiomioma/tratamento farmacológico , Leiomioma/genética , Leiomioma/metabolismo , Complexo Mediador/genética , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Neoplasias Hormônio-Dependentes/genética , Neoplasias Hormônio-Dependentes/metabolismo , Neoplasias Hormônio-Dependentes/patologia , Progesterona/farmacologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Tecidos Suporte , Neoplasias Uterinas/tratamento farmacológico , Neoplasias Uterinas/genética , Neoplasias Uterinas/metabolismo
5.
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
6.
Oncogene ; 39(20): 4045-4060, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32214198

RESUMO

Epidemiologic and histopathologic findings and the laying hen model support the long-standing incessant ovulation hypothesis and cortical inclusion cyst involvement in sporadic ovarian cancer development. MicroRNA-200 (miR-200) family is highly expressed in ovarian cancer. Herewith, we show that ovarian surface epithelial (OSE) cells with ectopic miR-200 expression formed stabilized cysts in three-dimensional (3D) organotypic culture with E-cadherin fragment expression and steroid hormone pathway activation, whereas ovarian cancer 3D cultures with miR-200 knockdown showed elevated TGF-ß expression, mitotic spindle disorientation, increased lumenization, disruption of ROCK-mediated myosin II phosphorylation, and SRC signaling, which led to histotype-dependent loss of collective movement in tumor spread. Gene expression profiling revealed that epithelial-mesenchymal transition and hypoxia were the top enriched gene sets regulated by miR-200 in both OSE and ovarian cancer cells. The molecular changes uncovered by the in vitro studies were verified in both human and laying hen ovarian cysts and tumor specimens. As miR-200 is also essential for ovulation, our results of estrogen pathway activation in miR-200-expressing OSE cells add another intriguing link between incessant ovulation and ovarian carcinogenesis.


Assuntos
Carcinogênese/metabolismo , Regulação Neoplásica da Expressão Gênica , MicroRNAs/biossíntese , Cistos Ovarianos/metabolismo , Neoplasias Ovarianas/metabolismo , RNA Neoplásico/biossíntese , Carcinogênese/genética , Carcinogênese/patologia , Feminino , Humanos , MicroRNAs/genética , Cistos Ovarianos/genética , Cistos Ovarianos/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , RNA Neoplásico/genética
7.
Biomed Res Int ; 2020: 5831064, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32104698

RESUMO

Background: Long noncoding RNAs (lncRNAs) can function as competing endogenous RNAs (ceRNAs) and interact with microRNAs (miRNAs) to regulate target gene expression, which can greatly influence tumor development and progression. Different tumor-node-metastasis (TNM) stages of hepatocellular carcinoma (HCC) defined by the American Joint Committee on Cancer (AJCC) have different clinical results. Our purpose was to comprehensively analyze differentially expressed (DE) lncRNAs, miRNAs, and mRNAs in stage I HCC and identify prognosis-associated RNAs. Methods: RNA-seq data were obtained from The Cancer Genome Atlas (TCGA) database. A stage I HCC-associated miRNA-lncRNA-mRNA network was constructed. Next, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway analyses of ceRNA-associated DEmRNAs were performed using Database for Annotation, Visualization, and Integrated Discovery (DAVID) 6.8 and Clusterprofile in the R package. The protein-protein interaction (PPI) network of the above mRNAs was then constructed using STRING. Finally, the association between lncRNAs and mRNAs in the ceRNA network and prognosis of patients was further analyzed. Linear regression analysis of the above lncRNAs and mRNAs associated with overall survival was performed. Results: After a comparison between HCC and adjacent nontumor tissues, 778 lncRNAs, 1608 mRNAs, and 102 miRNAs that were abnormally expressed were identified. The ceRNA network was composed of 56 DElncRNAs, 14 DEmiRNAs, and 30 DEmRNAs. Functional analysis results showed that 30 DEmRNAs were enriched in 14 GO biological process categories and 6 KEGG categories (false discovery rate (FDR) < 0.05). A PPI network was composed of 22 nodes and 58 edges. We detected 4 DElncRNAs (BPESC1, AC061975.6, AC079341.1, and CLLU1) and 6 DEmRNAs (CEP55, E2F1, E2F7, EZH2, G6PD, and SLC7A11) that had significant influences on the overall survival (OS) of stage I HCC patients (P < 0.05). lncRNA BPESC1 was positively correlated with mRNA CEP55 via miR-424, and lncRNA AC061975.6 was positively correlated with mRNA E2F1 via miR-519d. Conclusion: Our study identified novel lncRNAs and mRNAs that were associated with the progression and prognosis of stage I HCC and further investigated the regulatory mechanism of lncRNA-mediated ceRNAs in the development of stage I HCC.


Assuntos
Carcinoma Hepatocelular , Bases de Dados de Ácidos Nucleicos , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Neoplasias Hepáticas , RNA Neoplásico , Idoso , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , Feminino , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , RNA Neoplásico/biossíntese , RNA Neoplásico/genética
8.
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
9.
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
10.
Artif Cells Nanomed Biotechnol ; 48(1): 393-407, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31913710

RESUMO

LncRNA PTENP1 is a competitive endogenous RNA (ceRNA) involved in decoying miR-106b in multiple diseases. This study investigates the interaction of PTENP1 and miR-106b in cell proliferation, apoptosis and epithelial-mesenchymal transition (EMT) in cervical cancer. The expressions of PTENP1, miR-106b and PTEN were determined in cervical cancer tissues, adjacent normal tissues, cervical cancer cells (HeLa, SiHa, C33A and CasKi) and normal cervical epithelial H8 cells. Up-regulation of PTENP1 and down-regulation of miR-106b were conducted in HeLa and CasKi cells by transfecting cells with corresponding miRNA mimics and inhibitors. Bioinformatics analysis, luciferase reporter assay and RNA-pull down assay were performed to verify the association of miR-106b, PTEN, and PTENP1. Cell growth and cell apoptosis were determined by CCK-8 and flow cytometry analysis. It was found that the expressions of PTENP1 and PTEN were up-regulated and that of miR-106b were down-regulated in cervical cancer tissues and cells. PTENP1 localized in cytoplasm and competitively bound to miR-106b. Up-regulation of PTENP1 and down-regulation of miR-106b contributed to increased expressions of PTEN and E-cadherin. Decreased expression of miR-106b, ZEB1, Snail and Vimentin, resulted in inhibiting cell proliferation and promoting cell apoptosis. Over-expression of PTENP1 and miR-106b accelerated cell proliferation and slowed down cell apoptosis. miR-106b inhibited the expression of PTEN. Our results suggest that LncRNA PTENP1 inhibits cervical cancer progression by competitively binding to miR-106b, leading to promote PTEN expression, inhibit cell proliferation and EMT and induce cell apoptosis in cervical cancer cells.


Assuntos
Apoptose , Regulação Leucêmica da Expressão Gênica , Genes Supressores de Tumor , RNA Longo não Codificante/biossíntese , RNA Neoplásico/biossíntese , Neoplasias do Colo do Útero/metabolismo , Feminino , Células HeLa , Humanos , MicroRNAs , RNA Longo não Codificante/genética , RNA Neoplásico/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia
11.
Sci Rep ; 10(1): 1175, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31980715

RESUMO

Thrombospondin-1 (TSP-1) is a multifunctional matrix protein with antitumor activities due in part to its ability to inhibit angiogenesis, which in turn contributes to determine the fate of many tumours. Previous studies have shown that TSP-1 expression supports normal kidney angiostasis, and decreased TSP-1 levels contribute to the angiogenic phenotype of renal cell carcinomas (RCC). The loss of the von Hippel-Lindau tumour suppressor gene (VHL) in these tumours favours stabilization of the Hypoxia Inducible Factors (HIF), which in turn contribute to adapt tumour cells to hostile environments promoting tumour progression. However, HIF-independent regulation of certain genes might also be involved. We have previously shown that TSP-1 is regulated in hypoxia in clear cell RCC (ccRCC) in a HIF-independent manner; however, the effect of VHL protein (pVHL) on TSP-1 expression has not been evaluated. Our results proved that pVHL loss or mutation in its alpha or beta domain significantly decreased TSP-1 levels in ccRCC in a HIF-independent manner. Furthermore, this regulation proved to be important for ccRCC cells behaviour showing that decreased TSP-1 levels rendered ccRCC cells more migratory. This data substantiates a unique regulation pattern for TSP-1 in a pVHL-dependent manner, which may be relevant in the aggressiveness of ccRCC.


Assuntos
Carcinoma de Células Renais/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/patologia , Proteínas de Neoplasias/fisiologia , Trombospondina 1/biossíntese , Proteína Supressora de Tumor Von Hippel-Lindau/fisiologia , Linhagem Celular Tumoral , Movimento Celular , Meios de Cultura Livres de Soro , Regulação para Baixo , Técnicas de Silenciamento de Genes , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Junções Intercelulares/metabolismo , Mutação de Sentido Incorreto , Invasividade Neoplásica , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Domínios Proteicos/genética , Interferência de RNA , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , RNA Interferente Pequeno/genética , Trombospondina 1/genética , Proteína Supressora de Tumor Von Hippel-Lindau/antagonistas & inibidores , Proteína Supressora de Tumor Von Hippel-Lindau/genética
12.
Artif Cells Nanomed Biotechnol ; 48(1): 353-361, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31899963

RESUMO

Background: OIP5-AS1 has been reported to be aberrantly expressed in multiple cancers and associated with clinical outcomes. We conducted this study to assess the generalized prognostic value of OIP5-AS1 in cancers.Methods: PubMed, Web of science, and Cochrane Library were searched for eligible studies. Hazards ratios (HRs) or odd ratios (ORs) with 95% confidence intervals (CIs) were pooled to estimate the prognostic value of OIP5-AS1 in cancers, including overall survival (OS), age, gender, tumor size, clinical stage, and lymph node metastasis (LNM). Publication bias was measured by Begg's test and funnel plot. Sensitivity analysis were used to detect the stability of pooled results.Results: Overall, eleven studies containing 713 patients were eventually enrolled. The pooled results showed that high OIP5-AS1 expression was correlated with shorter OS (HR = 0.48, 95%CI: 0.35-0.64), regardless of the sample size, tumor type and follow-up time. Furthermore, elevated expression of OIP5-AS1 indicated advanced clinical stage (OR = 2.12, 95% CI: 1.06-4.23), but not associated with age, gender, tumor size and LNM. No publication bias was detected.Conclusion: High expression of lncRNA OIP5-AS1 may predict a poor OS and advanced clinical stage, implicating that OIP5-AS1 may be a possible prognostic factor in cancers.


Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias , RNA Longo não Codificante/biossíntese , RNA Neoplásico/biossíntese , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Estadiamento de Neoplasias , Neoplasias/metabolismo , Neoplasias/mortalidade , Neoplasias/patologia , Taxa de Sobrevida
13.
Sci Rep ; 10(1): 1277, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31992741

RESUMO

The long non-coding RNA NEAT1 locus is transcribed into two overlapping isoforms, NEAT1_1 and NEAT1_2, of which the latter is essential for the assembly of nuclear paraspeckles. NEAT1 is abnormally expressed in a wide variety of human cancers. Emerging evidence suggests that the two isoforms have distinct functions in gene expression regulation, and recently it was shown that NEAT1_2, but not NEAT1_1, expression predicts poor clinical outcome in cancer. Here, we report that NEAT1_2 expression correlates with HER2-positive breast cancers and high-grade disease. We provide evidence that NEAT1_1 and NEAT1_2 have distinct expression pattern among different intrinsic breast cancer subtypes. Finally, we show that NEAT1_2 expression and paraspeckle formation increase upon lactation in humans, confirming what has previously been demonstrated in mice.


Assuntos
Neoplasias da Mama/metabolismo , Regulação Neoplásica da Expressão Gênica , RNA Longo não Codificante/biossíntese , RNA Neoplásico/biossíntese , Neoplasias da Mama/patologia , Feminino , Humanos , Células MCF-7
14.
Int J Cancer ; 146(8): 2326-2335, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-31469413

RESUMO

Many long intergenic noncoding RNAs (lincRNAs) serve as cancer biomarkers for diagnosis or prognostication. To understand the role of lincRNAs in the rare neuroendocrine tumors pheochromocytoma and paraganglioma (PCPG), we performed first time in-depth characterization of lincRNA expression profiles and correlated findings to clinical outcomes of the disease. RNA-Seq data from patients with PCPGs and 17 other tumor types from The Cancer Genome Atlas and other published sources were obtained. Differential expression analysis and a machine-learning model were used to identify transcripts specific to PCPGs, as well as established PCPG molecular subtypes. Similarly, lincRNAs specific to aggressive PCPGs were identified, and univariate and multivariate analysis was performed for metastasis-free survival. The results were validated in independent samples using RT-PCR. From a pan-cancer context, PCPGs had a specific and unique lincRNA profile. Among PCPGs, five different molecular subtypes were identified corresponding to the established molecular classification. Upregulation of 13 lincRNAs was found to be associated with aggressive/metastatic PCPGs. RT-PCR validation confirmed the overexpression of four lincRNAs in metastatic compared to non-metastatic PCPGs. Kaplan-Meier analysis identified five lincRNAs as prognostic markers for metastasis-free survival of patients in three subtypes of PCPGs. Stratification of PCPG patients with a risk-score formulated using multivariate analysis of lincRNA expression profiles, presence of key driver mutations, tumor location, and hormone secretion profiles showed significant differences in metastasis-free survival. PCPGs thus exhibit a specific lincRNA expression profile that also corresponds to the established molecular subgroups and can be potential marker for the aggressive/metastatic PCPGs.


Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Tumores Neuroendócrinos/genética , Paraganglioma/genética , Feocromocitoma/genética , RNA não Traduzido/genética , Neoplasias das Glândulas Suprarrenais/metabolismo , Neoplasias das Glândulas Suprarrenais/patologia , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Humanos , Metástase Neoplásica , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Paraganglioma/metabolismo , Paraganglioma/patologia , Feocromocitoma/metabolismo , Feocromocitoma/patologia , Prognóstico , Intervalo Livre de Progressão , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , RNA não Traduzido/biossíntese , Transcriptoma
15.
Cell Prolif ; 53(1): e12723, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31828845

RESUMO

OBJECTIVE: The long non-coding RNA zinc finger E-box-binding homeobox 1 antisense 1 (ZEB1-AS1) acts as an oncogenic regulator in many human tumours. In the present study, we identify the role and potential molecular biological mechanisms of ZEB1-AS1 in colon adenocarcinoma (COAD). METHODS: QRT-PCR was used to detect the expression of ZEB1-AS1, miR-455-3p and p21-activated kinases 2 (PAK2) in COAD tissues. CCK8 assay, EdU assay, transwell assay and scratch wound assay were used to explore the biological function of ZEB1-AS1 in COAD cells. Bioinformatics, luciferase reporter assays and an RNA pull-down assay were used to demonstrate the mechanism of ZEB1-AS1. We further explore the role of ZEB1-AS1 in vivo though xenograft tumour assay. RESULTS: We found that ZEB1-AS1 expression was significantly up-regulated in COAD tissues, and high ZEB1-AS1 level was correlated with the poor prognosis of COAD patients. MiR-455-3p plays an anti-cancer role in COAD by targeting PAK2. We confirmed that ZEB1-AS1 promotes PAK2 expression by sponging miR-455-3p, thus facilitating COAD cell growth and metastasis. CONCLUSIONS: To sum up, this result illustrates the novel molecular mechanism of ZEB1-AS1 in COAD and provides a new target for the diagnosis and treatment of COAD patients.


Assuntos
Adenocarcinoma/metabolismo , Neoplasias do Colo/metabolismo , Regulação Neoplásica da Expressão Gênica , MicroRNAs/biossíntese , Proteínas de Neoplasias/metabolismo , RNA Longo não Codificante/biossíntese , RNA Neoplásico/biossíntese , Transdução de Sinais , Quinases Ativadas por p21/metabolismo , Adenocarcinoma/patologia , Animais , Neoplasias do Colo/patologia , Feminino , Células HCT116 , Células HT29 , Humanos , Masculino , Camundongos , Metástase Neoplásica , Regulação para Cima
16.
Mol Cell Biochem ; 464(1-2): 39-50, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31691157

RESUMO

Ovarian cancer (OC) is the most lethal gynecologic malignancy and long non-coding RNAs (lncRNAs) have been acknowledged as important regulators in human OC. This study aimed to investigate the function and underlying mechanisms of LINC00504 in OC. The expression levels of LINC00504 in human OC tissues and cell lines were investigated by qRT-PCR analysis. The OC cell proliferation, and apoptosis were evaluated by MTT assay, colony-formation assay, Caspase-3 activity assay, and nucleosome ELISA assay, respectively. The metabolic shift in OC cells was examined by aerobic glycolysis analysis. Dual-luciferase activity reporter assay and mRNA-miRNA pull-down assay were conducted to validate the interaction between LINC00504 and miR-1244. LINC00504 was upregulated in OC cell lines and specimens. Knockdown of LINC00504 inhibited cell proliferation, enhanced apoptosis, decreased glycolysis-related gene (PKM2, HK2, and PDK1) expression, and altered aerobic glycolysis in OC cells and vice versa. LINC00504 downregulated miR-1244 expression levels by acting as an endogenous sponge of miR-1244. Inhibition of miR-1244 diminished the effects of LINC00504 on OC cells. Our study shows that LINC00504 promotes OC cell progression and stimulates aerobic glycolysis by interacting with miR-1244, which indicates that LINC00504 might act as a promising therapeutic target for OC treatment.


Assuntos
Regulação Neoplásica da Expressão Gênica , Glicólise , MicroRNAs/biossíntese , Neoplasias Ovarianas/metabolismo , RNA Longo não Codificante/biossíntese , RNA Neoplásico/biossíntese , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , MicroRNAs/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , RNA Longo não Codificante/genética , RNA Neoplásico/genética
17.
Inflamm Res ; 69(2): 167-178, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31865399

RESUMO

OBJECTIVE: To elucidate the regulation, function of the chemokine CXC-motif ligand 12 (CXCL12) and its receptors (CXCR) 4 and 7 in prostate cancer tumor microenvironment. MATERIAL: In-silico-analysis of expression in prostate cancer tissues. In-vitro comparison, testing of regulation in human prostate cancer cells LNCaP, DU145, and PC3. TREATMENT: Dihydrotestosterone (DHT) treatments (0-10 nM) were for 0-48 h. The inflammatory agent Flagellin treatment (20 ng/ml) was for 2 h. Migration assays were performed for 24 h using 10 ng/ml CXCL12. METHODS: Real-time PCR, western analysis, and migration assays were used to determine mRNA, protein, and functional changes, respectively. RESULTS: Malignant prostate cancer tissues exhibit higher CXCR4/7 mRNA ratio, and higher CXCR7 mRNA levels were detected in the androgen-responsive LNCaP cells. Putative androgen-responsive elements were identified in CXCR4, 7 gene, and exposure to DHT, flagellin increased CXCR4 mRNA but decreased CXCR7 mRNA levels in LNCaP cells. Androgen receptor siRNA significantly attenuated the effects of DHT on CXCR4, 7 mRNA in LNCaP cells. However, DHT and flagellin only decrease CXCR7 protein and additively increased migration of LNCaP cells towards CXCL12. CONCLUSIONS: Down regulation of CXCR7 protein by DHT and flagellin increased migration, supporting CXCR7 as decoy receptor counteracting CXCL12/CXCR4-mediated migration in prostate cancer cells.


Assuntos
Androgênios/metabolismo , Inflamação/metabolismo , Neoplasias da Próstata/genética , Receptores CXCR4/genética , Receptores CXCR/genética , Linhagem Celular Tumoral , Movimento Celular , Quimiocina CXCL12/biossíntese , Quimiocina CXCL12/genética , Simulação por Computador , Di-Hidrotestosterona/farmacologia , Flagelina/farmacologia , Humanos , Masculino , Neoplasias da Próstata/patologia , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , Receptores Androgênicos/biossíntese , Receptores Androgênicos/genética , Receptores CXCR/biossíntese , Receptores CXCR4/biossíntese , Microambiente Tumoral
18.
Artif Cells Nanomed Biotechnol ; 48(1): 188-196, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31865777

RESUMO

Background: Glioblastoma multiforme (GBM) is one of the most prevailing primary brain tumours among adults and most aggressive cancers. Despite multiple developments in medical and surgical treatments, GBM is still a deadly disease with a high mortality rate. Here, this study was performed to investigate the function of circPVT1 on GBM.Methods: CCK-8 and flow cytometry were utilised to estimate viability and apoptosis in both cells. qRT-PCR was performed to determine circPVT1 and miR-199a-5p expression. Western blot was conducted to determine apoptosis, migration and EMT-related proteins levels when silencing circPVT1. Subsequently, these parameters were re-tested after up-regulating miR-199a-5p.Results: CircPVT1 was highly expressed in GBM tissues. Silencing circPVT1 raised two cells apoptosis and reduced viability and migration capacity. Moreover, EGF-induced EMT was repressed by silencing circPVT1. In addition, miR-199a-5p expression was elevated when silencing circPVT1. And silencing circPVT1 exerted above changes via up-regulating miR-199a-5p. Finally, silencing circPVT1 repressed YAP1 and PI3K/AKT pathways via up-regulating miR-199a-5p.Conclusion: Our data suggested that silencing circPVT1 inhibited viability, migration, EGF-induced EMT and promoted apoptosis as well as repressed YAP1 and PI3K/AKT pathways by up-regulating miR-199a-5p.HIGHLIGHTSCircPVT1 expression is highly expressed in GBM tissues;Si-circPVT1 represses migration and promoted apoptosis in U539 and U251 cells;Si-circPVT1 represses migration and promoted apoptosis when elevating miR-199a-5p;Si-circPVT1 represses EGF-induced EMT when increasing miR-199a-5p;Si-circPVT1 suppresses YAP1 and PI3K/AKT pathways by up-regulating miR-199-5p.


Assuntos
Regulação da Expressão Gênica , Inativação Gênica , Glioblastoma , MicroRNAs , RNA Circular , RNA Neoplásico , Regulação para Cima , Linhagem Celular Tumoral , Feminino , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Masculino , MicroRNAs/biossíntese , MicroRNAs/genética , Metástase Neoplásica , RNA Circular/biossíntese , RNA Circular/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética
19.
Artif Cells Nanomed Biotechnol ; 48(1): 326-335, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31878795

RESUMO

Thyroid cancer is a frequently happened malignancy in human endocrine system. Papillary thyroid cancer (PTC) presents 70-80% of all thyroid cancer cases. Herein, we probed the possible oncogenic function of long non-coding RNA (lncRNA) highly up-regulated in liver cancer (HULC) in PTC. First, the HULC and microRNA-106a (miR-106a) expressions in PTC tissues and cells were tested. Plasmids or miRNAs transfections were done for altering HULC and miR-106a expressions. Then, cells viability and apoptosis, along with cell proliferative, migratory and invasive abilities, were tested, respectively. The PI3K/AKT and Wnt/ß-catenin pathways activities were measured. Finally, the animal model of PTC was constructed and the tumour volumes and weights were gauged. We discovered that HULC and miR-106a had relative high expression levels in PTC tissues and cells. HULC overexpression enhanced TPC-1 cells viability and cell proliferative, migratory and invasive abilities. Silencing HULC induced TPC-1 cell apoptosis. miR-106a engaged in the oncogenic impacts of HULC. Moreover, HULC overexpression boosted PI3K/AKT and Wnt/ß-catenin pathways activities via raising miR-106a expression. Besides, HULC overexpression enhanced the volumes and weights of PTC tumours. To sum up, HULC exhibited oncogenic function on PTC in vitro and in vivo.


Assuntos
Proliferação de Células , Regulação Neoplásica da Expressão Gênica , RNA Longo não Codificante/biossíntese , RNA Neoplásico/biossíntese , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Via de Sinalização Wnt , Linhagem Celular Tumoral , Humanos , Invasividade Neoplásica , RNA Longo não Codificante/genética , RNA Neoplásico/genética , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia
20.
Int J Radiat Oncol Biol Phys ; 106(1): 174-181, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31525407

RESUMO

PURPOSE: We aimed to study radiation-induced gene expression changes and to identify differences in gene expression between patients with and without response to radiation therapy (RT) for invasive breast cancer with the purpose of exploring whether a predictive signature could be developed. Such a signature could assist in optimizing individualized locoregional treatment. METHODS AND MATERIALS: RNA-seq using next-generation sequencing was performed on fresh frozen samples from pretreatment biopsies and post-RT surgery specimens from patients with low-risk breast cancer treated within the multicenter preoperative accelerated partial breast irradiation trial. Patients were treated with preoperative RT (10 × 4 Gy in 10 days or 5 × 6 Gy in 5 days) and a lumpectomy 6 weeks thereafter. The response of the tumor to RT was evaluated by pathologic assessment. To analyze the gene expression data, unsupervised and supervised clustering was performed. Gene expression profiles were compared between biopsies of responders and nonresponders and between samples before and after RT. RESULTS: Ninety-four samples from 77 patients were analyzed: 68 pretreatment biopsies and 26 post-RT surgery specimens. Six patients had a (near) complete pathologic response, 3 patients had a good response, 32 patients had a partial response, and 22 patients had no or very limited response. Comparing patients with and without response to RT, 25 genes were significantly differentially expressed and were not linked to a pathway. Comparison of samples before and after RT identified significant changes in gene expression. Genes involved in p53 signaling, TNFA1 signaling, apoptosis, epithelial mesenchymal transition, and inflammatory response were upregulated. Genes involved in mitotic spindle, G2M checkpoint, and E2F targets were downregulated. CONCLUSIONS: Radiation-induced gene expression changes mainly involved p53 signaling, cell cycle regulation, DNA repair, and inflammatory response. No clinically significant differences could be identified in gene expression between patients with and without response to RT.


Assuntos
Neoplasias da Mama/radioterapia , Carcinoma Ductal de Mama/radioterapia , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Terapia Neoadjuvante , RNA Neoplásico/análise , Transcriptoma , Biópsia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/cirurgia , Ensaios Clínicos Fase II como Assunto/estatística & dados numéricos , Feminino , Secções Congeladas , Perfilação da Expressão Gênica/métodos , Humanos , Mastectomia , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Medicina de Precisão , RNA Mensageiro/análise , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Tolerância a Radiação/genética , Análise de Sequência de RNA , Resultado do Tratamento
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