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1.
Anticancer Res ; 40(10): 5539-5544, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988877

RESUMO

BACKGROUND/AIM: Endothelin-1 (ET-1) is overexpressed in many types of cancer, inhibiting the release of the microRNA 15a (miR-15a) and inducing the production of Mxi-2. Our aim was to identify a molecular complex regulating p53 activity in prostate cancer (PCa). MATERIALS AND METHODS: DU145 cells were treated with ET-1, MAPK p38 inhibitor, Endothelin A receptor inhibitor (ETAR inhibitor) and Endothelin B receptor inhibitor (ETBR inhibitor). Extracts were analysed using Western Blot, immunoprecipitation and qRT-PCR. Furthermore, prostate cancer patient samples were analysed using qRT-PCR and ELISA. RESULTS: The hypothesised molecular complex was identified, with miR-15a, microRNA 1285 (miR-1285) and Mxi-2 levels up-regulated in patients in relation to increasing aggressiveness of PCa. CONCLUSION: A complex composed of Argonaut 2 (Ago2)/Mxi-2/miR-1285 is involved in PCa. The expression of Mxi-2 correlates with increasing PCa aggressiveness and might be used as a non-invasive marker for the diagnosis and progression of PCa.


Assuntos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteína Quinase 14 Ativada por Mitógeno/genética , Neoplasias da Próstata/genética , Proteína Supressora de Tumor p53/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Argonauta/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Antagonistas do Receptor de Endotelina A/farmacologia , Antagonistas do Receptor de Endotelina B/farmacologia , Humanos , Masculino , MicroRNAs/genética , Neoplasias da Próstata/patologia , Receptor de Endotelina A/genética , Receptor de Endotelina B/genética , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
2.
Anticancer Res ; 40(10): 5601-5609, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988884

RESUMO

BACKGROUND/AIM: Since pathways involving LRRC17 are related to the survival of patients with various cancers, we analyzed LRRC17 as a prognostic gene in serous ovarian cancer. MATERIALS AND METHODS: Data were collected from Gene Expression Omnibus (GSE9891, GSE13876, and GSE26712) and The Cancer Genome Atlas (TCGA). We performed survival analyses using C statistics, area under the curve, survival plot with optimal cutoff level, and cox proportional regression. Zebrafish embryos were used as an in vivo model. RESULTS: The prognosis of patients with high LRRC17 expression was poorer than that of patients with low LRRC17 expression. Multivariate regression analysis showed that LRRC17 expression, age, and stage were independently related with survival. Knockdown of lrrc17 reduced survival rate and delayed development in zebrafish embryos. We also found that lrrc17 is important for cell viability by protecting from p53-dependent apoptosis. CONCLUSION: LRRC17 could be a prognostic gene in ovarian cancer as it regulates cancer cell viability through the p53 pathway.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Ovarianas/genética , Proteínas/genética , Proteína Supressora de Tumor p53/genética , Idoso , Apoptose/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Técnicas de Silenciamento de Genes , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Prognóstico
3.
Anticancer Res ; 40(10): 5631-5639, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988887

RESUMO

BACKGROUND/AIM: DNA damage response (DDR), wherein p21 is a cell fate determinant, is a potential cancer therapeutic target. Molecular expression during DDR was explored in ovarian clear-cell carcinoma (CCC). MATERIALS AND METHODS: CHK1, CHK2, TP53 and p21 expression in DDR was examined using immunostaining in surgical sections of CCC (n=22). Molecular alterations in two types of CCC cell lines, JHOC-5 and JHOC-9, were investigated using western blot analysis. RESULTS: Expression of DDR-associated molecules was noted in most patients. While high p21 expression was found in half of the patients, the remaining patients exhibited low p21 expression. Treatment with UC2288, a p21 inhibitor, attenuated proliferation of both cell lines, more prominently in JHOC-9, resulting in reduced viability and subsequent apoptosis. CONCLUSION: p21 Inhibitor induced cell death in cells with high p21 expression, suggesting that p21 suppression can be a therapeutic strategy to treat patients with CCC.


Assuntos
Quinase 1 do Ponto de Checagem/genética , Quinase do Ponto de Checagem 2/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Neoplasias Ovarianas/genética , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Dano ao DNA/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia
4.
Anticancer Res ; 40(10): 5659-5666, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988890

RESUMO

BACKGROUND/AIM: Long interspersed nuclear element-1 (LINE-1) methylation status is a marker for global DNA methylation. However, the relationship between LINE-1 methylation and the biology of lung adenocarcinoma remains unclear. Here, we aimed to examine the role of LINE-1 in lung cancer. MATERIALS AND METHODS: LINE-1 methylation levels were quantified by bisulfite pyrosequencing of resected tumor specimens from 162 patients with lung adenocarcinoma. The relationships of LINE-1 methylation with clinicopathological factors, gene mutations, and Ki-67 immunoreactivity were investigated. RESULTS: LINE-1 hypomethylation was associated with tumor invasion and advanced stage. TP53 mutations were more frequently detected in the LINE-1 hypomethylation group than in the hypermethylation group. LINE-1 hypomethylation was associated with poor recurrence-free survival, high maximum standardized uptake value in positron-emission tomography, and high Ki-67 expression in tumors. CONCLUSION: LINE-1 hypomethylation was associated with high-grade malignancy and poor prognosis in lung adenocarcinoma, but was not related to driver mutations.


Assuntos
Adenocarcinoma de Pulmão/genética , Biomarcadores Tumorais/genética , Metilação de DNA/genética , Elementos Nucleotídeos Longos e Dispersos/genética , Adenocarcinoma de Pulmão/patologia , Adulto , Idoso , Núcleo Celular/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Antígeno Ki-67/genética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Prognóstico , Proteína Supressora de Tumor p53/genética
5.
Anticancer Res ; 40(10): 5883-5893, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988919

RESUMO

BACKGROUND/AIM: Somatic mutations were investigated in 21 patients with postmenopausal estrogen receptor (ER)-positive and human epidermal growth factor receptor-2 (HER-2)-positive (ER+HER2+) breast cancer (BC) treated with neoadjuvant letrozole and lapatinib, to identify their distinct molecular landscape. PATIENTS AND METHODS: We used tissue samples of 21 patients from phase II Neo ALL-IN cohort, and somatic alterations were examined using targeted exome sequencing performed in Foundation Medicine, Inc. (FMI). RESULTS: TP53 (61.9%) and PIK3CA (57.1%) were the two most frequently mutated genes that were inter-correlated (p=0.026). They were associated with unfavorable clinical outcomes, particularly when accompanying PIK3CA mutations at exon 9 in helical domains. Meanwhile, MLL2 alteration was negatively associated with mutations of TP53 or PIK3CA, and it tended to be present in patients with low KI-67 levels and no initial nodal involvement. Moreover, patients with MLL2 mutations numerically showed more favorable overall response rates (ORR) (80% vs. 56.2%) and better 5-year event-free survival (EFS) rates (100% vs. 87.5%) compared to the wild-type. CONCLUSION: Mutations in TP53 and PIK3CA hotspot at exon 9 may be potential negative predictors of ER+HER2+ BC treated with neoadjuvant letrozole and lapatinib, while MLL2 inactivating mutation might confer therapeutic benefit in these patients.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/genética , Proteínas de Ligação a DNA/genética , Proteínas de Neoplasias/genética , Proteína Supressora de Tumor p53/genética , Idoso , Biomarcadores Tumorais/genética , Mama/efeitos dos fármacos , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Receptor alfa de Estrogênio/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lapatinib/administração & dosagem , Letrozol/administração & dosagem , Pessoa de Meia-Idade , Mutação/genética , Intervalo Livre de Progressão , Receptor ErbB-2/genética
6.
Nat Commun ; 11(1): 4586, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32934222

RESUMO

Frequent mutation of the tumour suppressor RNF43 is observed in many cancers, particularly colon malignancies. RNF43, an E3 ubiquitin ligase, negatively regulates Wnt signalling by inducing degradation of the Wnt receptor Frizzled. In this study, we discover that RNF43 activity requires phosphorylation at a triplet of conserved serines. This phospho-regulation of RNF43 is required for zebrafish development and growth of mouse intestinal organoids. Cancer-associated mutations that abrogate RNF43 phosphorylation cooperate with active Ras to promote tumorigenesis by abolishing the inhibitory function of RNF43 in Wnt signalling while maintaining its inhibitory function in p53 signalling. Our data suggest that RNF43 mutations cooperate with KRAS mutations to promote multi-step tumorigenesis via the Wnt-Ras-p53 axis in human colon cancers. Lastly, phosphomimetic substitutions of the serine trio restored the tumour suppressive activity of extracellular oncogenic mutants. Therefore, harnessing phospho-regulation of RNF43 might be a potential therapeutic strategy for tumours with RNF43 mutations.


Assuntos
Carcinogênese/metabolismo , Receptores Wnt/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Carcinogênese/genética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Proteína Oncogênica p21(ras)/genética , Proteína Oncogênica p21(ras)/metabolismo , Fosforilação , Proteólise , Receptores Wnt/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina-Proteína Ligases/genética , Via de Sinalização Wnt
7.
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
8.
Anticancer Res ; 40(9): 4979-4987, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878786

RESUMO

BACKGROUND/AIM: Multiple myeloma is a highly heterogeneous disease of clonal plasma cells. Histone deacetylase (HDAC) inhibitors are promising anticancer drugs but their precise mechanisms of actions are not well understood. MATERIALS AND METHODS: Cell-cycle regulation and pro-apoptotic effects of two histone deacetylase inhibitors, suberohydroxamic acid (SAHA) and suberoylanilide hydroxamic acid (SBHA), were analyzed in multiple myeloma cell lines RPMI8226 and U266 with differing TP53 status using gene-expression analysis. RESULTS: Enhanced expression of cyclin-dependent kinase inhibitor 1A (CDKN1A/p21WAF/CIP1) detected in the TP53-deleted U266 cell line after SAHA treatment indicates the P53-independent mode of transcriptional activation of CDKN1A gene. In contrast, CDKN1A gene expression was significantly increased by both SBHA and SAHA treatment of TP53-mutated RPMI8226 cells. CONCLUSION: SAHA appears to be a potentially effective pro-apoptotic and anticancer drug with universal application in the treatment of heterogeneous populations of multiple myeloma cells.


Assuntos
Inibidor de Quinase Dependente de Ciclina p21/genética , Mieloma Múltiplo/patologia , Proteína Supressora de Tumor p53/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Proteína Supressora de Tumor p53/genética
9.
Chem Biol Interact ; 330: 109236, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32866467

RESUMO

A series of novel pyrrolopyrimidine urea derivatives were synthesized and evaluated for their anticancer activity against colon cancer cell lines. Compounds showed the remarkable cytotoxic activity on HCT-116 wt cell line. The most potent compound 4c (IC50 = 0.14 µM) induced apoptosis in HCT-116 wt and HCT-116 p53-/- cell lines. Otherwise, treatment of HCT-116 BAX-/-BAK-/- cells with compound 4c didn't lead to activation of apoptosis, suggesting that compound 4c induces apoptotic cell death by activating BAX/BAK-dependent pathway. Moreover, while the compound 4c increase the activation of caspase-3 and caspase-9 levels in HCT-116 wt and HCT-116 p53-/- cells, caspase-3 or caspase-9 activation was not observed in HCT-116 BAX-/-BAK-/- cells. In addition, compound 4c induced mitochondrial apoptosis in cells grown as oncospheroids, which better mimic the in vivo milieu of tumors. 4c treatment also activated JNK along with inhibition of prosurvival kinases such as Akt and ERK 1/2 in HCT-116 wt and HCT-116 p53 -/- cells as well as in HCT-116 BAX-/-BAK-/- cells. Notably, our results indicated that compound 4c induced mitochondrial apoptosis through activation p53-independent apoptotic signaling pathways.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Pirimidinas/farmacologia , Pirróis/farmacologia , Proteína Supressora de Tumor p53/fisiologia , Caspase 3/genética , Caspase 9/genética , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Técnicas de Inativação de Genes , Células HCT116 , Humanos , Mitocôndrias/metabolismo , Pirimidinas/síntese química , Pirimidinas/química , Pirróis/síntese química , Pirróis/química , Proteína Supressora de Tumor p53/genética , Proteína Killer-Antagonista Homóloga a bcl-2/genética , Proteína X Associada a bcl-2/genética
10.
Nat Commun ; 11(1): 4527, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32913197

RESUMO

Evasion of programmed cell death represents a critical form of oncogene addiction in cancer cells. Understanding the molecular mechanisms underpinning cancer cell survival despite the oncogenic stress could provide a molecular basis for potential therapeutic interventions. Here we explore the role of pro-survival genes in cancer cell integrity during clonal evolution in non-small cell lung cancer (NSCLC). We identify gains of MCL-1 at high frequency in multiple independent NSCLC cohorts, occurring both clonally and subclonally. Clonal loss of functional TP53 is significantly associated with subclonal gains of MCL-1. In mice, tumour progression is delayed upon pharmacologic or genetic inhibition of MCL-1. These findings reveal that MCL-1 gains occur with high frequency in lung adenocarcinoma and can be targeted therapeutically.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Evolução Clonal , Variações do Número de Cópias de DNA , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Progressão da Doença , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Transgênicos , Mutação , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Cultura Primária de Células , Estudos Prospectivos , Proteínas Proto-Oncogênicas p21(ras)/genética , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , RNA-Seq , Estudos Retrospectivos , Esferoides Celulares , Tiofenos/farmacologia , Tiofenos/uso terapêutico , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genética , Proteína Supressora de Tumor p53/genética , Microtomografia por Raio-X
11.
PLoS Pathog ; 16(8): e1008792, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32813746

RESUMO

Tumor suppressors can exert pro-proliferation functions in specific contexts. In the beta human papillomavirus type 38 (HPV38) experimental model, the viral proteins E6 and E7 promote accumulation of a wild-type (WT) p53 form in human keratinocytes (HKs), promoting cellular proliferation. Inactivation of p53 by different means strongly decreases the proliferation of HPV38 E6/E7 HKs. This p53 form is phosphorylated at S392 by the double-stranded RNA-dependent protein kinase PKR, which is highly activated by HPV38. PKR-mediated S392 p53 phosphorylation promotes the formation of a p53/DNMT1 complex, which inhibits expression of integrin alpha 1 (ITGA1), a repressor of epidermal growth factor receptor (EGFR) signaling. Ectopic expression of ITGA1 in HPV38 E6/E7 HKs promotes EGFR degradation, inhibition of cellular proliferation, and cellular death. Itga1 expression was also inhibited in the skin of HPV38 transgenic mice that have an elevated susceptibility to UV-induced skin carcinogenesis. In summary, these findings reveal the existence of a specific WT p53 form that displays pro-proliferation properties.


Assuntos
Proteínas de Transporte/antagonistas & inibidores , Proliferação de Células , Queratinócitos/patologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas Oncogênicas Virais/metabolismo , Proteínas E7 de Papillomavirus/metabolismo , Infecções por Papillomavirus/complicações , Proteínas Repressoras/metabolismo , Neoplasias Cutâneas/etiologia , Proteína Supressora de Tumor p53/metabolismo , Animais , Células Cultivadas , Regulação para Baixo , Humanos , Queratinócitos/imunologia , Queratinócitos/virologia , Camundongos , Camundongos Transgênicos , Proteínas Oncogênicas Virais/genética , Papillomaviridae/isolamento & purificação , Proteínas E7 de Papillomavirus/genética , Infecções por Papillomavirus/virologia , Proteínas Repressoras/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Proteína Supressora de Tumor p53/genética
12.
Nat Commun ; 11(1): 3839, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737294

RESUMO

Chromatin regulates spatiotemporal gene expression during neurodevelopment, but it also mediates DNA damage repair essential to proliferating neural progenitor cells (NPCs). Here, we uncover molecularly dissociable roles for nucleosome remodeler Ino80 in chromatin-mediated transcriptional regulation and genome maintenance in corticogenesis. We find that conditional Ino80 deletion from cortical NPCs impairs DNA double-strand break (DSB) repair, triggering p53-dependent apoptosis and microcephaly. Using an in vivo DSB repair pathway assay, we find that Ino80 is selectively required for homologous recombination (HR) DNA repair, which is mechanistically distinct from Ino80 function in YY1-associated transcription. Unexpectedly, sensitivity to loss of Ino80-mediated HR is dependent on NPC division mode: Ino80 deletion leads to unrepaired DNA breaks and apoptosis in symmetric NPC-NPC divisions, but not in asymmetric neurogenic divisions. This division mode dependence is phenocopied following conditional deletion of HR gene Brca2. Thus, distinct modes of NPC division have divergent requirements for Ino80-dependent HR DNA repair.


Assuntos
ATPases Associadas a Diversas Atividades Celulares/genética , Proteína BRCA2/genética , Cromatina/química , Proteínas de Ligação a DNA/genética , Células-Tronco Neurais/metabolismo , Neurogênese/genética , Reparo de DNA por Recombinação , ATPases Associadas a Diversas Atividades Celulares/deficiência , Animais , Apoptose/genética , Proteína BRCA2/deficiência , Divisão Celular , Cromatina/metabolismo , Montagem e Desmontagem da Cromatina , DNA/genética , DNA/metabolismo , Quebras de DNA de Cadeia Dupla , Proteínas de Ligação a DNA/deficiência , Embrião de Mamíferos , Regulação da Expressão Gênica no Desenvolvimento , Camundongos , Camundongos Transgênicos , Neocórtex/citologia , Neocórtex/crescimento & desenvolvimento , Neocórtex/metabolismo , Células-Tronco Neurais/citologia , Transdução de Sinais , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Fator de Transcrição YY1/genética , Fator de Transcrição YY1/metabolismo
13.
J Cancer Res Clin Oncol ; 146(11): 2851-2859, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32743759

RESUMO

PURPOSE: TP53/EGFR co-mutation has been reported to affect the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in lung adenocarcinoma (LUAD). However, its impact on survival is unclear. In this analysis, we explored the prognostic effect of TP53/EGFR co-mutation in LUAD. METHODS: Clinical data and transcriptome sequencing of LUAD patients with matched genomic data were downloaded from the Cancer Genome Atlas (TCGA) database for overall survival (OS) analysis. Differential expression genes (DEGs) were recognized by R software and bioconductor package. Clusterprofiler was used for functional analysis. STRING was used for estimating PPI information and plug-in CytoHubba to screen hub modules in Cytoscape. The association between tumor mutation burden (TMB) and survival was also analyzed. RESULTS: OS was shorter for patients carrying TP53 mutation (MUT) than that of wild type (WT) (37.7 m vs 52.8 m; p = 0.040, HR = 1.38, 95% CI 1.01-1.89). Dual TP53/EGFR-MUT was associated with inferior OS compared with the dual WT/WT cohort (38.4 m vs 51.9 m; p = 0.023, HR 1.83, 95% CI 0.95-3.52). 316 DEGs between dual TP53/EGFR-MUT and dual WT/WT samples were obtained and functional analysis made known that DEGs were strikingly enriched in regulating the metabolism of important amino acids, cell division, cell cycle regulation, cell adhesion, and extracellular matrix composition. KEGG analysis discovered that DEGs were mainly enriched in signaling pathways such as PI3K-Akt, cytokine-cytokine receptor interaction, focal adhesions, and extracellular matrix receptor interaction. PPI network suggested that GPC3, CCL28, GPR37, and NPY genes were up-regulated in dual mutation samples. OS in the high TMB cohort was significantly better than that in the low TMB in patients with TP53 MUT(43.2 m vs 32.4 m; P = 0.007, HR = 0.52, 95% CI: 0.34-0.81), as well as in the combination of TP53 MUT and EGFR WT group (44.4 m vs 31.2 m; P = 0.021, HR = 0.55, 95% CI 0.34 - 0.89). CONCLUSIONS: TP53 MUT is a poor prognostic factor in LUAD patients, and the prognosis of TP53/EGFR co-mutation is worse. GPC3, CCL28, GPR37, and NPY may be novel prognostic markers and potential therapeutic targets for patients with dual TP53/EGFR mutation LUAD.


Assuntos
Adenocarcinoma de Pulmão/genética , Neoplasias Pulmonares/genética , Proteína Supressora de Tumor p53/genética , Adenocarcinoma de Pulmão/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Receptores ErbB/genética , Feminino , Genes erbB-1 , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida
14.
Nat Commun ; 11(1): 4287, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32855419

RESUMO

Warsaw Breakage Syndrome (WABS) is a rare disorder related to cohesinopathies and Fanconi anemia, caused by bi-allelic mutations in DDX11. Here, we report multiple compound heterozygous WABS cases, each displaying destabilized DDX11 protein and residual DDX11 function at the cellular level. Patient-derived cell lines exhibit sensitivity to topoisomerase and PARP inhibitors, defective sister chromatid cohesion and reduced DNA replication fork speed. Deleting DDX11 in RPE1-TERT cells inhibits proliferation and survival in a TP53-dependent manner and causes chromosome breaks and cohesion defects, independent of the expressed pseudogene DDX12p. Importantly, G-quadruplex (G4) stabilizing compounds induce chromosome breaks and cohesion defects which are strongly aggravated by inactivation of DDX11 but not FANCJ. The DNA helicase domain of DDX11 is essential for sister chromatid cohesion and resistance to G4 stabilizers. We propose that DDX11 is a DNA helicase protecting against G4 induced double-stranded breaks and concomitant loss of cohesion, possibly at DNA replication forks.


Assuntos
Anormalidades Múltiplas/etiologia , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , DNA Helicases/genética , DNA Helicases/metabolismo , Quadruplex G , Troca de Cromátide Irmã , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Proliferação de Células , RNA Helicases DEAD-box/química , DNA Helicases/química , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Estabilidade Proteica , Pseudogenes , RNA Helicases/genética , RNA Helicases/metabolismo , Rad51 Recombinase/genética , Rad51 Recombinase/metabolismo , Síndrome , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
15.
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
16.
Cochrane Database Syst Rev ; 7: CD012022, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32735048

RESUMO

BACKGROUND: Chronic lymphocytic leukaemia (CLL) is the most common cancer of the lymphatic system in Western countries. Several clinical and biological factors for CLL have been identified. However, it remains unclear which of the available prognostic models combining those factors can be used in clinical practice to predict long-term outcome in people newly-diagnosed with CLL. OBJECTIVES: To identify, describe and appraise all prognostic models developed to predict overall survival (OS), progression-free survival (PFS) or treatment-free survival (TFS) in newly-diagnosed (previously untreated) adults with CLL, and meta-analyse their predictive performances. SEARCH METHODS: We searched MEDLINE (from January 1950 to June 2019 via Ovid), Embase (from 1974 to June 2019) and registries of ongoing trials (to 5 March 2020) for development and validation studies of prognostic models for untreated adults with CLL. In addition, we screened the reference lists and citation indices of included studies. SELECTION CRITERIA: We included all prognostic models developed for CLL which predict OS, PFS, or TFS, provided they combined prognostic factors known before treatment initiation, and any studies that tested the performance of these models in individuals other than the ones included in model development (i.e. 'external model validation studies'). We included studies of adults with confirmed B-cell CLL who had not received treatment prior to the start of the study. We did not restrict the search based on study design. DATA COLLECTION AND ANALYSIS: We developed a data extraction form to collect information based on the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies (CHARMS). Independent pairs of review authors screened references, extracted data and assessed risk of bias according to the Prediction model Risk Of Bias ASsessment Tool (PROBAST). For models that were externally validated at least three times, we aimed to perform a quantitative meta-analysis of their predictive performance, notably their calibration (proportion of people predicted to experience the outcome who do so) and discrimination (ability to differentiate between people with and without the event) using a random-effects model. When a model categorised individuals into risk categories, we pooled outcome frequencies per risk group (low, intermediate, high and very high). We did not apply GRADE as guidance is not yet available for reviews of prognostic models. MAIN RESULTS: From 52 eligible studies, we identified 12 externally validated models: six were developed for OS, one for PFS and five for TFS. In general, reporting of the studies was poor, especially predictive performance measures for calibration and discrimination; but also basic information, such as eligibility criteria and the recruitment period of participants was often missing. We rated almost all studies at high or unclear risk of bias according to PROBAST. Overall, the applicability of the models and their validation studies was low or unclear; the most common reasons were inappropriate handling of missing data and serious reporting deficiencies concerning eligibility criteria, recruitment period, observation time and prediction performance measures. We report the results for three models predicting OS, which had available data from more than three external validation studies: CLL International Prognostic Index (CLL-IPI) This score includes five prognostic factors: age, clinical stage, IgHV mutational status, B2-microglobulin and TP53 status. Calibration: for the low-, intermediate- and high-risk groups, the pooled five-year survival per risk group from validation studies corresponded to the frequencies observed in the model development study. In the very high-risk group, predicted survival from CLL-IPI was lower than observed from external validation studies. Discrimination: the pooled c-statistic of seven external validation studies (3307 participants, 917 events) was 0.72 (95% confidence interval (CI) 0.67 to 0.77). The 95% prediction interval (PI) of this model for the c-statistic, which describes the expected interval for the model's discriminative ability in a new external validation study, ranged from 0.59 to 0.83. Barcelona-Brno score Aimed at simplifying the CLL-IPI, this score includes three prognostic factors: IgHV mutational status, del(17p) and del(11q). Calibration: for the low- and intermediate-risk group, the pooled survival per risk group corresponded to the frequencies observed in the model development study, although the score seems to overestimate survival for the high-risk group. Discrimination: the pooled c-statistic of four external validation studies (1755 participants, 416 events) was 0.64 (95% CI 0.60 to 0.67); 95% PI 0.59 to 0.68. MDACC 2007 index score The authors presented two versions of this model including six prognostic factors to predict OS: age, B2-microglobulin, absolute lymphocyte count, gender, clinical stage and number of nodal groups. Only one validation study was available for the more comprehensive version of the model, a formula with a nomogram, while seven studies (5127 participants, 994 events) validated the simplified version of the model, the index score. Calibration: for the low- and intermediate-risk groups, the pooled survival per risk group corresponded to the frequencies observed in the model development study, although the score seems to overestimate survival for the high-risk group. Discrimination: the pooled c-statistic of the seven external validation studies for the index score was 0.65 (95% CI 0.60 to 0.70); 95% PI 0.51 to 0.77. AUTHORS' CONCLUSIONS: Despite the large number of published studies of prognostic models for OS, PFS or TFS for newly-diagnosed, untreated adults with CLL, only a minority of these (N = 12) have been externally validated for their respective primary outcome. Three models have undergone sufficient external validation to enable meta-analysis of the model's ability to predict survival outcomes. Lack of reporting prevented us from summarising calibration as recommended. Of the three models, the CLL-IPI shows the best discrimination, despite overestimation. However, performance of the models may change for individuals with CLL who receive improved treatment options, as the models included in this review were tested mostly on retrospective cohorts receiving a traditional treatment regimen. In conclusion, this review shows a clear need to improve the conducting and reporting of both prognostic model development and external validation studies. For prognostic models to be used as tools in clinical practice, the development of the models (and their subsequent validation studies) should adapt to include the latest therapy options to accurately predict performance. Adaptations should be timely.


Assuntos
Leucemia Linfocítica Crônica de Células B/mortalidade , Modelos Teóricos , Adulto , Fatores Etários , Viés , Biomarcadores Tumorais , Calibragem , Intervalos de Confiança , Análise Discriminante , Intervalo Livre de Doença , Feminino , Genes p53/genética , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Estadiamento de Neoplasias , Prognóstico , Intervalo Livre de Progressão , Receptores de Antígenos de Linfócitos B/genética , Reprodutibilidade dos Testes , Proteína Supressora de Tumor p53/genética
17.
Nat Commun ; 11(1): 3904, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32764536

RESUMO

A major challenge in chemotherapy is chemotherapy resistance in cells lacking p53. Here we demonstrate that NIP30, an inhibitor of the oncogenic REGγ-proteasome, attenuates cancer cell growth and sensitizes p53-compromised cells to chemotherapeutic agents. NIP30 acts by binding to REGγ via an evolutionarily-conserved serine-rich domain with 4-serine phosphorylation. We find the cyclin-dependent phosphatase CDC25A is a key regulator for NIP30 phosphorylation and modulation of REGγ activity during the cell cycle or after DNA damage. We validate CDC25A-NIP30-REGγ mediated regulation of the REGγ target protein p21 in vivo using p53-/- and p53/REGγ double-deficient mice. Moreover, Phosphor-NIP30 mimetics significantly increase the growth inhibitory effect of chemotherapeutic agents in vitro and in vivo. Given that NIP30 is frequently mutated in the TCGA cancer database, our results provide insight into the regulatory pathway controlling the REGγ-proteasome in carcinogenesis and offer a novel approach to drug-resistant cancer therapy.


Assuntos
Autoantígenos/metabolismo , Proteínas Nucleares/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/metabolismo , Proteína Supressora de Tumor p53/deficiência , Animais , Autoantígenos/genética , Ciclo Celular , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Resistencia a Medicamentos Antineoplásicos , Células HEK293 , Xenoenxertos , Humanos , Camundongos , Camundongos Knockout , Proteínas Nucleares/genética , Fosforilação , Complexo de Endopeptidases do Proteassoma/deficiência , Complexo de Endopeptidases do Proteassoma/genética , Proteína Supressora de Tumor p53/genética , Fosfatases cdc25/metabolismo
18.
PLoS Genet ; 16(8): e1008953, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32776944

RESUMO

Apoptosis of cochlear hair cells is a key step towards age-related hearing loss. Although numerous genes have been implicated in the genetic causes of late-onset, progressive hearing loss, few show direct links to the proapoptotic process. By genome-wide linkage analysis and whole exome sequencing, we identified a heterozygous p.L183V variant in THOC1 as the probable cause of the late-onset, progressive, non-syndromic hearing loss in a large family with autosomal dominant inheritance. Thoc1, a member of the conserved multisubunit THO/TREX ribonucleoprotein complex, is highly expressed in mouse and zebrafish hair cells. The thoc1 knockout (thoc1 mutant) zebrafish generated by gRNA-Cas9 system lacks the C-startle response, indicative of the hearing dysfunction. Both Thoc1 mutant and knockdown zebrafish have greatly reduced hair cell numbers, while the latter can be rescued by embryonic microinjection of human wild-type THOC1 mRNA but to significantly lesser degree by the c.547C>G mutant mRNA. The Thoc1 deficiency resulted in marked apoptosis in zebrafish hair cells. Consistently, transcriptome sequencing of the mutants showed significantly increased gene expression in the p53-associated signaling pathway. Depletion of p53 or applying the p53 inhibitor Pifithrin-α significantly rescued the hair cell loss in the Thoc1 knockdown zebrafish. Our results suggested that THOC1 deficiency lead to late-onset, progressive hearing loss through p53-mediated hair cell apoptosis. This is to our knowledge the first human disease associated with THOC1 mutations and may shed light on the molecular mechanism underlying the age-related hearing loss.


Assuntos
Proteínas de Ligação a DNA/genética , Surdez/genética , Células Ciliadas Auditivas Internas/metabolismo , Proteínas de Ligação a RNA/genética , Proteína Supressora de Tumor p53/genética , Animais , Apoptose/genética , Benzotiazóis/farmacologia , Proteína 9 Associada à CRISPR/genética , Proteínas de Ligação a DNA/deficiência , Surdez/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Inativação de Genes , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Auditivas/patologia , Células Ciliadas Auditivas Internas/patologia , Humanos , Camundongos , Mutação , RNA Guia/genética , Transdução de Sinais/efeitos dos fármacos , Tolueno/análogos & derivados , Tolueno/farmacologia , Proteína Supressora de Tumor p53/antagonistas & inibidores , Sequenciamento Completo do Exoma , Peixe-Zebra/genética
19.
Nat Commun ; 11(1): 3644, 2020 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-32686686

RESUMO

Colorectal cancer (CRC) is a biologically heterogeneous disease. To characterize its mutational profile, we conduct targeted sequencing of 205 genes for 2,105 CRC cases with survival data. Our data shows several findings in addition to enhancing the existing knowledge of CRC. We identify PRKCI, SPZ1, MUTYH, MAP2K4, FETUB, and TGFBR2 as additional genes significantly mutated in CRC. We find that among hypermutated tumors, an increased mutation burden is associated with improved CRC-specific survival (HR = 0.42, 95% CI: 0.21-0.82). Mutations in TP53 are associated with poorer CRC-specific survival, which is most pronounced in cases carrying TP53 mutations with predicted 0% transcriptional activity (HR = 1.53, 95% CI: 1.21-1.94). Furthermore, we observe differences in mutational frequency of several genes and pathways by tumor location, stage, and sex. Overall, this large study provides deep insights into somatic mutations in CRC, and their potential relationships with survival and tumor features.


Assuntos
Neoplasias Colorretais/genética , Proteínas de Neoplasias/genética , Neoplasias do Colo/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação INDEL , Mutação , Prognóstico , Proteína Supressora de Tumor p53/genética
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