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1.
Gene ; 766: 145151, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-32950635

RESUMO

Smoking tobacco is the major hazard for lung cancer in Indian subcontinent especially men, compare to woman where, other important risk factors such as air pollutions are responsible. So, the aim of the study is to compare chronic smokers (CS) and non-smokers living in areas with air quality categorized as poor (AQI 201-300) or moderate (AQI 101-200). We measured the expression of non-small cell lung cancer (NSCLC) biomarkers;. IDH1, CEA, Cyfra21-1, and TPA through quantitative Real-Time PCR (qRT-PCR) and compared the levels of upregulation of the transcripts in stage IIIa NSCLC over control benign tissues among the smoking and AQI settings. Though the all biomarkers were significantly up-regulated in tumor tissues compared to control benign tissues, the fold change increase of IDH1 and CEA was highest in CS-poor/moderate AQI, followed by non-smokers-poor AQI and non-smokers moderate AQI. This indicates the aggressiveness and poor prognosis in CS living in either poor or moderate AQI areas. The level of Cyfra21-1 was lower in in the CS groups in comparison to non-smokers in the poor AQI area. This suggest higher Lung Squamous cell carcinoma histology in non-smokers living areas with poor AQI. Hence, we conclude that poor air quality can be as injurious for lung cancers as chronic smoking.


Assuntos
Antígenos de Neoplasias/genética , Antígeno Carcinoembrionário/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Isocitrato Desidrogenase/genética , Queratina-19/genética , Neoplasias Pulmonares/genética , Fumar/genética , Poluição do Ar , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/genética , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , não Fumantes , Prognóstico , Fumantes , Transcriptoma/genética
2.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(10): 884-889, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33148382

RESUMO

Objective To analyze the physicochemical properties, structure and function of melanoma-associated antigen D4 (MAGE-D4) protein, and then construct the eukaryotic expression vector of MAGE-D4. Methods The physicochemical properties, structure and function of MAGE-D4 protein were analyzed by bioinformatics. Using MAGE-D4/pMAL-C2 prokaryotic recombinant plasmid as the template, PCR product digested by restriction enzyme was connected with pEGFP-C1 eukaryotic expression plasmid and transformed into E. coli. Ligation products were identified by antibiotic screening, enzyme digestion and sequencing. Then the recombinant plasmid was transfected into A549 lung cancer cells by liposome. Results MAGE-D4 protein was an unstable hydrophilic protein without transmembrane structure and signal peptide. Its secondary structure was mainly α-helix. MAGE-D4 contained multiple functional modification sites and was mainly located in the nucleus. SLLLVILGV might be a restricted T cell epitope of HLA-A*0201 derived from MAGE-D4. The first three proteins to potentially interact with MAGE-D4 were NSMCE4A, MLANA/MART-1 and BAGE5. DNA sequencing showed that the recombinant plasmid contained full-length coding sequence (CDS) of MAGE-D4 and it could be successfully transfected into A549 lung cancer cells. Conclusion MAGE-D4 protein is an unstable nuclear protein, which may play functions by interacting with a variety of melanoma-related proteins. The peptide derived from MAGE-D4 may have strong immunogenicity. The eukaryotic expression vector of MAGE-D4 has been successfully constructed.


Assuntos
Antígenos de Neoplasias/genética , Biologia Computacional , Vetores Genéticos , Proteínas de Neoplasias/genética , Células A549 , Epitopos de Linfócito T , Escherichia coli , Eucariotos , Vetores Genéticos/genética , Humanos , Plasmídeos/genética , Transfecção
3.
PLoS One ; 15(10): e0225487, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33119615

RESUMO

Receptor for advanced glycation end products (RAGE) has been implicated in the pathophysiology of Alzheimers disease(AD) due to its ability to bind amyloid-beta (Aß42) and mediate inflammatory response. G82S RAGE polymorphism is associated with AD but the molecular mechanism for this association is not understood. Our previous in silico study indicated a higher binding affinity for mutated G82S RAGE, which could be caused due to changes in N linked glycosylation at residue N81. To confirm this hypothesis, in the present study molecular dynamics (MD) simulations were used to simulate the wild type (WT) and G82S glycosylated structures of RAGE to identify the global structural changes and to find the binding efficiency with Aß42 peptide. Binding pocket analysis of the MD trajectory showed that cavity/binding pocket in mutant G82S glycosylated RAGE variants is more exposed and accessible to external ligands compared to WT RAGE, which can enhance the affinity of RAGE for Aß. To validate the above concept, an in vitro binding study was carried using SHSY5Y cell line expressing recombinant WT and mutated RAGE variant individually to which HiLyte Fluor labeled Aß42 was incubated at different concentrations. Saturated binding kinetics method was adopted to determine the Kd values for Aß42 binding to RAGE. The Kd value for Aß42- WT and Aß42-mutant RAGE binding were 92±40 nM (95% CI-52 to 152nM; R2-0.92) and 45±20 nM (95% CI -29 to 64nM; R2-0.93), respectively. The Kd value of <100nM observed for both variants implicates RAGE as a high-affinity receptor for Aß42 and mutant RAGE has higher affinity compared to WT. The alteration in binding affinity is responsible for activation of the inflammatory pathway as implicated by enhanced expression of TNFα and IL6 in mutant RAGE expressing cell line which gives a mechanistic view for the G82S RAGE association with AD.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Antígenos de Neoplasias/química , Antígenos de Neoplasias/metabolismo , Proteínas Quinases Ativadas por Mitógeno/química , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Polimorfismo de Nucleotídeo Único , Antígenos de Neoplasias/genética , Sítios de Ligação , Linhagem Celular , Cristalografia por Raios X , Predisposição Genética para Doença , Glicosilação , Humanos , Interleucina-6/genética , Proteínas Quinases Ativadas por Mitógeno/genética , Modelos Moleculares , Simulação de Dinâmica Molecular , Ligação Proteica , Fator de Necrose Tumoral alfa/genética
4.
Nat Commun ; 11(1): 4931, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004795

RESUMO

Testis-restricted melanoma antigen (MAGE) proteins are frequently hijacked in cancer and play a critical role in tumorigenesis. MAGEs assemble with E3 ubiquitin ligases and function as substrate adaptors that direct the ubiquitination of novel targets, including key tumor suppressors. However, how MAGEs recognize their targets is unknown and has impeded the development of MAGE-directed therapeutics. Here, we report the structural basis for substrate recognition by MAGE ubiquitin ligases. Biochemical analysis of the degron motif recognized by MAGE-A11 and the crystal structure of MAGE-A11 bound to the PCF11 substrate uncovered a conserved substrate binding cleft (SBC) in MAGEs. Mutation of the SBC disrupted substrate recognition by MAGEs and blocked MAGE-A11 oncogenic activity. A chemical screen for inhibitors of MAGE-A11:substrate interaction identified 4-Aminoquinolines as potent inhibitors of MAGE-A11 that show selective cytotoxicity. These findings provide important insights into the large family of MAGE ubiquitin ligases and identify approaches for developing cancer-specific therapeutics.


Assuntos
Antígenos de Neoplasias/ultraestrutura , Proteínas de Neoplasias/ultraestrutura , Neoplasias/tratamento farmacológico , Ubiquitina-Proteína Ligases/metabolismo , Fatores de Poliadenilação e Clivagem de mRNA/metabolismo , Motivos de Aminoácidos , Aminoquinolinas/farmacologia , Aminoquinolinas/uso terapêutico , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinogênese/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Células HeLa , Ensaios de Triagem em Larga Escala , Humanos , Mutagênese , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/patologia , Estudo de Prova de Conceito , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/genética , Domínios Proteicos/genética , Mapeamento de Interação de Proteínas , Relação Estrutura-Atividade , Especificidade por Substrato/efeitos dos fármacos , Especificidade por Substrato/genética , Ubiquitinação/efeitos dos fármacos , Ubiquitinação/genética
5.
Nat Commun ; 11(1): 5332, 2020 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-33087697

RESUMO

Cytotoxic T lymphocyte (CTL)-based cancer immunotherapies have shown great promise for inducing clinical regressions by targeting tumor-associated antigens (TAA). To expand the TAA landscape of pancreatic ductal adenocarcinoma (PDAC), we performed tandem mass spectrometry analysis of HLA class I-bound peptides from 35 PDAC patient tumors. This identified a shared HLA-A*0101 restricted peptide derived from co-transcriptional activator Vestigial-like 1 (VGLL1) as a putative TAA demonstrating overexpression in multiple tumor types and low or absent expression in essential normal tissues. Here we show that VGLL1-specific CTLs expanded from the blood of a PDAC patient could recognize and kill in an antigen-specific manner a majority of HLA-A*0101 allogeneic tumor cell lines derived not only from PDAC, but also bladder, ovarian, gastric, lung, and basal-like breast cancers. Gene expression profiling reveals VGLL1 as a member of a unique group of cancer-placenta antigens (CPA) that may constitute immunotherapeutic targets for patients with multiple cancer types.


Assuntos
Antígenos de Neoplasias/imunologia , Neoplasias da Mama/imunologia , Proteínas de Ligação a DNA/imunologia , Neoplasias Pancreáticas/imunologia , Fatores de Transcrição/imunologia , Antígenos de Neoplasias/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Neoplasias da Mama/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/terapia , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Proteínas de Ligação a DNA/genética , Feminino , Perfilação da Expressão Gênica , Antígeno HLA-A1/imunologia , Humanos , Imunoterapia Adotiva , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , Placenta/imunologia , Gravidez , Prognóstico , Linfócitos T Citotóxicos/imunologia , Fatores de Transcrição/genética
6.
Nat Commun ; 11(1): 4740, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958755

RESUMO

The immune system can recognize and attack cancer cells, especially those with a high load of mutation-induced neoantigens. Such neoantigens are abundant in DNA mismatch repair (MMR)-deficient, microsatellite-unstable (MSI) cancers. MMR deficiency leads to insertion/deletion (indel) mutations at coding microsatellites (cMS) and to neoantigen-inducing translational frameshifts. Here, we develop a tool to quantify frameshift mutations in MSI colorectal and endometrial cancer. Our results show that frameshift mutation frequency is negatively correlated to the predicted immunogenicity of the resulting peptides, suggesting counterselection of cell clones with highly immunogenic frameshift peptides. This correlation is absent in tumors with Beta-2-microglobulin mutations, and HLA-A*02:01 status is related to cMS mutation patterns. Importantly, certain outlier mutations are common in MSI cancers despite being related to frameshift peptides with functionally confirmed immunogenicity, suggesting a possible driver role during MSI tumor evolution. Neoantigens resulting from shared mutations represent promising vaccine candidates for prevention of MSI cancers.


Assuntos
Mutação da Fase de Leitura , Repetições de Microssatélites/genética , Neoplasias/genética , Neoplasias/imunologia , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Antígenos HLA/genética , Humanos , Mutação INDEL , Vigilância Imunológica , Instabilidade de Microssatélites , Taxa de Mutação , Seleção Genética , Microglobulina beta-2/genética
7.
Nucleic Acids Res ; 48(18): 10313-10328, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-32976585

RESUMO

Transcription of integrated DNA from viruses or transposable elements is tightly regulated to prevent pathogenesis. The Human Silencing Hub (HUSH), composed of Periphilin, TASOR and MPP8, silences transcriptionally active viral and endogenous transgenes. HUSH recruits effectors that alter the epigenetic landscape and chromatin structure, but how HUSH recognizes target loci and represses their expression remains unclear. We identify the physicochemical properties of Periphilin necessary for HUSH assembly and silencing. A disordered N-terminal domain (NTD) and structured C-terminal domain are essential for silencing. A crystal structure of the Periphilin-TASOR minimal core complex shows Periphilin forms an α-helical homodimer, bound by a single TASOR molecule. The NTD forms insoluble aggregates through an arginine/tyrosine-rich sequence reminiscent of low-complexity regions from self-associating RNA-binding proteins. Residues required for TASOR binding and aggregation were required for HUSH-dependent silencing and genome-wide deposition of repressive mark H3K9me3. The NTD was functionally complemented by low-complexity regions from certain RNA-binding proteins and proteins that form condensates or fibrils. Our work suggests the associative properties of Periphilin promote HUSH aggregation at target loci.


Assuntos
Antígenos de Neoplasias/ultraestrutura , Proteínas Nucleares/ultraestrutura , Proteínas de Ligação a RNA/química , Transcrição Genética , Antígenos de Neoplasias/química , Antígenos de Neoplasias/genética , Cristalografia por Raios X , Elementos de DNA Transponíveis/genética , Epigênese Genética/genética , Inativação Gênica , Humanos , Proteínas Nucleares/química , Proteínas Nucleares/genética , Fosfoproteínas/química , Fosfoproteínas/genética , Agregados Proteicos/genética , Ligação Proteica/genética , Conformação Proteica em alfa-Hélice , Domínios Proteicos/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/ultraestrutura , Vírus/genética
8.
Autophagy ; 16(10): 1923-1924, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32809888

RESUMO

The melanoma-associated antigen family A (MAGEA) antigens are expressed in a wide variety of malignant tumors but not in adult somatic cells, rendering them attractive targets for cancer immunotherapy. Recent studies uncovered a role for MAGEA6 in suppression of macroautophagy/autophagy implicating MAGEA6 in tumorigenesis. The impact of cancer-associated MAGEA6 mutations on tumor pathophysiology are less well explored. In pancreatic cancer cell models, MAGEA6 inhibits autophagy, facilitating pancreatic cancer initiation. However, autophagy places a brake on cancer progression and is released upon MAGEA6 degradation, which can be induced by nutrient deficiency or by acquisition of cancer-associated mutations that reinstitute autophagy. Further cancer-associated mutations of the broader MAGEA genes frequently result in degradation of the corresponding protein products by proteasome-dependent machinery, potentially jeopardizing the utility of MAGEA genes as immunotherapeutic targets. Altogether, our findings provide mechanistic insight into the divergent roles of MAGEA6 during pancreatic cancer initiation and progression, and could inform cancer immunotherapeutic strategies for targeting MAGEA antigens.


Assuntos
Autofagia , Neoplasias Pancreáticas , Adulto , Antígenos de Neoplasias/genética , Humanos , Imunoterapia , Proteínas de Neoplasias/genética , Pâncreas , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia
9.
PLoS One ; 15(8): e0237814, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32804975

RESUMO

Schaaf-Yang syndrome (SYS) is a neurodevelopmental disorder caused by truncating variants in the paternal allele of MAGEL2, located in the Prader-Willi critical region, 15q11-q13. Although the phenotypes of SYS overlap those of Prader-Willi syndrome (PWS), including neonatal hypotonia, feeding problems, and developmental delay/intellectual disability, SYS patients show autism spectrum disorder and joint contractures, which are atypical phenotypes for PWS. Therefore, we hypothesized that the truncated Magel2 protein could potentially produce gain-of-function toxic effects. To test the hypothesis, we generated two engineered mouse models; one, an overexpression model that expressed the N-terminal region of Magel2 that was FLAG tagged with a strong ubiquitous promoter, and another, a genome-edited model that carried a truncating variant in Magel2 generated using the CRISPR/Cas9 system. In the overexpression model, all transgenic mice died in the fetal or neonatal period indicating embryonic or neonatal lethality of the transgene. Therefore, overexpression of the truncated Magel2 could show toxic effects. In the genome-edited model, we generated a mouse model carrying a frameshift variant (c.1690_1924del; p(Glu564Serfs*130)) in Magel2. Model mice carrying the frameshift variant in the paternal or maternal allele of Magel2 were termed Magel2P:fs and Magel2M:fs, respectively. The imprinted expression and spatial distribution of truncating Magel2 transcripts in the brain were maintained. Although neonatal Magel2P:fs mice were lighter than wildtype littermates, Magel2P:fs males and females weighed the same as their wildtype littermates by eight and four weeks of age, respectively. Collectively, the overexpression mouse model may recapitulate fetal or neonatal death, which are the severest phenotypes for SYS. In contrast, the genome-edited mouse model maintains genomic imprinting and distribution of truncated Magel2 transcripts in the brain, but only partially recapitulates SYS phenotypes. Therefore, our results imply that simple gain-of-function toxic effects may not explain the patho-mechanism of SYS, but rather suggest a range of effects due to Magel2 variants as in human SYS patients.


Assuntos
Antígenos de Neoplasias/genética , Mutação/genética , Proteínas/genética , Animais , Antígenos de Neoplasias/química , Antígenos de Neoplasias/metabolismo , Peso Corporal , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Edição de Genes , Regulação da Expressão Gênica , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Linhagem , Fenótipo , Proteínas/química , Proteínas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
10.
Yi Chuan ; 42(6): 599-612, 2020 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-32694118

RESUMO

Colorectal cancer (CRC) is a malignant cancer with high incidence and mortality in the world. Immunotherapy targeting neoantigens can induce durable tumor regression in cancer patients, but is almost limited to personalized precision therapy, due to the individual differences of unique neoantigens. With the discovery of many common oncogenic mutations, and such mutation-associated neoantigens could cover more patients, and hence are valuable in clinical field. However, whether the common neoantigens can be identified in CRC is unknown. Combining the somatic mutations data from 321 CRC patients with a filter standard and 7 predicted algorithms, we screened and obtained 25 HLA-A*1101-restricted common neoantigens with a high binding affinity (IC50<50 nmol/L) and presentation score (>0.90). Besides the positive epitope KRAS_G12V8-16, 11 out of 25 common neoantigens specifically induced in vitro pre- stimulated cytotoxic lymphocyte (CTL) to secrete interferon gamma (IFN-γ). Moreover, combining cell-sorting technology and single-cell RNA sequencing, the immune repertoire profiles of C1orf170_S418G413-421 and KRAS_G12V8-16-specific CTL were analyzed and validated. Their related T-cell receptor engineered T cell (TCR-T) cells could also recognize the neoantigens and secrete IFN-γ. Hence, we have established a method to screen for common neoantigens with immunogenicity in CRC based on the public somatic mutation library. It can provide essential peptide and TCR information for immunotherapies, such as peptides, dendritic cells (DC) vaccines, TCR-like antibodies, TCR-T, etc., for the CRC and other cancers, which has practical application value in the clinics.


Assuntos
Antígenos de Neoplasias , Neoplasias Colorretais , Antígenos de Neoplasias/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/terapia , Detecção Precoce de Câncer , Humanos , Mutação , Receptores de Antígenos de Linfócitos T/genética
11.
Mol Cell ; 79(4): 645-659.e9, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32692974

RESUMO

Stress granules (SGs) are membrane-less ribonucleoprotein condensates that form in response to various stress stimuli via phase separation. SGs act as a protective mechanism to cope with acute stress, but persistent SGs have cytotoxic effects that are associated with several age-related diseases. Here, we demonstrate that the testis-specific protein, MAGE-B2, increases cellular stress tolerance by suppressing SG formation through translational inhibition of the key SG nucleator G3BP. MAGE-B2 reduces G3BP protein levels below the critical concentration for phase separation and suppresses SG initiation. Knockout of the MAGE-B2 mouse ortholog or overexpression of G3BP1 confers hypersensitivity of the male germline to heat stress in vivo. Thus, MAGE-B2 provides cytoprotection to maintain mammalian spermatogenesis, a highly thermosensitive process that must be preserved throughout reproductive life. These results demonstrate a mechanism that allows for tissue-specific resistance against stress and could aid in the development of male fertility therapies.


Assuntos
Grânulos Citoplasmáticos/genética , DNA Helicases/genética , Proteínas de Ligação a Poli-ADP-Ribose/genética , Biossíntese de Proteínas , RNA Helicases/genética , Proteínas com Motivo de Reconhecimento de RNA/genética , Estresse Fisiológico/genética , Regiões 5' não Traduzidas , Animais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Grânulos Citoplasmáticos/metabolismo , Grânulos Citoplasmáticos/patologia , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , DNA Helicases/metabolismo , Feminino , Células HCT116 , Células HeLa , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , RNA Helicases/metabolismo , Proteínas com Motivo de Reconhecimento de RNA/metabolismo , Espermatogônias/citologia , Espermatogônias/patologia , Testículo/citologia , Testículo/metabolismo
13.
BMC Med Genet ; 21(1): 148, 2020 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-32660489

RESUMO

BACKGROUND: Gastric cancer is one of the four most common cancer that causing death worldwide. Genome-Wide Association Studies (GWAS) have shown that genetic diversities MUC1 (Mucin 1) and PSCA (Prostate Stem Cell Antigen) genes are involved in gastric cancer. The aim of this study was avaluating the association of rs4072037G > A polymorphism in MUC1 and rs2294008 C > T in PSCA gene with risk of gastric cancer in northern Iran. METHODS: DNA was extracted from 99 formalin fixed paraffin-embedded (FFPE) tissue samples of gastric cancer and 96 peripheral blood samples from healthy individuals (sex matched) as controls. Two desired polymorphisms, 5640G > A and 5057C > T for MUC1 and PSCA genes were genotyped using PCR-RFLP method. RESULTS: The G allele at rs4072037 of MUC1 gene was associated with a significant decreased gastric cancer risk (OR = 0.507, 95% CI: 0.322-0.799, p = 0.003). A significant decreased risk of gastric cancer was observed in people with either AG vs. AA, AG + AA vs. GG and AA+GG vs. AG genotypes of MUC1 polymorphism (OR = 4.296, 95% CI: 1.190-15.517, p = 0.026), (OR = 3.726, 95% CI: 2.033-6.830, p = 0.0001) and (OR = 0.223, 95% CI: 0.120-0.413, p = 0.0001) respectively. Finally, there was no significant association between the PSCA 5057C > T polymorphism and risk of gastric cancer in all genetic models. CONCLUSION: Results indicated that the MUC1 5640G > A polymorphism may have protective effect for gastric cancer in the Northern Iran population and could be considered as a potential molecular marker in gastric cancer.


Assuntos
Antígenos de Neoplasias/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Mucina-1/genética , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único/genética , Neoplasias Gástricas/genética , Idoso , Estudos de Casos e Controles , Feminino , Proteínas Ligadas por GPI/genética , Frequência do Gene/genética , Humanos , Irã (Geográfico) , Masculino , Fatores de Risco
14.
Biochim Biophys Acta Rev Cancer ; 1874(1): 188384, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32531324

RESUMO

Cancer regression often fails after systemic immune activation, especially for solid tumors due to their local immunosuppressive microenvironments. Among these, the pancreatic cancer microenvironment is unique and an important reason for resistance to anti-cancer treatments that include immunotherapy. In this review, the three main "BAD" characteristics that create and maintain this immunosuppressive microenvironment are discussed for effector T cells: Barriers to overcome, Attraction problems, and their Disabilities. These inhibit both effector T-cell activation and infiltration, reducing immunotherapy effectiveness. Combination approaches for killing the "BAD" aim to normalize the tumor microenvironment and are recommended to enhance anti-cancer immune-system efficacy in pancreatic cancer.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imunoterapia Adotiva/métodos , Neoplasias Pancreáticas/terapia , Microambiente Tumoral/efeitos dos fármacos , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Antineoplásicos Imunológicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Humanos , Ativação Linfocitária/efeitos dos fármacos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Mutação , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Resultado do Tratamento , Evasão Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
15.
J Pathol ; 251(3): 336-347, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32432338

RESUMO

Intestinal-type gastric adenocarcinoma arises in a field of pre-existing metaplasia. While biomarkers of cancer and metaplasia have been identified, the definition of dysplastic transition as a critical point in the evolution of cancer has remained obscure. We have evaluated Trop2 as a putative marker of the transition from metaplasia to dysplasia in the stomach in multiple mouse models of metaplasia induction and progression. In addition, TROP2 expression was evaluated in human samples by immunostaining tissue microarrays for metaplasia, dysplasia, and gastric cancer. Dysplastic mouse organoids were evaluated in vitro following shRNA knockdown of Trop2 expression. In mouse models, no Trop2 was observed in the normal corpus and Trop2 was not induced in acute models of metaplasia induction with either L635 or DMP-777. In Mist1-Kras mice, Trop2 expression was not observed in metaplasia at 1 month after Kras induction, but was observed in dysplastic glands at 3-4 months after Kras induction. In human tissues, no Trop2 was observed in normal corpus mucosa or SPEM, but Trop2 expression was observed in incomplete intestinal metaplasia, with significantly less expression in complete intestinal metaplasia. Trop2 expression was observed in all dysplastic and 84% of gastric cancer lesions, although expression levels were variable. Dysplastic mouse organoids from Mist1-Kras mice expressed Trop2 strongly. Knockdown of Trop2 with shRNA markedly reduced organoid growth and budding behavior, and induced the upregulation of apical villin expression. We conclude that Trop2 is upregulated in the transition to dysplasia in the stomach and promotes dysplastic cell behaviors. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Antígenos de Neoplasias/metabolismo , Moléculas de Adesão Celular/metabolismo , Transformação Celular Neoplásica/metabolismo , Mucosa Gástrica/metabolismo , Lesões Pré-Cancerosas/metabolismo , Neoplasias Gástricas/metabolismo , Animais , Antígenos de Neoplasias/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Moléculas de Adesão Celular/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Células Cultivadas , Modelos Animais de Doenças , Mucosa Gástrica/patologia , Genes ras , Humanos , Metaplasia , Camundongos Transgênicos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Organoides , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia , Transdução de Sinais , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Regulação para Cima
16.
Nat Med ; 26(7): 1054-1062, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32461698

RESUMO

Remarkable progress in molecular analyses has improved our understanding of the evolution of cancer cells toward immune escape1-5. However, the spatial configurations of immune and stromal cells, which may shed light on the evolution of immune escape across tumor geographical locations, remain unaddressed. We integrated multiregion exome and RNA-sequencing (RNA-seq) data with spatial histology mapped by deep learning in 100 patients with non-small cell lung cancer from the TRACERx cohort6. Cancer subclones derived from immune cold regions were more closely related in mutation space, diversifying more recently than subclones from immune hot regions. In TRACERx and in an independent multisample cohort of 970 patients with lung adenocarcinoma, tumors with more than one immune cold region had a higher risk of relapse, independently of tumor size, stage and number of samples per patient. In lung adenocarcinoma, but not lung squamous cell carcinoma, geometrical irregularity and complexity of the cancer-stromal cell interface significantly increased in tumor regions without disruption of antigen presentation. Decreased lymphocyte accumulation in adjacent stroma was observed in tumors with low clonal neoantigen burden. Collectively, immune geospatial variability elucidates tumor ecological constraints that may shape the emergence of immune-evading subclones and aggressive clinical phenotypes.


Assuntos
Adenocarcinoma de Pulmão/genética , Antígenos de Neoplasias/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Recidiva Local de Neoplasia/genética , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/patologia , Antígenos de Neoplasias/imunologia , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Aprendizado Profundo , Exoma/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , RNA-Seq , Recidiva , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Sequenciamento Completo do Exoma
17.
Science ; 368(6490): 497-505, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32355025

RESUMO

Androgen deprivation is the cornerstone of prostate cancer treatment. It results in involution of the normal gland to ~90% of its original size because of the loss of luminal cells. The prostate regenerates when androgen is restored, a process postulated to involve stem cells. Using single-cell RNA sequencing, we identified a rare luminal population in the mouse prostate that expresses stemlike genes (Sca1 + and Psca +) and a large population of differentiated cells (Nkx3.1 +, Pbsn +). In organoids and in mice, both populations contribute equally to prostate regeneration, partly through androgen-driven expression of growth factors (Nrg2, Rspo3) by mesenchymal cells acting in a paracrine fashion on luminal cells. Analysis of human prostate tissue revealed similar differentiated and stemlike luminal subpopulations that likewise acquire enhanced regenerative potential after androgen ablation. We propose that prostate regeneration is driven by nearly all persisting luminal cells, not just by rare stem cells.


Assuntos
Androgênios/metabolismo , Próstata/fisiologia , Próstata/cirurgia , Neoplasias da Próstata/cirurgia , Regeneração , Antagonistas de Androgênios/uso terapêutico , Proteína de Ligação a Androgênios/genética , Animais , Antígenos de Neoplasias/genética , Ataxina-1/genética , Diferenciação Celular/genética , Proteínas Ligadas por GPI/genética , Expressão Gênica , Proteínas de Homeodomínio/genética , Humanos , Masculino , Células-Tronco Mesenquimais/fisiologia , Camundongos , Proteínas de Neoplasias/genética , Fatores de Crescimento Neural/genética , Tamanho do Órgão , Organoides/metabolismo , Organoides/fisiologia , Próstata/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Regeneração/genética , Análise de Sequência de RNA , Análise de Célula Única , Trombospondinas/genética , Fatores de Transcrição/genética
18.
Nat Commun ; 11(1): 1759, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32273506

RESUMO

Genomics-based neoantigen discovery can be enhanced by proteomic evidence, but there remains a lack of consensus on the performance of different quality control methods for variant peptide identification in proteogenomics. We propose to use the difference between accurately predicted and observed retention times for each peptide as a metric to evaluate different quality control methods. To this end, we develop AutoRT, a deep learning algorithm with high accuracy in retention time prediction. Analysis of three cancer data sets with a total of 287 tumor samples using different quality control strategies results in substantially different numbers of identified variant peptides and putative neoantigens. Our systematic evaluation, using the proposed retention time metric, provides insights and practical guidance on the selection of quality control strategies. We implement the recommended strategy in a computational workflow named NeoFlow to support proteogenomics-based neoantigen prioritization, enabling more sensitive discovery of putative neoantigens.


Assuntos
Antígenos de Neoplasias/metabolismo , Genômica/métodos , Neoplasias/metabolismo , Proteogenômica/métodos , Proteômica/métodos , Algoritmos , Antígenos de Neoplasias/genética , Biologia Computacional/métodos , Aprendizado Profundo , Humanos , Neoplasias/genética , Neoplasias/imunologia , Peptídeos/genética , Peptídeos/imunologia , Peptídeos/metabolismo , Proteoma/genética , Proteoma/imunologia , Proteoma/metabolismo , Espectrometria de Massas em Tandem/métodos
19.
Am J Surg Pathol ; 44(7): 893-900, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32317605

RESUMO

PRAME (PReferentially expressed Antigen in MElanoma) is a melanoma-associated antigen. Although diffuse immunoreactivity for PRAME is found in most primary cutaneous melanomas, melanocytic nevi express PRAME usually only in a subpopulation of tumor cells or not at all. Hence, testing for PRAME expression has the potential to provide useful information for the assessment for diagnostically ambiguous melanocytic neoplasms. Many of the latter tumors are currently studied by cytogenetic methods for ancillary evidence in support of or against a diagnosis of melanoma. In this study we analyzed 110 diagnostically problematic melanocytic tumors comparing results for PRAME immunohistochemistry (IHC) with those from fluorescence in situ hybridization and/or single nucleotide polymorphism-array, and each with the final diagnostic interpretation. In 90% of cases there was concordance between PRAME IHC and cytogenetic tests results, and in 92.7% concordance between PRAME IHC and the final diagnosis. The high concordance between PRAME IHC and cytogenetic test results as well as the final diagnosis supports the use of PRAME IHC as an ancillary test in the evaluation of ambiguous primary cutaneous melanocytic neoplasms, especially given its practical advantage of lower cost and faster turnaround over cytogenetic or gene expression studies. However, our results indicate that PRAME IHC and cytogenetic tests for melanocytic tumors are not entirely interchangeable and on occasion each type of test may yield false-negative or false-positive results.


Assuntos
Antígenos de Neoplasias , Biomarcadores Tumorais , Análise Citogenética , Imuno-Histoquímica , Melanoma/diagnóstico , Nevo Pigmentado/diagnóstico , Neoplasias Cutâneas/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Criança , Pré-Escolar , Diagnóstico Diferencial , Reações Falso-Negativas , Reações Falso-Positivas , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Melanoma/genética , Melanoma/metabolismo , Melanoma/patologia , Pessoa de Meia-Idade , Nevo Pigmentado/genética , Nevo Pigmentado/metabolismo , Nevo Pigmentado/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Adulto Jovem
20.
Sci Rep ; 10(1): 4025, 2020 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-32132574

RESUMO

Non-small-cell lung cancer (NSCLC) represents most of lung cancers, is often diagnosed at an advanced metastatic stage. Therefore, exploring the mechanisms underlying metastasis is key to understanding the development of NSCLC. The expression of B cell receptor-associated protein 31 (BCAP31), calreticulin, glucose-regulated protein 78, and glucose-regulated protein 94 were analyzed using immunohistochemical staining of 360 NSCLC patients. It resulted that the high-level expression of the four proteins, but particularly BCAP31, predicted inferior overall survival. What's more, BCAP31 was closely associated with histological grade and p53 status, which was verified by seven cohorts of NSCLC transcript microarray datasets. Then, three NSCLC cell lines were transfected to observe behavior changes BCAP31 caused, we found the fluctuation of BCAP31 significantly influenced the migration, invasion of NSCLC cells. To identify the pathway utilized by BCAP31, Gene Set Enrichment Analysis was firstly performed, showing Akt/m-TOR/p70S6K pathway was the significant one, which was verified by immunofluorescence, kinase phosphorylation and cellular behavioral observations. Finally, the data of label-free mass spectroscopy implied that BCAP31 plays a role in a fundamental biological process. This study provides the first demonstration of BCAP31 as a novel prognostic factor related to metastasis and suggests a new therapeutic strategy for NSCLC.


Assuntos
Antígenos de Neoplasias/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Transdução de Sinais , Células A549 , Idoso , Antígenos de Neoplasias/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Metástase Neoplásica , Proteínas de Neoplasias/genética , Testículo
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