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1.
Gene ; 766: 145163, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-32980450

RESUMO

BACKGROUND: Cardia adenocarcinoma (CA) is a distinct form of gastric cancer, and the optimal means of treating it remains controversial. At present, the role of the condensation complex gene non-SMC condensin I complex subunit G (NCAPG) in CA is uncertain, and as such the present study was designed to elucidate its importance in this oncogenic context. METHODS: We first used bioinformatics approaches to assess NCAPG expression profiles in CA using public databases. Protein profiling was also used to examine the expression of this protein in CA tumors and adjacent tissues from 20 patients. Then the expression of NCAPG in CA samples was quantified via qRT-PCR and Western blotting. NCAPG knockdown and overexpression in the SGC-7901 and AGS cell lines were subsequently performed, after which the expression of key proteins associated with epithelial-mesenchymal transition (EMT; E-cadherin, vimentin, N-cadherin, Snail, Slug) and the regulation of apoptotic responses (caspase-3, Bax, Bcl-2) was measured. The mechanistic role of NCAPG in CA was additionally studied by analyzing proteins associated with Wnt/ß-catenin signaling including Wnt1, phosphorylated GSK3ß, ß-catenin, and phosphorylated ß- catenin. The impact of NCAPG on the migration, survival, and invasion of CA cells was further examined. RESULTS: CA samples exhibited high NCAPG expression. When this gene was overexpressed in cell lines, it reduced caspase-3, Bax, and E-cadherin levels whereas it elevated Bcl-2, vimentin, N-cadherin, Snail, and Slug levels. NCAPG overexpression also resulted in the enhanced expression of Wnt1, phosphorylated GSK3ß, and total ß-catenin and the reduced expression of phosphorylated ß-catenin. The knockdown of NCAPG, in contrast, yielded the opposite phenotype. At a functional level, the overexpression of NCAPG improved the apoptotic resistance of CA cells while driving them to undergo EMT and to become more invasive and migratory. CONCLUSIONS: NCAPG overexpression can promote EMT and suppress tumor cell apoptosis via the activation of Wnt/ß-catenin signaling.


Assuntos
Adenocarcinoma/genética , Apoptose/genética , Cárdia/patologia , Proteínas de Ciclo Celular/genética , Transição Epitelial-Mesenquimal/genética , Neoplasias Gástricas/genética , Via de Sinalização Wnt/genética , beta Catenina/genética , Adenocarcinoma/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Oncogenes/genética , Neoplasias Gástricas/patologia , Vimentina/genética
2.
Adv Exp Med Biol ; 1287: 155-168, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33034031

RESUMO

Thyroid cancer is the most common malignancy of the endocrine system with a steadily rising incidence. The term "thyroid cancer" encompasses a spectrum of subtypes, namely papillary thyroid cancer, follicular thyroid cancer, anaplastic thyroid cancer, and medullary thyroid cancer. Each subtype differs histopathologically and in degrees of cellular differentiation, which may be in part due to signaling of the Notch pathway. The Notch pathway is an evolutionarily conserved signal transduction mechanism that regulates cell proliferation, differentiation, survival, stem cell maintenance, embryonic and adult development, epithelial-mesenchymal transition, and angiogenesis. Its role in cancer biology is controversial, as it has been shown to play both an oncogenic and tumor-suppressive role in many different types of cancers. This discordance holds true for each subtype of thyroid cancer, indicating that Notch signaling is likely cell type and context dependent. Whether oncogenic or not, Notch signaling has proven to be significantly involved in the tumorigenesis of thyroid cancer and has thus earned interest as a therapeutic target. Advancement in the understanding of Notch signaling in thyroid cancer holds great promise for the development of novel treatment strategies to benefit patients.


Assuntos
Receptores Notch/metabolismo , Transdução de Sinais , Neoplasias da Glândula Tireoide/metabolismo , Humanos , Oncogenes , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia
3.
Adv Exp Med Biol ; 1287: 169-181, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33034032

RESUMO

The Notch signaling pathway controls normal embryonic development and tissue homeostasis of many cell types. It regulates cell proliferation, fate, differentiation, and cell death by short-range signaling between nearby cells that come in contact. The Notch pathway has also been critically involved in the pathobiology of a variety of malignancies, regulating cancer initiation and development, as well as early stages of cancer progression, by adjusting conserved cellular programs. Fibroblasts, an essential for tumor growth component of stroma, have also been affected by Notch regulation. Sequencing Notch gene mutations have been identified in a number of human tumors, revealing information on the progression of specific cancer types, such as ovarian cancer and melanoma, immune-associated tumors such as myeloid neoplasms, but especially in lymphocytic leukemia. Activation of the Notch can be either oncogenic or it may contain growth-suppressive functions, acting as a tumor suppressor in other hematopoietic cells, hepatocytes, skin, and pancreatic epithelium.


Assuntos
Progressão da Doença , Neoplasias/patologia , Receptores Notch , Transdução de Sinais , Genes Supressores de Tumor , Humanos , Neoplasias/genética , Oncogenes , Receptores Notch/metabolismo
4.
Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi ; 38(10): 721-725, 2020 Oct 20.
Artigo em Chinês | MEDLINE | ID: mdl-33142371

RESUMO

Objective: To study the effect of p38 mitogen-activated protein kinase (MAPK) gene silencing on expression of apoptotic genes and oncogenes in hepatocytes treated with PM(2.5). Methods: From June to September 2019, according to the p38MAPK gene mRNA sequence provided by GenBank, three interfering sequences were designed and synthesized, ligated into PLVX-shRNA2-puro after annealing, and the recombinant lentiviral vector was transfected into L02 hepatocytes. The p38MAPK silencing cells were identified by real-time fluorescent quantitative PCR and western blotting. The normal L02 cells and p38MAPK silencing cells were treated with 50 µg/mL PM(2.5) water soluble solution, 10 µmol/L positive control Cr(6+), and a blank control group was set up, the treatment time was 24 h. The mRNA levels of oncogenes (c-fos, c-myc, k-ras) , tumor suppressor gene (p53) and apoptotic genes (Caspase-3, Caspase-8, Caspase-9) were detected by real-time PCR. The protein levels of oncogenes and apoptotic genes were detected by Western blotting. Results: The expression levels of p38MAPK mRNA and protein in p38MAPK gene silencing cells were significantly lower than those in L02 hepatocytes (P<0.05) , and the p38MAPK gene silencing cell line was successfully constructed. Compared with the blank control group, the expression levels of the oncogenes c-fos, c-myc, k-ras and the apoptosis genes Caspase-3, Caspase-8 and Caspase-9 increased, the expression level of tumor suppressor gene p53 decreased in the L02 hepatocyte group treated with PM(2.5) water soluble matter, and the differences were statistically significant (P<0.05) . Compared with the L02 hepatocytes group treated with PM(2.5) water soluble matter, the expression levels of the oncogenes c-fos, c-myc, k-ras and apoptosis genes Caspase-3, Caspase-8 and Caspase-9 decreased, the expression level of tumor suppressor gene p53 increased in the p38MAPK gene silencing cells group treated with PM(2.5) water soluble matter, and the differences were statistically significant (P<0.05) . Conclusion: PM(2.5) has effects on the expression of oncogenes, tumor suppressor genes and apoptotic genes in L02 hepatocytes, while p38MAPK gene silencing can inhibit the effects of PM(2.5) on L02 hepatocytes.


Assuntos
Hepatócitos , Oncogenes , Apoptose , Inativação Gênica , Humanos , Material Particulado
5.
Anticancer Res ; 40(11): 6009-6015, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33109539

RESUMO

Cancer is a medical condition which has a molecular basis. Proto-oncogenes are the first regulatory factors of this biological process. They act in transmitting signals, resulting as growth factors. Modifications of these genes, called oncogenes, lead to the appearance of cancer cells. The activation process leading to proto-oncogenes are chromosomal translocation, point mutation, and gene amplification. Concerning the clonal theory of oncogenesis, it is believed that a tumor starts from a cell. Furthermore, there is close association between tumor development and inhibition of apoptosis or programmed cell death, providing cell immortality. Angiogenesis and angiogenic factors found to be expressed in tumors and may play a key role in tumor formation and development. Tumor-suppressor genes block the growth of cancer and contribute to the normal development of cells. This article highlights the evidence that neoplasms develop as the after-effect of the increase of acquired and physical genetic variations in proto-oncogenes and tumor-suppressor genes; these form a target group in the cells of neoplasms. Tumor formation and development are characterized by individual processes, working synergistically, and an understanding of each individual process may provide a better basis for further anticancer research.


Assuntos
Carcinogênese/genética , Genes Supressores de Tumor , Oncogenes , Apoptose/genética , Humanos , Neoplasias/irrigação sanguínea , Neoplasias/genética , Neovascularização Patológica/genética
6.
Artigo em Chinês | MEDLINE | ID: mdl-33036527

RESUMO

Objective: To construct the c-myc gene silenced hepatocytes, study the effect of c-myc gene silence on expression of oncogenes and apoptosis genes in hepatocytes treated with PM2.5. Methods: According to the c-myc gene mRNA sequence provided by GenBank, three interfering sequences were designed and synthesized, the recombinant lentiviral vector was transfected into L02 hepatocytes. The real-time quantitative PCR and western blotting were used to identify the effect of c-myc gene silencing. L02 cells and c-myc gene silenced cells were used as experimental subjects. The normal L02 cells and c-myc silenced cells were treated with 50 µg/ml PM(2.5) water soluble solution, 10 µM positive control Cr(6+) and a blank control, the treatment period was 24 h. The mRNA levels of oncogenes (c-myc, c-fos, k-ras, p53) and apoptotic genes (Caspase-3, Caspase-8, Caspase-9) were detected by real-time PCR. The protein levels of oncogenes and apoptotic genes were detected by western blotting. Results: The mRNA level and protein level of c-myc decreased by 81% and 70% in c-myc silenced cells when compared with the normal L02 hepatocytes, the above results indicate that c-myc gene silenced cells were successfully constructed. After c-myc silenced cells were treated with PM2.5 water soluble solution, The mRNA levels of c-myc, c-fos, and k-ras decreased by 84.1%, 45.4%, and 54.6% (P<0.05) , p53 increased by 192.9% (P<0.05) , and the expression of Caspase-3, Caspase-8, and Caspase-9 decreased by 24.4%, 36.1%, 60.9% (P<0.05) . In the Cr(6+) positive control group, the expression of c-myc, c-fos, and k-ras decreased by 72.1%, 82.2%, and 54.0% (P<0.05) , p53 increased by 250.0% (P<0.05) , the expression of Caspase-3, Caspase-8, and Caspase-9 decreased by 34.6%, 36.0%, 68.9% (P<0.05) , respectively, when compared with the normal L02 hepatocytes (P<0.05) . Western blotting results showed that the protein levels of c-myc and c-fos increased, p53 decreased after PM(2.5) exposure; the protein levels of Caspase-3, Caspase-8, Caspase-9 increased after PM(2.5) exposure (P<0.05) . When in comparison with the c-myc silenced group, the protein levels of c-myc and c-fos decreased, p53 protein increased in PM(2).5 exposed group (P<0.05) . Conclusion: c-myc gene silenced cells were successfully constructed in this paper. PM(2.5) could promote the expression of oncogenes and apoptotic genes in L02 cells, and c-myc gene silencing can inhibit the expression of oncogenes and apoptotic genes after PM(2.5) treatment in L02 cells.


Assuntos
Genes myc , Oncogenes , Apoptose , Genes myc/genética , Hepatócitos , Humanos , Proteínas Proto-Oncogênicas c-fos
7.
Bull Cancer ; 107(11): 1148-1160, 2020 Nov.
Artigo em Francês | MEDLINE | ID: mdl-33039132

RESUMO

Tumorigenesis has traditionally been considered as a multi-step process involving the activation of oncogenes as well as the inactivation of tumor suppressor genes. However, the mechanisms driving cancer initiation and progression are not restricted to molecular alterations and instead should be viewed as a complex process that interfaces with the entire organism. This didactic review provides an integrated and global view of the key fundamental principles of cancer development.


Assuntos
Carcinogênese , Apoptose , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Carcinoma in Situ/patologia , Proliferação de Células , Progressão da Doença , Meio Ambiente , Inativação Gênica , Genes Supressores de Tumor , Instabilidade Genômica , Humanos , Inflamação/complicações , Mutação , Invasividade Neoplásica , Metástase Neoplásica , Neoplasias/irrigação sanguínea , Neoplasias/etiologia , Neoplasias/patologia , Células Neoplásicas Circulantes , Neovascularização Patológica/etiologia , Oncogenes , Lesões Pré-Cancerosas , Ativação Transcricional , Microambiente Tumoral
8.
Nat Commun ; 11(1): 4676, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938922

RESUMO

Translation efficiency varies considerably between different mRNAs, thereby impacting protein expression. Translation of the stress response master-regulator ATF4 increases upon stress, but the molecular mechanisms are not well understood. We discover here that translation factors DENR, MCTS1 and eIF2D are required to induce ATF4 translation upon stress by promoting translation reinitiation in the ATF4 5'UTR. We find DENR and MCTS1 are only needed for reinitiation after upstream Open Reading Frames (uORFs) containing certain penultimate codons, perhaps because DENR•MCTS1 are needed to evict only certain tRNAs from post-termination 40S ribosomes. This provides a model for how DENR and MCTS1 promote translation reinitiation. Cancer cells, which are exposed to many stresses, require ATF4 for survival and proliferation. We find a strong correlation between DENR•MCTS1 expression and ATF4 activity across cancers. Furthermore, additional oncogenes including a-Raf, c-Raf and Cdk4 have long uORFs and are translated in a DENR•MCTS1 dependent manner.


Assuntos
Fator 4 Ativador da Transcrição/genética , Fatores de Iniciação em Eucariotos/metabolismo , Biossíntese de Proteínas , Ribossomos/metabolismo , Regiões 5' não Traduzidas , Fator 4 Ativador da Transcrição/metabolismo , Proteínas de Ciclo Celular/genética , Códon , Fator de Iniciação 2 em Eucariotos/genética , Fator de Iniciação 2 em Eucariotos/metabolismo , Fatores de Iniciação em Eucariotos/genética , Regulação da Expressão Gênica , Células HeLa , Humanos , Neoplasias/genética , Proteínas Oncogênicas/genética , Oncogenes , Fases de Leitura Aberta , RNA Mensageiro , RNA de Transferência/genética , RNA de Transferência/metabolismo , Subunidades Ribossômicas Menores de Eucariotos/genética , Subunidades Ribossômicas Menores de Eucariotos/metabolismo , Ribossomos/genética
9.
PLoS One ; 15(9): e0238477, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32877461

RESUMO

Somatic copy number alterations (CNA) are common in endometrial serous carcinoma (ESC). We used the Tumor Cancer Genome Atlas Pan Cancer dataset (TCGA Pan Can) to explore the impact of somatic CNA and gene expression levels (mRNA) of cancer-related genes in ESC. Results were correlated with clinico-pathologic parameters such as age of onset, disease stage, progression-free survival (PFS) and overall survival (OS) (n = 108). 1,449 genes with recurrent somatic CNA were identified, observed in 10% or more tumor samples. Somatic CNA and mRNA expression levels were highly correlated (r> = 0.6) for 383 genes. Among these, 45 genes were classified in the Tier 1 category of Cancer Genome Census-Catalogue of Somatic Mutations in Cancer. Eighteen of 45 Tier 1 genes had highly correlated somatic CNA and mRNA expression levels including ARNT, PIK3CA, TBLXR1, ASXL1, EIF4A2, HOOK3, IKBKB, KAT6A, TCEA1, KAT6B, ERBB2, BRD4, KEAP1, PRKACA, DNM2, SMARCA4, AKT2, SS18L1. Our results are in agreement with previously reported somatic CNA for ERBB2, BRD4 and PIK3C in ESC. In addition, AKT2 (p = 0.002) and KAT6A (p = 0.015) amplifications were more frequent in tumor samples from younger patients (<60), and CEBPA (p = 0.028) and MYC (p = 0.023) amplifications were more common with advanced (stage III and IV) disease stage. Patients with tumors carrying KAT6A and MYC amplifications had shorter PFS and OS. The hazard ratio (HR) of KAT6A was 2.82 [95 CI 1.12-7.07] for PFS and 3.87 [95 CI 1.28-11.68] for OS. The HR of MYC was 2.25 [95 CI 1.05-4.81] and 2.62[95 CI 1.07-6.41] for PFS and OS, respectively.


Assuntos
Neoplasias do Endométrio/genética , Histona Acetiltransferases/genética , Biomarcadores Tumorais/genética , Classe I de Fosfatidilinositol 3-Quinases , Cistadenocarcinoma Seroso/genética , Variações do Número de Cópias de DNA/genética , DNA Helicases , Bases de Dados Genéticas , Intervalo Livre de Doença , Neoplasias do Endométrio/patologia , Feminino , Perfilação da Expressão Gênica/métodos , Histona Acetiltransferases/metabolismo , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch , Mutação , Fator 2 Relacionado a NF-E2 , Proteínas Nucleares/genética , Oncogenes , Neoplasias Ovarianas/patologia , Prognóstico , Intervalo Livre de Progressão , Fatores de Transcrição , Transcriptoma/genética
10.
Nat Commun ; 11(1): 4551, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917870

RESUMO

Circular RNAs (circRNAs) have recently gained substantial attention in the cancer research field where most, including the putative oncogene ciRS-7 (CDR1as), have been proposed to function as competitive endogenous RNAs (ceRNAs) by sponging specific microRNAs. Here, we report the first spatially resolved cellular expression patterns of ciRS-7 in colon cancer and show that ciRS-7 is completely absent in the cancer cells, but highly expressed in stromal cells within the tumor microenvironment. Additionally, our data suggest that this generally apply to classical oncogene-driven adenocarcinomas, but not to other cancers, including malignant melanoma. Moreover, we find that correlations between circRNA and mRNA expression, which are commonly interpreted as evidence of a ceRNA function, can be explained by different cancer-to-stromal cell ratios among the studied tumor specimens. Together, these results have wide implications for future circRNA studies and highlight the importance of spatially resolving expression patterns of circRNAs proposed to function as ceRNAs.


Assuntos
Neoplasias do Colo/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismo , RNA Circular/metabolismo , RNA Longo não Codificante/metabolismo , Microambiente Tumoral/genética , Idoso , Neoplasias do Colo/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oncogenes/genética , Estudos Prospectivos , RNA Circular/genética , RNA Longo não Codificante/genética , Análise Espacial
11.
Nat Commun ; 11(1): 4581, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917893

RESUMO

Yes-associated protein 1 (YAP) is a transcriptional regulator with critical roles in mechanotransduction, organ size control, and regeneration. Here, using advanced tools for real-time visualization of native YAP and target gene transcription dynamics, we show that a cycle of fast exodus of nuclear YAP to the cytoplasm followed by fast reentry to the nucleus ("localization-resets") activates YAP target genes. These "resets" are induced by calcium signaling, modulation of actomyosin contractility, or mitosis. Using nascent-transcription reporter knock-ins of YAP target genes, we show a strict association between these resets and downstream transcription. Oncogenically-transformed cell lines lack localization-resets and instead show dramatically elevated rates of nucleocytoplasmic shuttling of YAP, suggesting an escape from compartmentalization-based control. The single-cell localization and transcription traces suggest that YAP activity is not a simple linear function of nuclear enrichment and point to a model of transcriptional activation based on nucleocytoplasmic exchange properties of YAP.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Sistemas CRISPR-Cas , Cálcio/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Regulação da Expressão Gênica , Técnicas de Introdução de Genes , Células HEK293 , Humanos , Mecanotransdução Celular/fisiologia , Oncogenes/genética , Fatores de Transcrição/genética
12.
Mol Cell ; 79(6): 878-880, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32946762

RESUMO

Recent work by Kadosh et al. (2020) suggests that mutant p53 activity in gut epithelia is influenced by local production of microbial metabolites. The switch of p53 from tumor suppressor to oncogene is location-dependent and is impacted by microbially derived gallic acid.


Assuntos
Microbioma Gastrointestinal , Carcinogênese , Humanos , Oncogenes , Proteína Supressora de Tumor p53/genética
13.
Nat Commun ; 11(1): 4374, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873787

RESUMO

Oncogene amplification, a major driver of cancer pathogenicity, is often mediated through focal amplification of genomic segments. Recent results implicate extrachromosomal DNA (ecDNA) as the primary driver of focal copy number amplification (fCNA) - enabling gene amplification, rapid tumor evolution, and the rewiring of regulatory circuitry. Resolving an fCNA's structure is a first step in deciphering the mechanisms of its genesis and the fCNA's subsequent biological consequences. We introduce a computational method, AmpliconReconstructor (AR), for integrating optical mapping (OM) of long DNA fragments (>150 kb) with next-generation sequencing (NGS) to resolve fCNAs at single-nucleotide resolution. AR uses an NGS-derived breakpoint graph alongside OM scaffolds to produce high-fidelity reconstructions. After validating its performance through multiple simulation strategies, AR reconstructed fCNAs in seven cancer cell lines to reveal the complex architecture of ecDNA, a breakage-fusion-bridge and other complex rearrangements. By reconstructing the rearrangement signatures associated with an fCNA's generative mechanism, AR enables a more thorough understanding of the origins of fCNAs.


Assuntos
Amplificação de Genes , Genômica/métodos , Neoplasias/genética , Oncogenes/genética , Linhagem Celular Tumoral , Mapeamento Cromossômico/métodos , Análise Citogenética , Genoma Humano/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos
14.
Anticancer Res ; 40(10): 5667-5671, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988891

RESUMO

BACKGROUND: Renal cell carcinoma (RCC) is a common urological cancer, and its risk correlates with environmental factors such as obesity, smoking and hypertension. Microarray technology enables analysis of the expression pattern of the whole phosphatome, members of which are involved in many cellular pathways and may act as either tumour suppressors or oncogenes in cancers. MATERIALS AND METHODS: We analysed data for the expression level of 87 out of 107 known protein phosphatase genes included in the Hugo Gene Nomenclature Committee Website for 72 RCC tissues and paired healthy tissues obtained from the GEO Database. RESULTS: Our analysis revealed overexpression of DUSP1, DUSP4, PTP4A3, PTPRC and PTPRE genes at all examined stages of RCC. Moreover, we found overexpression of PTPN12 at stage 2, overexpression of CDKN3 at stages 3 and 4, and overexpression of DUSP10 and PTPN22 at stages 2, 3 and 4. Lower expression of DUSP9, PTPR9 and PTPRO was also observed at all stages. CONCLUSION: Significant changes in expression patterns of protein tyrosine phosphatase genes confirm the involvement of this group in crucial carcinogenesis pathways underlying RCC. Thus, we postulate that protein tyrosine phosphatases play an important role in RCC promotion and progression, and may be considered as potential therapeutic targets.


Assuntos
Carcinoma de Células Renais/genética , Proliferação de Células/genética , Oncogenes/genética , Proteínas Tirosina Fosfatases/genética , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Proteínas Inibidoras de Quinase Dependente de Ciclina/genética , Fosfatase 1 de Especificidade Dupla/genética , Fosfatases de Especificidade Dupla/genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Antígenos Comuns de Leucócito/genética , Masculino , Fosfatases da Proteína Quinase Ativada por Mitógeno/genética , Proteínas de Neoplasias/genética , Estadiamento de Neoplasias , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/genética , Proteínas Tirosina Fosfatases Classe 4 Semelhantes a Receptores/genética , Fatores de Risco , Transdução de Sinais/genética , Fumar/efeitos adversos
15.
Nat Genet ; 52(9): 891-897, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32807987

RESUMO

Extrachromosomal DNA (ecDNA) amplification promotes intratumoral genetic heterogeneity and accelerated tumor evolution1-3; however, its frequency and clinical impact are unclear. Using computational analysis of whole-genome sequencing data from 3,212 cancer patients, we show that ecDNA amplification frequently occurs in most cancer types but not in blood or normal tissue. Oncogenes were highly enriched on amplified ecDNA, and the most common recurrent oncogene amplifications arose on ecDNA. EcDNA amplifications resulted in higher levels of oncogene transcription compared to copy number-matched linear DNA, coupled with enhanced chromatin accessibility, and more frequently resulted in transcript fusions. Patients whose cancers carried ecDNA had significantly shorter survival, even when controlled for tissue type, than patients whose cancers were not driven by ecDNA-based oncogene amplification. The results presented here demonstrate that ecDNA-based oncogene amplification is common in cancer, is different from chromosomal amplification and drives poor outcome for patients across many cancer types.


Assuntos
Cromossomos/genética , DNA/genética , Amplificação de Genes/genética , Neoplasias/genética , Oncogenes/genética , Linhagem Celular Tumoral , Cromatina/genética , Humanos
16.
Nat Commun ; 11(1): 4330, 2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32859912

RESUMO

Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research.


Assuntos
Mutação , Neoplasias/genética , Oncogenes/genética , Caracteres Sexuais , Instabilidade Cromossômica , Exoma , Feminino , Genoma Humano , Instabilidade Genômica , Humanos , Modelos Logísticos , Masculino , Fases de Leitura Aberta , beta Catenina/genética
17.
Proc Natl Acad Sci U S A ; 117(35): 21609-21617, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32817420

RESUMO

The circadian clock is a global regulatory mechanism that controls the expression of 50 to 80% of transcripts in mammals. Some of the genes controlled by the circadian clock are oncogenes or tumor suppressors. Among these Myc has been the focus of several studies which have investigated the effect of clock genes and proteins on Myc transcription and MYC protein stability. Other studies have focused on effects of Myc mutation or overproduction on the circadian clock in comparison to their effects on cell cycle progression and tumorigenesis. Here we have used mice with mutations in the essential clock genes Bmal1, Cry1, and Cry2 to gain further insight into the effect of the circadian clock on this important oncogene/oncoprotein and tumorigenesis. We find that mutation of both Cry1 and Cry2, which abolishes the negative arm of the clock transcription-translation feedback loop (TTFL), causes down-regulation of c-MYC, and mutation of Bmal1, which abolishes the positive arm of TTFL, causes up-regulation of the c-MYC protein level in mouse spleen. These findings must be taken into account in models of the clock disruption-cancer connection.


Assuntos
Ritmo Circadiano/fisiologia , Proteínas Proto-Oncogênicas c-myc/genética , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Animais , Proteínas CLOCK/genética , Proteínas de Ciclo Celular/metabolismo , Relógios Circadianos/genética , Ritmo Circadiano/genética , Criptocromos/metabolismo , Feminino , Regulação da Expressão Gênica , Genes myc , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oncogenes , Proteínas Circadianas Period/metabolismo , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo
18.
Nat Commun ; 11(1): 3808, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732999

RESUMO

Large-scale cancer genomic studies enable the systematic identification of mutations that lead to the genesis and progression of tumors, uncovering the underlying molecular mechanisms and potential therapies. While some such mutations are recurrently found in many tumors, many others exist solely within a few samples, precluding detection by conventional recurrence-based statistical approaches. Integrated analysis of somatic mutations and RNA expression data across 12 tumor types reveals that mutations of cancer genes are usually accompanied by substantial changes in expression. We use topological data analysis to leverage this observation and uncover 38 elusive candidate cancer-associated genes, including inactivating mutations of the metalloproteinase ADAMTS12 in lung adenocarcinoma. We show that ADAMTS12-/- mice have a five-fold increase in the susceptibility to develop lung tumors, confirming the role of ADAMTS12 as a tumor suppressor gene. Our results demonstrate that data integration through topological techniques can increase our ability to identify previously unreported cancer-related alterations.


Assuntos
Proteínas ADAMTS/genética , Adenocarcinoma de Pulmão/genética , Predisposição Genética para Doença/genética , Neoplasias Pulmonares/genética , Animais , Linhagem Celular Tumoral , Biologia Computacional/métodos , Análise de Dados , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação/genética , Recidiva Local de Neoplasia/genética , Oncogenes/genética
19.
Proc Natl Acad Sci U S A ; 117(34): 20681-20688, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32788368

RESUMO

Quantifying evolutionary dynamics of cancer initiation and progression can provide insights into more effective strategies of early detection and treatment. Here we develop a mathematical model of colorectal cancer initiation through inactivation of two tumor suppressor genes and activation of one oncogene, accounting for the well-known path to colorectal cancer through loss of tumor suppressors APC and TP53 and gain of the KRAS oncogene. In the model, we allow mutations to occur in any order, leading to a complex network of premalignant mutational genotypes on the way to colorectal cancer. We parameterize the model using experimentally measured parameter values, many of them only recently available, and compare its predictions to epidemiological data on colorectal cancer incidence. We find that the reported lifetime risk of colorectal cancer can be recovered using a mathematical model of colorectal cancer initiation together with experimentally measured mutation rates in colorectal tissues and proliferation rates of premalignant lesions. We demonstrate that the order of driver events in colorectal cancer is determined primarily by the fitness effects that they provide, rather than their mutation rates. Our results imply that there may not be significant immune suppression of untreated benign and malignant colorectal lesions.


Assuntos
Carcinogênese/genética , Neoplasias Colorretais/genética , Neoplasias do Colo/genética , Progressão da Doença , Genes APC/fisiologia , Genes p53/genética , Genes ras , Humanos , Modelos Teóricos , Mutação , Taxa de Mutação , Oncogenes , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Supressora de Tumor p53/genética
20.
Hum Cell ; 33(4): 946-953, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32772230

RESUMO

Long noncoding RNA (lncRNA) is a newly identified type of noncoding RNA with a length of more than 200 nucleotides. The latest research shows that lncRNAs play important roles in the occurrence and development of human tumours by acting both as carcinogenic genes and as tumour suppressor genes. LncRNAs plays a role in various biological processes, such as cell growth, apoptosis, migration and invasion. The newly discovered lncRNA DDX11-AS1 is abnormally highly expressed in various malignant tumours, such as hepatocellular carcinoma, colorectal cancer, osteosarcoma, bladder cancer, NSCLC and gastric cancer. DDX11-AS1 mainly regulates the expression of related genes through direct or indirect ways to perform its functions in carcinogenicity. These results indicate that DDX11-AS1 may be a marker or therapeutic target of tumours. This review summarizes the biological function and mechanism of DDX11-AS1 in the process of tumour development.


Assuntos
RNA Helicases DEAD-box/genética , DNA Helicases/genética , Neoplasias/genética , Neoplasias/patologia , RNA Longo não Codificante/genética , Apoptose/genética , Biomarcadores Tumorais , Carcinogênese/genética , Proliferação de Células/genética , RNA Helicases DEAD-box/fisiologia , DNA Helicases/fisiologia , Regulação Neoplásica da Expressão Gênica/genética , Genes Supressores de Tumor , Humanos , Terapia de Alvo Molecular , Invasividade Neoplásica/genética , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Oncogenes , Prognóstico , RNA Longo não Codificante/fisiologia
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