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1.
Wei Sheng Yan Jiu ; 49(5): 711-723, 2020 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-33070810

RESUMO

OBJECTIVE: To investigate the expression and biological significance of LINC00310 in the malignant transformation of human bronchial epithelial cells(16 HBE) induced by glycidyl methacrylate(GMA). METHODS: The 16 HBE cells recovered successfully used 1 µg/mL dimethyl sulfoxide(DMSO) as the solvent control group, and the final concentration was 8 µg/mL GMA as the treatment group, and were subcultured after repeated exposure 3 times for 72 hours each time. The 10 th, 20 th and 30 th generation cells of the GMA treatment group and corresponding DMSO control group were collected. The LncRNA microarrays was used to analyze the expression changes of LINC00310 in different periods, and the target gene and function prediction was performed by NCBI and cBioPortal bioinformatics database, and real-time quantification PCR(qPCR) was used to detect the relative expression levels of LINC00310 and predicted target genes. RESULTS: The result of the microarray showed that LINC00310 in the GMA-treated group was down-regulated by 2. 02-fold, up-regulated by 6. 17-fold, and up-regulated by 2. 03-fold in the pre-transformation, mid-term, and late, respectively. The result of qPCR confirmed that the expression of LINC00310 relative expression level of 10 th, 20 th and 30 th generation cells was consistent with the microarray result, which were down-regulated by 2. 76-fold, up-regulated by 2. 68-fold, and up-regulated by 3. 09-fold. Consistently, the relative expression of the target gene C-Myc was statistically significant in 20 th and 30 th generation cells. CONCLUSION: LINC00310 induced low expression in the early stage of malignant transformation of 16 HBE cells induced by GMA, and was highly expressed in the middle and late stages. It indicated that LINC00310 may play a cancer-promoting role in the process of cell malignant transformation through C-Myc.


Assuntos
Compostos de Epóxi , Metacrilatos , Transformação Celular Neoplásica/genética , Células Epiteliais , Compostos de Epóxi/toxicidade , Humanos , Metacrilatos/toxicidade , RNA Longo não Codificante
2.
Anticancer Res ; 40(9): 5081-5090, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878796

RESUMO

BACKGROUND/AIM: Triple negative breast cancer (TNBC) is an aggressive type of breast cancer with limited targets for chemotherapy. This study evaluated the inhibitory effects of novel imidazo[2,1-b]oxazole-based rapidly accelerated fibrosarcoma (RAF) inhibitors, KIST0215-1 and KIST0215-2, on epithelial cell transformation and TNBC tumorigenesis. MATERIALS AND METHODS: Immunoblotting, BrdU incorporation assay, reporter gene assay, and soft agar assay analyses were performed. In vivo effects were studied using the BALB/c mouse xenograft model. RESULTS: KIST0215-1 and KIST0215-2 inhibited the RAFs-MEK1/2-ERK1/2 signalling pathway induced by EGF in MDA-MB-231 cells, which inhibited c-fos transcriptional activity and activator protein-1 transactivation activity. KIST0215-1 and KIST0215-2 also prevented neoplastic transformation of JB6 C141 mouse epidermal cells induced by EGF and consistently suppressed the growth of tumours formed by 4T1 cells in BALB/c mice. CONCLUSION: Inhibition of RAF kinases using KIST0215-1 and KIST0215-2 is a promising chemotherapeutic strategy to treat TNBC.


Assuntos
Antineoplásicos/farmacologia , Transformação Celular Neoplásica/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Imidazóis/farmacologia , Neoplasias de Mama Triplo Negativas/etiologia , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/genética , Feminino , Genes Reporter , Humanos , Imidazóis/química , Camundongos , Estrutura Molecular , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Nat Commun ; 11(1): 4085, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32796935

RESUMO

Intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are non-invasive neoplasms that are often observed in association with invasive pancreatic cancers, but their origins and evolutionary relationships are poorly understood. In this study, we analyze 148 samples from IPMNs, MCNs, and small associated invasive carcinomas from 18 patients using whole exome or targeted sequencing. Using evolutionary analyses, we establish that both IPMNs and MCNs are direct precursors to pancreatic cancer. Mutations in SMAD4 and TGFBR2 are frequently restricted to invasive carcinoma, while RNF43 alterations are largely in non-invasive lesions. Genomic analyses suggest an average window of over three years between the development of high-grade dysplasia and pancreatic cancer. Taken together, these data establish non-invasive IPMNs and MCNs as origins of invasive pancreatic cancer, identifying potential drivers of invasion, highlighting the complex clonal dynamics prior to malignant transformation, and providing opportunities for early detection and intervention.


Assuntos
Progressão da Doença , Genômica , Cisto Pancreático/genética , Neoplasias Pancreáticas/genética , Carcinogênese/genética , Transformação Celular Neoplásica/genética , Exoma/genética , Dosagem de Genes , Humanos , Mutação , Cisto Pancreático/patologia , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Proteína Smad4/genética
4.
Nat Commun ; 11(1): 3945, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32770028

RESUMO

TP53 missense mutations leading to the expression of mutant p53 oncoproteins are frequent driver events during tumorigenesis. p53 mutants promote tumor growth, metastasis and chemoresistance by affecting fundamental cellular pathways and functions. Here, we demonstrate that p53 mutants modify structure and function of the Golgi apparatus, culminating in the increased release of a pro-malignant secretome by tumor cells and primary fibroblasts from patients with Li-Fraumeni cancer predisposition syndrome. Mechanistically, interacting with the hypoxia responsive factor HIF1α, mutant p53 induces the expression of miR-30d, which in turn causes tubulo-vesiculation of the Golgi apparatus, leading to enhanced vesicular trafficking and secretion. The mut-p53/HIF1α/miR-30d axis potentiates the release of soluble factors and the deposition and remodeling of the ECM, affecting mechano-signaling and stromal cells activation within the tumor microenvironment, thereby enhancing tumor growth and metastatic colonization.


Assuntos
Neoplasias da Mama/genética , Transformação Celular Neoplásica/genética , Complexo de Golgi/patologia , Síndrome de Li-Fraumeni/genética , MicroRNAs/metabolismo , Proteína Supressora de Tumor p53/genética , Animais , Biópsia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica/metabolismo , Feminino , Fibroblastos , Regulação Neoplásica da Expressão Gênica , Complexo de Golgi/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Síndrome de Li-Fraumeni/patologia , Camundongos , Microtúbulos/metabolismo , Microtúbulos/patologia , Mutação , Cultura Primária de Células , Vesículas Secretórias/metabolismo , Vesículas Secretórias/patologia , Transdução de Sinais/genética , Pele/citologia , Pele/patologia , Microambiente Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Gene ; 761: 145028, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-32763490

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignancies and inflicts high mortality worldwide. The effect of tumor microenvironment components on HCC oncogenesis remains unknown. In particular, the nonleukocyte portion of the stromal fraction (SF) is poorly understood. METHODS: We comprehensively evaluated the proportional cell counts and gene expression data from The Cancer Genome Atlas (TCGA) to examine the contributions of cell components to the tumor microenvironment. Single-cell sequencing data from the Gene Expression Omnibus (GEO) were also analyzed to verify the association between the nonleukocyte SF and genes. We classified HCC using a hierarchical clustering method based on diversity of nonleukocyte SF-related gene expression among different components, and we used an appropriate GEO dataset to verify the clusters with a support vector machine (SVM) model. The prognosis of subtypes and their relationship with tumor microenvironmental cell proportions, clinicopathogenesis factors, and other indicators were evaluated. RESULTS: Based on linear regression, 711 genes related to nonleukocyte SF were selected from the TCGA dataset. We classified HCC into three subtypes using genes related to the nonleukocyte SF. Additionally, the GEO single-cell sequencing data confirmed the relationship between genes and the nonleukocyte SF. The tumor microenvironment of Type 2 contained the most significant mutually reinforcing interaction between the nonleukocyte SF and tumor cells. Meanwhile, Type 2 patients had the poorest prognosis and the most severe tumor-node-metastasis (TNM) stages, histological grades, etc. The analysis based on the GEO dataset verified the classification results with an SVM model. Type 2 was associated with worse clinicopathological characteristics, including tumor grading and staging, than the other types. In addition, the pathway analysis revealed that signals related to the SF and cell proliferation were significantly enhanced in Type 2 compared to the other group, which consisted of Types 1 and 3. CONCLUSION: The nonleukocyte SF in the tumor microenvironment contributed greatly to HCC oncogenesis. We can use these HCC classification criteria to stratify patients into subtypes for personalized treatment.


Assuntos
Carcinoma Hepatocelular/genética , Células Estromais/metabolismo , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica/genética , Bases de Dados Genéticas , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Genômica , Humanos , Neoplasias Hepáticas/genética , Masculino , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Microambiente Tumoral/genética
6.
J Clin Pathol ; 73(10): 611-615, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32727816

RESUMO

Isocitrate dehydrogenase 1 (IDH1) encodes a protein which catalyses the oxidative decarboxylation of isocitrate to α-ketoglutarate. Mutant IDH1 favours the production of 2-hydroxyglutarate, an oncometabolite with multiple downstream effects which promote tumourigenesis. IDH1 mutations have been described in a number of neoplasms most notably low-grade diffuse gliomas, conventional central and periosteal cartilaginous tumours and cytogenetically normal acute myeloid leukaemia. Post zygotic somatic mutations of IDH1 characterise the majority of cases of Ollier disease and Maffucci syndrome. IDH1 mutations are uncommon in epithelial neoplasia but have been described in cholangiocarcinoma.


Assuntos
Isocitrato Desidrogenase/fisiologia , Neoplasias/genética , Carcinogênese/genética , Transformação Celular Neoplásica/genética , Predisposição Genética para Doença/genética , Humanos
7.
PLoS One ; 15(6): e0234566, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32603365

RESUMO

Hashimoto's thyroiditis (HT) is present in the background of around 30% of papillary thyroid carcinomas (PTCs). The genetic predisposition effect of this autoimmune condition is not thoroughly understood. We analyzed the microarray expression profiles of 13 HT, eight PTCs with (w/) coexisting HT, six PTCs without (w/o) coexisting HT, six micro PTCs (mPTCs), and three normal thyroid (TN) samples. Based on a false discovery rate (FDR)-adjusted p-value ≤ 0.05 and a fold change (FC) > 2, four comparison groups were defined, which were HT vs. TN; PTC w/ HT vs. TN; PTC w/o HT vs. TN; and mPTC vs. TN. A Venn diagram displayed 15 different intersecting and non-intersecting differentially expressed gene (DEG) sets, of which a set of 71 DEGs, shared between the two comparison groups HT vs. TN ∩ PTC w/ HT vs. TN, harbored the relatively largest number of genes related to immune and inflammatory functions; oxidative stress and reactive oxygen species (ROS); DNA damage and DNA repair; cell cycle; and apoptosis. The majority of the 71 DEGs were upregulated and the most upregulated DEGs included a number of immunoglobulin kappa variable genes, and other immune-related genes, e.g., CD86 molecule (CD86), interleukin 2 receptor gamma (IL2RG), and interferon, alpha-inducible protein 6 (IFI6). Upregulated genes preferentially associated with other gene ontologies (GO) were, e.g., STAT1, MMP9, TOP2A, and BRCA2. Biofunctional analysis revealed pathways related to immunogenic functions. Further data analysis focused on the set of non-intersecting 358 DEGs derived from the comparison group of HT vs. TN, and on the set of 950 DEGs from the intersection of all four comparison groups. In conclusion, this study indicates that, besides immune/inflammation-related genes, also genes associated with oxidative stress, ROS, DNA damage, DNA repair, cell cycle, and apoptosis are comparably more deregulated in a data set shared between HT and PTC w/ HT. These findings are compatible with the conception of a genetic sequence where chronic inflammatory response is accompanied by deregulation of genes and biofunctions associated with oncogenic transformation. The generated data set may serve as a source for identifying candidate genes and biomarkers that are practical for clinical application.


Assuntos
Perfilação da Expressão Gênica , Doença de Hashimoto/genética , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Adolescente , Adulto , Idoso , Transformação Celular Neoplásica/genética , Feminino , Predisposição Genética para Doença , Doença de Hashimoto/complicações , Humanos , Inflamação/genética , Masculino , Pessoa de Meia-Idade , Câncer Papilífero da Tireoide/complicações , Neoplasias da Glândula Tireoide/complicações , Regulação para Cima
8.
Nat Commun ; 11(1): 3715, 2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32709844

RESUMO

Esophageal squamous cell carcinoma (ESCC) is prevalent in some geographical regions of the world. ESCC development presents a multistep pathogenic process from inflammation to invasive cancer; however, what is critical in these processes and how they evolve is largely unknown, obstructing early diagnosis and effective treatment. Here, we create a mouse model mimicking human ESCC development and construct a single-cell ESCC developmental atlas. We identify a set of key transitional signatures associated with oncogenic evolution of epithelial cells and depict the landmark dynamic tumorigenic trajectories. An early downregulation of CD8+ response against the initial tissue damage accompanied by the transition of immune response from type 1 to type 3 results in accumulation and activation of macrophages and neutrophils, which may create a chronic inflammatory environment that promotes carcinogen-transformed epithelial cell survival and proliferation. These findings shed light on how ESCC is initiated and developed.


Assuntos
Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Regulação Neoplásica da Expressão Gênica , Análise de Célula Única/métodos , Transcriptoma , Animais , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Células Epiteliais/patologia , Neoplasias Esofágicas/imunologia , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T , Fatores de Transcrição , Microambiente Tumoral
9.
Nat Commun ; 11(1): 3696, 2020 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-32728046

RESUMO

ENCODE comprises thousands of functional genomics datasets, and the encyclopedia covers hundreds of cell types, providing a universal annotation for genome interpretation. However, for particular applications, it may be advantageous to use a customized annotation. Here, we develop such a custom annotation by leveraging advanced assays, such as eCLIP, Hi-C, and whole-genome STARR-seq on a number of data-rich ENCODE cell types. A key aspect of this annotation is comprehensive and experimentally derived networks of both transcription factors and RNA-binding proteins (TFs and RBPs). Cancer, a disease of system-wide dysregulation, is an ideal application for such a network-based annotation. Specifically, for cancer-associated cell types, we put regulators into hierarchies and measure their network change (rewiring) during oncogenesis. We also extensively survey TF-RBP crosstalk, highlighting how SUB1, a previously uncharacterized RBP, drives aberrant tumor expression and amplifies the effect of MYC, a well-known oncogenic TF. Furthermore, we show how our annotation allows us to place oncogenic transformations in the context of a broad cell space; here, many normal-to-tumor transitions move towards a stem-like state, while oncogene knockdowns show an opposing trend. Finally, we organize the resource into a coherent workflow to prioritize key elements and variants, in addition to regulators. We showcase the application of this prioritization to somatic burdening, cancer differential expression and GWAS. Targeted validations of the prioritized regulators, elements and variants using siRNA knockdowns, CRISPR-based editing, and luciferase assays demonstrate the value of the ENCODE resource.


Assuntos
Bases de Dados Genéticas , Genômica , Neoplasias/genética , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Redes Reguladoras de Genes , Humanos , Mutação/genética , Reprodutibilidade dos Testes , Fatores de Transcrição/metabolismo
10.
Adv Cancer Res ; 148: 1-26, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32723561

RESUMO

As a unique subpopulation of cancer cells, cancer stem cells (CSCs) acquire the resistance to conventional therapies and appear to be the prime cause of cancer recurrence. Like their normal counterparts, CSCs can renew themselves and generate differentiated progenies. Cancer stem cells are distinguished among heterogenous cancer cells by molecular markers and their capacity of efficiently forming new tumors composed of diverse and heterogenous cancer cells. Tumor heterogeneity can be inter- or intra-tumor, molecularly resulting from the accumulation of genetic and non-genetic alterations. Non-genetic alterations are mainly changes on epigenetic modifications of DNA and histone, and chromatin remodeling. As tumor-initiating cells and contributing to the tumor heterogeneity in the brain, glioblastoma stem cells (GSCs) attract extensive research interests. Epigenetic modifications confer on tumor cells including CSCs reversible and inheritable genomic changes and affect gene expression without alteration in DNA sequence. Here, we will review recent advances in histone demethylation, DNA methylation, RNA methylation and ubiquitination in glioblastomas and their impacts on tumorigenesis with a focus on CSCs.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Transformação Celular Neoplásica/patologia , Glioblastoma/genética , Glioblastoma/patologia , Células-Tronco Neoplásicas/patologia , Animais , Neoplasias Encefálicas/metabolismo , Transformação Celular Neoplásica/genética , Metilação de DNA , Epigênese Genética , Glioblastoma/metabolismo , Humanos , Células-Tronco Neoplásicas/metabolismo
11.
Adv Cancer Res ; 148: 171-199, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32723563

RESUMO

Cancer is a complex disease with high incidence and mortality rates. The important role played by the tumor microenvironment in regulating oncogenesis, tumor growth, and metastasis is by now well accepted in the scientific community. SPARC is known to participate in tumor-stromal interactions and impact cancer growth in ambiguous ways, which either enhance or suppress cancer aggressiveness, in a context-dependent manner. p53 transcription factor, a well-established tumor suppressor, has been reported to promote tumor growth in certain situations, such as hypoxia, thus displaying a duality in its action. Although both proteins are being tested in clinical trials, the synergistic relation between them is yet to be explored in clinical practice. In this review, we address the controversial roles of SPARC and p53 as double agents in cancer, briefly summarizing the interaction found between these two molecules and its importance in cancer.


Assuntos
Neoplasias/metabolismo , Neoplasias/patologia , Osteonectina/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Humanos , Neoplasias/genética , Osteonectina/genética , Proteína Supressora de Tumor p53/genética
12.
Nat Commun ; 11(1): 3671, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32699299

RESUMO

Epigenetic reprogramming is a cancer hallmark, but how it unfolds during early neoplastic events and its role in carcinogenesis and cancer progression is not fully understood. Here we show that resetting from primed to naïve human pluripotency results in acquisition of a DNA methylation landscape mirroring the cancer DNA methylome, with gradual hypermethylation of bivalent developmental genes. We identify a dichotomy between bivalent genes that do and do not become hypermethylated, which is also mirrored in cancer. We find that loss of H3K4me3 at bivalent regions is associated with gain of methylation. Additionally, we observe that promoter CpG island hypermethylation is not restricted solely to emerging naïve cells, suggesting that it is a feature of a heterogeneous intermediate population during resetting. These results indicate that transition to naïve pluripotency and oncogenic transformation share common epigenetic trajectories, which implicates reprogramming and the pluripotency network as a central hub in cancer formation.


Assuntos
Transformação Celular Neoplásica/genética , Reprogramação Celular , Metilação de DNA , Epigênese Genética , Neoplasias/genética , Animais , Linhagem Celular , Técnicas de Cocultura , Ilhas de CpG/genética , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Fibroblastos , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Células HEK293 , Histonas/genética , Histonas/metabolismo , Células-Tronco Embrionárias Humanas , Humanos , Camundongos , Oxigenases de Função Mista/genética , Oxigenases de Função Mista/metabolismo , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , RNA Interferente Pequeno/metabolismo
13.
J Vis Exp ; (160)2020 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-32658189

RESUMO

Many cancers are characterized by chromosomal translocations which result in the expression of oncogenic fusion transcription factors. Typically, these proteins contain an intrinsically disordered domain (IDD) fused with the DNA-binding domain (DBD) of another protein and orchestrate widespread transcriptional changes to promote malignancy. These fusions are often the sole recurring genomic aberration in the cancers they cause, making them attractive therapeutic targets. However, targeting oncogenic transcription factors requires a better understanding of the mechanistic role that low-complexity, IDDs play in their function. The N-terminal domain of EWSR1 is an IDD involved in a variety of oncogenic fusion transcription factors, including EWS/FLI, EWS/ATF, and EWS/WT1. Here, we use RNA-sequencing to investigate the structural features of the EWS domain important for transcriptional function of EWS/FLI in Ewing sarcoma. First shRNA-mediated depletion of the endogenous fusion from Ewing sarcoma cells paired with ectopic expression of a variety of EWS-mutant constructs is performed. Then RNA-sequencing is used to analyze the transcriptomes of cells expressing these constructs to characterize the functional deficits associated with mutations in the EWS domain. By integrating the transcriptomic analyses with previously published information about EWS/FLI DNA binding motifs, and genomic localization, as well as functional assays for transforming ability, we were able to identify structural features of EWS/FLI important for oncogenesis and define a novel set of EWS/FLI target genes critical for Ewing sarcoma. This paper demonstrates the use of RNA-sequencing as a method to map the structure-function relationship of the intrinsically disordered domain of oncogenic transcription factors.


Assuntos
Perfilação da Expressão Gênica , Proteínas de Fusão Oncogênica/química , Proteínas de Fusão Oncogênica/metabolismo , Proteína Proto-Oncogênica c-fli-1/química , Proteína Proto-Oncogênica c-fli-1/metabolismo , Proteína EWS de Ligação a RNA/química , Proteína EWS de Ligação a RNA/metabolismo , Relação Estrutura-Atividade , Sítios de Ligação , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Humanos , Mutação , Proteínas de Fusão Oncogênica/genética , Domínios Proteicos , Proteína Proto-Oncogênica c-fli-1/genética , Proteína EWS de Ligação a RNA/genética , Sarcoma de Ewing/genética , Sarcoma de Ewing/metabolismo , Sarcoma de Ewing/patologia
14.
Nat Commun ; 11(1): 2717, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32483112

RESUMO

Somatic inactivating mutations of ARID1A, a SWI/SNF chromatin remodeling gene, are prevalent in human endometrium-related malignancies. To elucidate the mechanisms underlying how ARID1A deleterious mutation contributes to tumorigenesis, we establish genetically engineered murine models with Arid1a and/or Pten conditional deletion in the endometrium. Transcriptomic analyses on endometrial cancers and precursors derived from these mouse models show a close resemblance to human uterine endometrioid carcinomas. We identify transcriptional networks that are controlled by Arid1a and have an impact on endometrial tumor development. To verify findings from the murine models, we analyze ARID1AWT and ARID1AKO human endometrial epithelial cells. Using a system biology approach and functional studies, we demonstrate that ARID1A-deficiency lead to loss of TGF-ß tumor suppressive function and that inactivation of ARID1A/TGF-ß axis promotes migration and invasion of PTEN-deleted endometrial tumor cells. These findings provide molecular insights into how ARID1A inactivation accelerates endometrial tumor progression and dissemination, the major causes of cancer mortality.


Assuntos
Carcinogênese/genética , Carcinoma Endometrioide/genética , Reprogramação Celular/genética , Proteínas de Ligação a DNA/genética , Neoplasias do Endométrio/genética , Fatores de Transcrição/genética , Animais , Carcinogênese/metabolismo , Carcinoma Endometrioide/metabolismo , Carcinoma Endometrioide/patologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Células Cultivadas , Proteínas de Ligação a DNA/metabolismo , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Endométrio/citologia , Endométrio/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Camundongos da Linhagem 129 , Camundongos Endogâmicos BALB C , Camundongos Knockout , Camundongos Transgênicos , Mutação , Fatores de Transcrição/metabolismo
15.
Nat Commun ; 11(1): 2711, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32483135

RESUMO

p16INK4a (CDKN2A) is a central tumor suppressor, which induces cell-cycle arrest and senescence. Cells expressing p16INK4a accumulate in aging tissues and appear in premalignant lesions, yet their physiologic effects are poorly understood. We found that prolonged expression of transgenic p16INK4a in the mouse epidermis induces hyperplasia and dysplasia, involving high proliferation rates of keratinocytes not expressing the transgene. Continuous p16INK4a expression increases the number of epidermal papillomas formed after carcinogen treatment. Wnt-pathway ligands and targets are activated upon prolonged p16INK4a expression, and Wnt inhibition suppresses p16INK4a-induced hyperplasia. Senolytic treatment reduces p16INK4a-expressing cell numbers, and inhibits Wnt activation and hyperplasia. In human actinic keratosis, a precursor of squamous cell carcinoma, p16INK4a-expressing cells are found adjacent to dividing cells, consistent with paracrine interaction. These findings reveal that chronic p16INK4a expression is sufficient to induce hyperplasia through Wnt-mediated paracrine stimulation, and suggest that this tumor suppressor can promote early premalignant epidermal lesion formation.


Assuntos
Transformação Celular Neoplásica/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Epiderme/metabolismo , Via de Sinalização Wnt/genética , Animais , Proliferação de Células/genética , Transformação Celular Neoplásica/metabolismo , Células Cultivadas , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Humanos , Hiperplasia/genética , Hiperplasia/metabolismo , Queratinócitos/metabolismo , Ceratose/genética , Ceratose/metabolismo , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Papiloma/genética , Papiloma/metabolismo , Papiloma/patologia
16.
Gene ; 754: 144839, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32504654

RESUMO

Wilms tumor is the most frequently occurring pediatric renal malignancy. Wilms tumor suppressor-1-associated protein (WTAP) is a vital component of N6-methyltransferase complex involved in tumorigenesis. However, the roles of WTAP gene single nucleotide polymorphisms (SNPs) in Wilms tumor risk have not been clarified to date. We successfully genotyped three WTAP gene SNPs using TaqMan assay in 405 Wilms tumor patients and 1197 cancer-free controls of Chinese children. Odds ratios (ORs) and 95% confidence intervals (CIs) were applied to determine the effects of WTAP gene SNPs on Wilms tumor risk. Carriers of the rs1853259 G variant are less susceptible to developing Wilms tumor, with an adjusted OR of 0.78 (AG vs. AA: 95% CI = 0.61-0.995, P = 0.046). Single locus analysis of rs9457712 G > A and rs7766006 G > T, as well as the combined analysis of risk genotypes, failed to unveil an association with Wilms tumor risk, respectively. Stratified analysis of the three SNPs and their combined risk effects showed more significant relationships with Wilms tumor risk under certain subgroups. In all, we found weak evidence of the association between WTAP gene SNPs and the risk of Wilms tumor. Further replication studies with greater sample size and different ethnicities are necessary to verify our findings.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Proteínas de Ciclo Celular/genética , Transformação Celular Neoplásica/genética , Neoplasias Renais/genética , Polimorfismo de Nucleotídeo Único , Fatores de Processamento de RNA/genética , Tumor de Wilms/genética , Estudos de Casos e Controles , Transformação Celular Neoplásica/patologia , China/epidemiologia , Feminino , Seguimentos , Predisposição Genética para Doença , Genótipo , Humanos , Lactente , Neoplasias Renais/epidemiologia , Neoplasias Renais/patologia , Masculino , Prognóstico , Tumor de Wilms/epidemiologia , Tumor de Wilms/patologia
17.
Cancer Sci ; 111(9): 3089-3099, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32579791

RESUMO

The telomere is the specialized nucleoprotein complex at the end of the chromosome. Its highly conserved 5'-TTAGGG-3' repeats and shelterin protein complexes form a protective loop structure to maintain the integrity and stability of linear chromosomes. Although human somatic cells gradually shorten telomeres to undergo senescence or crisis, cancer cells activate telomerase, or the recombination-based mechanism to maintain telomeres and exhibit immortality. As the most frequent non-coding mutations in cancer, gain-of-function mutations in the promoter region of the telomerase catalytic subunit, TERT, trigger telomerase activation. Promoter methylation and copy number gain are also associated with the enhanced TERT expression. Although telomerase inhibitors were pioneered from telomere-directed therapeutics, their efficacies are limited to cancer with short telomeres and some hematological malignancies. Other therapeutic approaches include a nucleoside analog incorporated to telomeres and TERT promoter-driven oncolytic adenoviruses. Tankyrase poly(ADP-ribose) polymerase, a positive regulator of telomerase, has been rediscovered as a target for Wnt-driven cancer. Meanwhile, telomeric nucleic acids form a higher-order structure called a G-quadruplex (G4). G4s are formed genome-wide and their dynamics affect various events, including replication, transcription, and translation. G4-stabilizing compounds (G4 ligands) exert anticancer effects and are in clinical investigations. Collectively, telomere biology has provided clues for deeper understanding of cancer, which expands opportunities to discover innovative anticancer drugs.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Telômero/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Transformação Celular Neoplásica/genética , Quadruplex G/efeitos dos fármacos , Terapia Genética , Humanos , Ligantes , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Terapia Viral Oncolítica , Regiões Promotoras Genéticas , RNA não Traduzido/genética , Telomerase/genética , Telomerase/metabolismo , Telômero/genética , Encurtamento do Telômero/efeitos dos fármacos
18.
Nat Commun ; 11(1): 3231, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32591511

RESUMO

Genomic instability (GI) predisposes cells to malignant transformation, however the molecular mechanisms that allow for the propagation of cells with a high degree of genomic instability remain unclear. Here we report that miR-181a is able to transform fallopian tube secretory epithelial cells through the inhibition of RB1 and stimulator-of-interferon-genes (STING) to propagate cells with a high degree of GI. MiR-181a targeting of RB1 leads to profound nuclear defects and GI generating aberrant cytoplasmic DNA, however simultaneous miR-181a mediated inhibition of STING allows cells to bypass interferon mediated cell death. We also found that high miR-181a is associated with decreased IFNγ response and lymphocyte infiltration in patient tumors. DNA oncoviruses are the only known inhibitors of STING that allow for cellular transformation, thus, our findings are the first to identify a miRNA that can downregulate STING expression to suppress activation of intrinsic interferon signaling. This study introduces miR-181a as a putative biomarker and identifies the miR-181a-STING axis as a promising target for therapeutic exploitation.


Assuntos
Carcinogênese/genética , Transformação Celular Neoplásica/genética , Imunidade Inata/genética , MicroRNAs/metabolismo , Transdução de Sinais , Animais , Linhagem Celular Tumoral , Núcleo Celular/patologia , Transformação Celular Neoplásica/patologia , Citocinese , Dano ao DNA , Células Epiteliais/patologia , Tubas Uterinas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Instabilidade Genômica , Células HEK293 , Humanos , Interferons/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , MicroRNAs/genética , Mitose , Gradação de Tumores , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo
19.
Proc Natl Acad Sci U S A ; 117(24): 13447-13456, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32482854

RESUMO

Precisely controlling the activation of transcription factors is crucial for physiology. After a transcription factor is activated and carries out its transcriptional activity, it also needs to be properly deactivated. Here, we report a deactivation mechanism of HIF-1 and several other oncogenic transcription factors. HIF-1 promotes the transcription of an ADP ribosyltransferase, TiPARP, which serves to deactivate HIF-1. Mechanistically, TiPARP forms distinct nuclear condensates or nuclear bodies in an ADP ribosylation-dependent manner. The TiPARP nuclear bodies recruit both HIF-1α and an E3 ubiquitin ligase HUWE1, which promotes the ubiquitination and degradation of HIF-1α. Similarly, TiPARP promotes the degradation of c-Myc and estrogen receptor. By suppressing HIF-1α and other oncogenic transcription factors, TiPARP exerts strong antitumor effects both in cell culture and in mouse xenograft models. Our work reveals TiPARP as a negative-feedback regulator for multiple oncogenic transcription factors, provides insights into the functions of protein ADP-ribosylation, and suggests activating TiPARP as an anticancer strategy.


Assuntos
Núcleo Celular/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Supressoras de Tumor/metabolismo , ADP-Ribosilação , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Receptor alfa de Estrogênio/metabolismo , Retroalimentação Fisiológica , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Camundongos , Poli(ADP-Ribose) Polimerases/química , Poli(ADP-Ribose) Polimerases/genética , Domínios e Motivos de Interação entre Proteínas , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Supressoras de Tumor/química , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
20.
Cancer Sci ; 111(9): 3195-3209, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32369664

RESUMO

Gastric cancer (GC) is one of the deadliest cancers worldwide, and the progression of gastric carcinogenesis (GCG) covers multiple complicated pathological stages. Molecular mechanisms of GCG are still unclear. Here, we undertook NMR-based metabolomic analysis of aqueous metabolites extracted from gastric tissues in an established rat model of GCG. We showed that the metabolic profiles were clearly distinguished among 5 histologically classified groups: control, gastritis, low-grade gastric dysplasia, high-grade gastric dysplasia (HGD), and GC. Furthermore, we carried out metabolic pathway analysis based on identified significant metabolites and revealed significantly disturbed metabolic pathways closely associated with the 4 pathological stages, including oxidation stress, choline phosphorylation, amino acid metabolism, Krebs cycle, and glycolysis. Three metabolic pathways were continually disturbed during the progression of GCG, including taurine and hypotaurine metabolism, glutamine and glutamate metabolism, alanine, aspartate, and glutamate metabolism. Both the Krebs cycle and glycine, serine, and threonine metabolism were profoundly impaired in both the HGD and GC stages, potentially due to abnormal energy supply for tumor cell proliferation and growth. Furthermore, valine, leucine, and isoleucine biosynthesis and glycolysis were significantly disturbed in the GC stage for higher energy requirement of the rapid growth of tumor cells. Additionally, we identified potential gastric tissue biomarkers for metabolically discriminating the 4 pathological stages, which also showed good discriminant capabilities for their serum counterparts. This work sheds light on the molecular mechanisms of GCG and is of benefit to the exploration of potential biomarkers for clinically diagnosing and monitoring the progression of GCG.


Assuntos
Transformação Celular Neoplásica/metabolismo , Espectroscopia de Ressonância Magnética , Metabolômica , Neoplasias Gástricas/etiologia , Neoplasias Gástricas/metabolismo , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Modelos Animais de Doenças , Suscetibilidade a Doenças , Metabolismo Energético , Humanos , Espectroscopia de Ressonância Magnética/métodos , Redes e Vias Metabólicas , Metaboloma , Metabolômica/métodos , Ratos , Neoplasias Gástricas/diagnóstico , Ensaios Antitumorais Modelo de Xenoenxerto
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