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1.
Transpl Immunol ; : 102139, 2024 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-39461381

RESUMO

BACKGROUND: To investigate the potential regulatory role of gene insertion or deletion (in/del) polymorphism in the occurrence of acute T cell-mediated rejection (aTCMR) after kidney transplantation. METHODS: We retrospectively analyzed the 5-year follow-up data of 133 recipients who underwent renal transplantation at the First Affiliated Hospital of Nanjing Medical University between February 1, 2010, and December 1, 2015. With target sequencing based on next-generation sequencing (NGS), tagger in/dels selection involved calculating the Hardy-Weinberg equilibrium (HWE), Minor Allele Frequency (MAF), and the linkage disequilibrium (LD) blocks. Significant in/dels associated with aTCMR were identified by intersecting the results obtained through analysis of covariance (ANCOVA) of clinical cofounders and model analysis in Rstudio using the "SNPassoc" package. Additionally, logistic models were employed to assess the associations between genotypes and the aTCMR occurrence in 5 years after surgery. RESULTS: NFATc1 rs55741427 insertion was identified to be significantly associated with the post-surgery aTCMR(OR = 2.66, P < 0.001). We constructed a conclusive model containing the occurrence of delayed graft function (DGF) and the insertion polymorphism of rs55741427, showing a favorable predictive ability (AUC = 0.766) for aTCMR after surgery. Based on the receiver operating characteristic (ROC) curve, all cases were stratified into aTCMR high-risk and low-risk groups. Kaplan-Meier curves for two groups revealed that the aTCMR high-risk group exhibited a more unfavorable graft survival outcome (P = 0.0048). CONCLUSION: Insertion mutation of rs55741427 was found to be statistically correlated with the post-surgery aTCMR during 5 years of follow-up. Our model identified DGF and insertion of rs55741427 as two crucial aTCMR-related hazards, and aTCMR high-risk group showed a worse graft prognosis.

2.
Redox Biol ; 76: 103350, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39265497

RESUMO

BRCA1 is one of the most frequently-mutated tumor suppressor genes in ovarian and breast cancers. Loss of BRCA1 triggers homologous recombination (HR) repair deficiency, consequently leading to genomic instability and PARP inhibitors (PARPi)-associated synthetic lethality. Although, the roles of BRCA1 in DNA repair and replication have been extensively investigated, its tumor suppressive functions beyond genome safeguard remain poorly understood. Here, we report that BRCA1 promotes ferroptosis susceptibility through catalyzing K6-linked polyubiquitination of GPX4 and subsequently accelerating GPX4 degradation. Depletion of BRCA1 induces ferroptosis resistance in ovarian cancer cells due to elevated GPX4 protein, and silence of GPX4 significantly suppresses the growth of BRCA1-deficient ovarian cancer xenografts. Importantly, we found that PARPi triggers ferroptosis in ovarian cancer cells, inhibition of GPX4 markedly increase PARPi-induced ferroptosis in BRCA1-deficient ovarian cancer cells. Combined treatment of GPX4 inhibitor and PARPi produces synergistic anti-tumor efficacy in BRCA1-deficient ovarian cancer cells, patient derived organoid (PDO) and xenografts. Thus, our study uncovers a novel mechanism via which BRCA1 exerts tumor suppressive function through regulating ferroptosis, and demonstrates the potential of GPX4 as a therapeutic target for BRCA1-mutant cancers.


Assuntos
Proteína BRCA1 , Ferroptose , Neoplasias Ovarianas , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Inibidores de Poli(ADP-Ribose) Polimerases , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Ferroptose/efeitos dos fármacos , Ferroptose/genética , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Feminino , Proteína BRCA1/genética , Proteína BRCA1/deficiência , Animais , Camundongos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Ubiquitinação/efeitos dos fármacos
3.
World J Urol ; 42(1): 439, 2024 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-39046536

RESUMO

PURPOSE: To confirm if the CYP17A1 gene regulates the ratio of T/E leading to MetS-BPH. METHODS: 824 men, aged 47-88 years, were recruited into this study through consecutive routine physical examination programs and long-term outpatient screening. Several parameters, including SNPs of CYP17A1 gene, total testosterone, estradiol, and the ratio of total testosterone to estradiol (T/E) were obtained for each participant. Based on the diagnosis of BPH, MetS, and MetS-BPH, the participants were divided into BPH and non-BPH groups, MetS and non-MetS groups, and MetS-BPH and non-MetS-BPH groups. Values of the obtained parameters were evaluated using one-way analysis of variance, Student's t-test, Chi-squared test, and logistic regression analysis. RESULTS: SNPs of the CYP17A1 gene, including the rs743572 genotypes (GG, GA, and AA), rs3781287 genotypes (GG, GT, TT), and rs4919686 genotypes (CC, CA, and AA), were present in every group. Only the GG genotype of rs743572 was independently associated with BPH (OR = 5.868, 95% CI: 3.363-7.974, P < 0.001), MetS (OR = 7.228, 95% CI: 3.925-11.331, P < 0.001), and MetS-BPH (OR = 3.417, 95% CI: 1.783-5.266, P < 0.001) after adjusting for age. In the population of genotype GG of rs743572, the decrease in T/E ratio was an independent risk factor for BPH (OR = 839.756, 95% CI: 36.978-1334.263, P = 0.001), MetS (OR = 376.988, 95% CI: 12.980-488.976, P < 0.003), and MetS-BPH (OR = 388.236, 95% CI: 24.869-495.363, P = 0.003). CONCLUSION: The GG genotype of rs743572 in CYP17A1 gene regulating the decrease of T/E ratio can be an independent risk factor for MetS-BPH populations. TRIAL REGISTRATION NUMBER: ChiCTR2200057632 "retrospectively registered". DATE OF REGISTRATION: March 15, 2022 "retrospectively registered".


Assuntos
Genótipo , Hiperplasia Prostática , Esteroide 17-alfa-Hidroxilase , Testosterona , Humanos , Esteroide 17-alfa-Hidroxilase/genética , Masculino , Pessoa de Meia-Idade , Idoso , Hiperplasia Prostática/genética , Estudos Retrospectivos , Idoso de 80 Anos ou mais , Fatores de Risco , Testosterona/sangue , Estradiol/sangue , Polimorfismo de Nucleotídeo Único , Estudos de Coortes
4.
Drug Resist Updat ; 76: 101120, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39053383

RESUMO

AIMS: This study aimed to elucidate the biological roles and regulatory mechanisms of B-cell lymphoma 7 protein family member A (BCL7A) in acute myeloid leukemia (AML), particularly its interaction with polypyrimidine tract binding protein 1 (PTBP1) and the effects on cancer progression and drug resistance. METHODS: BCL7A expression levels were analyzed in AML tissues and cell lines, focusing on associations with promoter hypermethylation. Interaction with PTBP1 and effects of differential expression of BCL7A were examined in vitro and in vivo. The impacts on cell proliferation, cycle progression, apoptosis, and differentiation were studied. Additionally, the regulatory roles of BCL7A on interferon regulatory factor 7 (IRF7) and 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) were assessed. RESULTS: BCL7A was downregulated in AML due to promoter hypermethylation and negatively regulated by PTBP1. Upregulation of BCL7A impeded AML cell growth, induced apoptosis, promoted cell differentiation, and decreased cell infiltration into lymph nodes, enhancing survival in mouse models. Overexpression of BCL7A upregulated IRF7 and downregulated HMGCS1, linking to reduced AML cell malignancy and decreased resistance to cytarabine. CONCLUSIONS: BCL7A acts as a tumor suppressor in AML, inhibiting malignant progression and enhancing drug sensitivity through the IRF7/HMGCS1 pathway. These findings suggest potential therapeutic targets for improving AML treatment outcomes.


Assuntos
Apoptose , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Ribonucleoproteínas Nucleares Heterogêneas , Leucemia Mieloide Aguda , Proteína de Ligação a Regiões Ricas em Polipirimidinas , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Animais , Camundongos , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , Proteína de Ligação a Regiões Ricas em Polipirimidinas/genética , Proliferação de Células/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas/genética , Metilação de DNA , Regiões Promotoras Genéticas , Progressão da Doença , Ensaios Antitumorais Modelo de Xenoenxerto , Masculino , Feminino , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Diferenciação Celular/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos
5.
Front Immunol ; 15: 1418061, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38903499

RESUMO

Extracellular vesicles (EVs), characterized by low immunogenicity, high biocompatibility and targeting specificity along with excellent blood-brain barrier permeability, are increasingly recognized as promising drug delivery vehicles for treating a variety of diseases, such as cancer, inflammation and viral infection. However, recent findings demonstrate that the intracellular delivery efficiency of EVs fall short of expectations due to phagocytic clearance mediated by the host mononuclear phagocyte system through Fcγ receptors, complement receptors as well as non-opsonic phagocytic receptors. In this text, we investigate a range of bacterial virulence proteins that antagonize host phagocytic machinery, aiming to explore their potential in engineering EVs to counteract phagocytosis. Special emphasis is placed on IdeS secreted by Group A Streptococcus and ImpA secreted by Pseudomonas aeruginosa, as they not only counteract phagocytosis but also bind to highly upregulated surface biomarkers αVß3 on cancer cells or cleave the tumor growth and metastasis-promoting factor CD44, respectively. This suggests that bacterial anti-phagocytic proteins, after decorated onto EVs using pre-loading or post-loading strategies, can not only improve EV-based drug delivery efficiency by evading host phagocytosis and thus achieve better therapeutic outcomes but also further enable an innovative synergistic EV-based cancer therapy approach by integrating both phagocytosis antagonism and cancer targeting or deactivation.


Assuntos
Vesículas Extracelulares , Fagocitose , Vesículas Extracelulares/imunologia , Vesículas Extracelulares/metabolismo , Fagocitose/imunologia , Humanos , Animais , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/imunologia , Neoplasias/imunologia , Neoplasias/terapia , Neoplasias/metabolismo , Integrina alfaVbeta3/metabolismo , Integrina alfaVbeta3/imunologia , Receptores de Hialuronatos/metabolismo , Receptores de Hialuronatos/imunologia , Pseudomonas aeruginosa/imunologia
6.
Front Pharmacol ; 15: 1329220, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38425652

RESUMO

In recent years, considerable achievements have been made in pediatric oncology with the innovation and development of antitumor drugs. However, compared to adults, children as a special group have not yet matured fully in terms of liver and kidney function. Moreover, pediatric patients are prone to more adverse drug reactions (ADRs) from the accumulation of antineoplastic drugs due to their smaller body size and larger body surface area. Chemotherapy-related ADRs have become a non-negligible factor that affects cancer remission. To date, studies on ADRs in pediatric cancer patients have emerged internationally, but few systematic summaries are available. Here, we reviewed the various systemic ADRs associated with antitumor drugs in children and adolescent patients, as well as the advances in strategies to cope with ADRs, which consisted of neurotoxicity, hematological toxicity, cardiotoxicity, ADRs of the respiratory system and gastrointestinal system and urinary system, ADRs of the skin and its adnexa, allergic reactions, and other ADRs. For clinicians and researchers, understanding the causes, symptoms, and coping strategies for ADRs caused by anticancer treatments will undoubtedly benefit more children.

7.
Mol Carcinog ; 63(3): 538-548, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38051288

RESUMO

N6 -methyladenosine (m6 A) modification has been identified as one of the most important epigenetic regulation mechanisms in the development of human cancers. However, the association between m6 A-associated single-nucleotide polymorphisms (m6 A-SNPs) and lung cancer risk remains largely unknown. Here, we identified m6 A-SNPs and examined the association of these m6 A-SNPs with lung cancer risk in 13,793 lung cancer cases and 14,027 controls. In silico functional annotation was used to identify causal m6 A-SNPs and target genes. Furthermore, methylated RNA immunoprecipitation and quantitative real-time polymerase chain reaction (MeRIP-qPCR) assay was performed to assess the m6 A modification level of different genotypes of the causal SNP. In vitro assays were performed to validate the potential role of the target gene in lung cancer. A total of 8794 m6 A-SNPs were detected, among which 397 SNPs in nine susceptibility loci were associated with lung cancer risk, including six novel loci. Bioinformatics analyses indicated that rs1321328 in 6q21 was located around the m6 A modification site of AK9 and significantly reduced AK9 expression (ß = -0.15, p = 2.78 × 10-8 ). Moreover, AK9 was significantly downregulated in lung cancer tissues than that in adjacent normal tissues of samples from the Cancer Genome Atlas and Nanjing Lung Cancer Cohort. MeRIP-qPCR assay suggested that C allele of rs1321328 could significantly decrease the m6 A modification level of AK9 compared with G allele. In vitro assays verified the tumor-suppressing role of AK9 in lung cancer. These findings shed light on the pathogenic mechanism of lung cancer susceptibility loci linked with m6 A modification.


Assuntos
Adenina , Neoplasias Pulmonares , Polimorfismo de Nucleotídeo Único , Humanos , Adenina/análogos & derivados , Epigênese Genética , Genes Supressores de Tumor , Neoplasias Pulmonares/genética , Adenilato Quinase/metabolismo
8.
Cell Rep ; 42(12): 113511, 2023 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-38043062

RESUMO

KRAS mutations are frequently detected in non-small cell lung cancers (NSCLCs). Although covalent KRASG12C inhibitors have been developed to treat KRASG12C-mutant cancers, effective treatments are still lacking for other KRAS-mutant NSCLCs. Thus, identifying a KRAS effector that confers poor prognosis would provide an alternative strategy for the treatment of KRAS-driven cancers. Here, we show that KRAS drives expression of deubiquitinase USP13 through Ras-responsive element-binding protein 1 (RREB1). Elevated USP13 promotes KRAS-mutant NSCLC metastasis, which is associated with poor prognosis in NSCLC patients. Mechanistically, USP13 interacts with and removes the K63-linked polyubiquitination of ß-catenin at lysine 508, which enhances the binding between ß-catenin and transcription factor TCF4. Importantly, we identify 2-methoxyestradiol as an effective inhibitor for USP13 from a natural compound library, and it could potently suppress the metastasis of KRAS-mutant NSCLC cells in vitro and in vivo. These findings identify USP13 as a therapeutic target for metastatic NSCLC with KRAS mutations.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , beta Catenina/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Neoplasias Pulmonares/patologia , Mutação/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteases Específicas de Ubiquitina/metabolismo
9.
Arch Biochem Biophys ; 747: 109757, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37742933

RESUMO

Glioblastoma (GBM) is one of the most aggressive and challenging cancers to treat. Despite extensive research on dozens of cancer cells, including GBM, the effect of cold atmospheric plasma (CAP) on the invasive migration of GBM cells has received limited attention, and the underlying mechanisms remain poorly understood. This study aims to investigate the potential molecular mechanism of ns-CAPJ in inhibiting the invasive migration of human GBM cells. The findings indicate that ns-CAPJ significantly reduces GBM cell invasion and migration, and induces apoptosis in GBM cells. Further mechanistic studies demonstrate a direct correlation between the suppression of the epithelial-mesenchymal transition (EMT) signaling pathway and ns-CAPJ's inhibitory effect on GBM cell invasion and migration. Additionally, combined with the N-acetyl cysteine (NAC, a ROS inhibitor) assay, we found that the ROS stimulated by the ns-CAPJ plays an important role in suppressing the EMT process. This work is expected to provide new insight into understanding the molecular mechanisms of how ns-CAPJ inhibits the proliferation and migration of human GBM cells.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/metabolismo , Transição Epitelial-Mesenquimal , Espécies Reativas de Oxigênio , Apoptose , Proliferação de Células , Linhagem Celular Tumoral , Movimento Celular , Neoplasias Encefálicas/metabolismo
10.
Can J Gastroenterol Hepatol ; 2023: 6882851, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37766807

RESUMO

Human antigen R (HuR), also known as ELAVL1, is a widely expressed RNA-binding protein (RBP) that has a significant impact on the development and advancement of tumors. Our previous study found that 5-fluorouracil (5-FU) may impede the proliferation and increase apoptosis in gastric cancer cells by reducing the nucleocytoplasmic shuttling of HuR. However, how posttranscriptional regulation influences HuR functions in gastric cancer remains to be elucidated. Here, we demonstrated that miR-325-3p has the potential to regulate the expression level of HuR by directly binding to its 3'UTR, which in turn led to a significant reduction in proliferation and an increase in apoptosis in gastric cancer cells. In addition, xenograft experiment showed that knockdown of HuR or overexpression of miR-325-3p group exhibited smaller tumor sizes after transplant of gastric cancer cells into zebrafish larvae. Thus, our findings offer new insights into the pathogenesis of gastric cancer and may potentially assist in identifying novel targets for drug therapy.


Assuntos
MicroRNAs , Neoplasias Gástricas , Humanos , Animais , Neoplasias Gástricas/genética , Peixe-Zebra , Apoptose/genética , Fluoruracila/farmacologia , Proliferação de Células/genética , MicroRNAs/genética
11.
Am J Hum Genet ; 110(9): 1574-1589, 2023 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-37562399

RESUMO

Splicing quantitative trait loci (sQTLs) have been demonstrated to contribute to disease etiology by affecting alternative splicing. However, the role of sQTLs in the development of non-small-cell lung cancer (NSCLC) remains unknown. Thus, we performed a genome-wide sQTL study to identify genetic variants that affect alternative splicing in lung tissues from 116 individuals of Chinese ancestry, which resulted in the identification of 1,385 sQTL-harboring genes (sGenes) containing 378,210 significant variant-intron pairs. A comprehensive characterization of these sQTLs showed that they were enriched in actively transcribed regions, genetic regulatory elements, and splicing-factor-binding sites. Moreover, sQTLs were largely distinct from expression quantitative trait loci (eQTLs) and showed significant enrichment in potential risk loci of NSCLC. We also integrated sQTLs into NSCLC GWAS datasets (13,327 affected individuals and 13,328 control individuals) by using splice-transcriptome-wide association study (spTWAS) and identified alternative splicing events in 19 genes that were significantly associated with NSCLC risk. By using functional annotation and experiments, we confirmed an sQTL variant, rs35861926, that reduced the risk of lung adenocarcinoma (rs35861926-T, OR = 0.88, 95% confidence interval [CI]: 0.82-0.93, p = 1.87 × 10-5) by promoting FARP1 exon 20 skipping to downregulate the expression level of the long transcript FARP1-011. Transcript FARP1-011 promoted the migration and proliferation of lung adenocarcinoma cells. Overall, our study provided informative lung sQTL resources and insights into the molecular mechanisms linking sQTL variants to NSCLC risk.


Assuntos
Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Locos de Características Quantitativas/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Estudo de Associação Genômica Ampla/métodos , Neoplasias Pulmonares/genética , Processamento Alternativo/genética , Adenocarcinoma de Pulmão/genética , Polimorfismo de Nucleotídeo Único/genética
12.
Ann Thorac Surg ; 116(5): 1006-1012, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37573993

RESUMO

BACKGROUND: The choice of postoperative pain management for patients who experience moderate to severe acute pain after thoracoscopic surgery is debatable. This study aimed to determine whether paravertebral block (PVB) provides more benefits than thoracic epidural analgesia (TEA) for thoracoscopic surgery. METHODS: From February 2020 to April 2022, patients without chronic pain who were scheduled to undergo thoracoscopic surgery were randomly assigned to the PVB group or the TEA group. The visual analogue scale score was used to measure the degree of pain when the patients were at rest or coughing. RESULTS: In total, 176 eligible patients were enrolled in this study. No significant difference in the visual analogue scale score was found between the 2 groups at rest (P = .395) or with coughing (P = .157). Additionally, there was no significant difference in the average pain score between these 2 states (P = .221). The median time for catheter placement in the PVB group was 5 minutes, which was shorter than that (14 minutes) in the TEA group (P < .001). Moreover, the catheter placement failure rate in the PVB group was lower than that in the TEA group (P = .038). The incidence of hypotension (P = .016) and urinary retention (P = .006) in the PVB group was lower than that in the TEA group. CONCLUSIONS: PVB can provide pain relief that is similar to that of TEA but with no additional puncture pain, a shorter catheter placement time, and fewer side effects in patients undergoing video-assisted thoracoscopic surgery.

13.
Mol Carcinog ; 62(10): 1518-1530, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37341611

RESUMO

RRM2 is the catalytic subunit of ribonucleotide reductase (RNR), which catalyzes de novo synthesis of deoxyribonucleotide triphosphates (dNTPs) and plays critical roles in cancer cell proliferation. RRM2 protein level is controlled by ubiquitination mediated protein degradation system; however, its deubiquitinase has not been identified yet. Here we showed that ubiquitin-specific peptidase 12 (USP12) directly interacts with and deubiquitinates RRM2 in non-small cell lung cancer (NSCLC) cells. Knockdown of USP12 causes DNA replication stress and retards tumor growth in vivo and in vitro. Meanwhile, USP12 protein levels were positively correlated to RRM2 protein levels in human NSCLC tissues. In addition, high expression of USP12 was associated with poor prognosis in NSCLC patients. Therefore, our study reveals that USP12 is a RRM2 regulator and targeting USP12 could be considered as a potential therapeutical strategy for NSCLC treatment.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Pulmonares/genética , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/metabolismo , Ubiquitinação
14.
Cell Death Dis ; 14(4): 271, 2023 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-37059712

RESUMO

Immune checkpoint blockade (ICB) is a promising treatment strategy for colorectal cancer (CRC) patients. However, most CRC patients do not response well to ICB therapy. Increasing evidence indicates that ferroptosis plays a critical role in immunotherapy. ICB efficacy may be enhanced by inducing tumor ferroptosis. Cytochrome P450 1B1 (CYP1B1) is a metabolic enzyme that participates in arachidonic acid metabolism. However, the role of CYP1B1 in ferroptosis remains unclear. In this study, we demonstrated that CYP1B1 derived 20-HETE activated the protein kinase C pathway to increase FBXO10 expression, which in turn promoted the ubiquitination and degradation of acyl-CoA synthetase long-chain family member 4 (ACSL4), ultimately inducing tumor cells resistance to ferroptosis. Furthermore, inhibiting CYP1B1 sensitized tumor cells to anti-PD-1 antibody in a mouce model. In addition, CYP1B1 expression was negatively correlated with ACSL4 expression, and high expression indicates poor prognosis in CRC. Taken together, our work identified CYP1B1 as a potential biomarker for enhancing anti-PD-1 therapy in CRC.


Assuntos
Neoplasias Colorretais , Ferroptose , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Citocromo P-450 CYP1B1/genética , Proteína Quinase C , Receptor de Morte Celular Programada 1/imunologia
15.
Int Immunopharmacol ; 117: 110036, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36940553

RESUMO

Acquired aplastic anemia (AA) is an autoimmune disease of bone marrow failure mediated by abnormally activated T cells, manifested by severe depletion of hematopoietic stem and progenitor cells (HSPCs) and peripheral blood cells. Due to the limitation of donors for hematopoietic stem cell transplantation, immunosuppressive therapy (IST) is currently an effective first-line treatment. However, a significant proportion of AA patients remain ineligible for IST, relapse, and develop other hematologic malignancies, such as acute myeloid leukemia after IST. Therefore, it is important to elucidate the pathogenic mechanisms of AA and to identify treatable molecular targets, which is an attractive way to improve these outcomes. In this review, we summarize the immune-related pathogenesis of AA, pharmacological targets, and clinical effects of the current mainstream immunosuppressive agents. It provides new insight into the combination of immunosuppressive drugs with multiple targets, as well as the discovery of new druggable targets based on current intervention pathways.


Assuntos
Anemia Aplástica , Transplante de Células-Tronco Hematopoéticas , Humanos , Anemia Aplástica/tratamento farmacológico , Imunossupressores/uso terapêutico , Terapia de Imunossupressão , Doadores de Tecidos
16.
J Gene Med ; 25(2): e3463, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36350267

RESUMO

BACKGROUND: Mammalian inositol 1,4,5-trisphosphate receptor (ITPR) genes encode ubiquitously expressed endoplasmic reticulum Ca2+ channels that have recently been shown to be closely linked to the pathogenesis of several cancers. However, few studies to date have explored associations between ITPR gene family single nucleotide polymorphisms (SNPs) and breast cancer risk. METHODS: In the present case-control study, 12 SNPs in the potential functional regions of the ITPR1, ITPR2, and ITPR3 genes were genotyped using an Illumina Infinium® Beadchip in 2095 Chinese women (1032 cases and 1063 controls). RESULTS: Multivariate logistic regression analyses indicated that a missense SNP in the ITPR3 coding region (rs2229642) was significantly related to breast cancer risk when using an additive model in this study (rs2229642-adjusted odds ratio = 1.40, 95% confidence interval = 1.12-1.74, p = 2.97 × 10-3 ). Expression quantitative trait loci analyses indicated that the SNP rs2229642 was associated with reduced ITPR3 expression levels (p = 3.2 × 10-7 ) and with marked reductions in the expressions of several proximal genes, including BAK1, GRM4, HLA-DOB, and UQCC2 (p = 0.013, 0.018, 3.4 × 10-3 , 3.8 × 10-5 ), suggesting that it may further regulate other genes associated with oncogenic susceptibility. Kaplan-Meier analyses indicated that the patients with higher ITPR3 expression exhibited significantly poorer outcomes compared to the patients with lower expression of this gene (hazard ratio = 1.11, 95% confidence interval = 1-1.23, p = 0.046). CONCLUSIONS: The results indicated that genetic variant in the coding region of ITPR3 gene may regulate the expressions of its host and some other cancer-related genes, as well as act as potential predictive biomarker for susceptibility to breast cancer in the Chinese population.


Assuntos
Neoplasias da Mama , Predisposição Genética para Doença , Animais , Humanos , Feminino , Receptores de Inositol 1,4,5-Trifosfato/genética , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , População do Leste Asiático , Genótipo , Mamíferos
17.
J Oncol ; 2022: 8394816, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36471887

RESUMO

Peptidyl arginine deiminase 1 (PADI1) catalyzes protein citrullination and has a role in regulating immune responses. The tumor immune microenvironment has been reported to be important in colorectal cancer (CRC), which was correlated with the ability of CRC patients to benefit from immunotherapy. However, there is a lack of molecular markers for matching CRC immunotherapy. Previously, single-gene risk models have only considered the effect of individual genes on intrinsic tumor properties, ignoring the role of genes and their co-expressed genes as a whole. In this study, we analyzed the differential expression of PADI1 in colorectal cancer (CRC). We found that PADI1 was highly expressed in CRC. Subgroup survival analysis revealed a prognostic survival difference for PADI1 in CRC patients aged less than 65 years, male, T stage, N0, M0, and stage I-II (p < 0.05). In addition, we analyzed the functions and signaling pathways associated with PADI1 in CRC and found that it was highly enriched in several immune-related functions and pathways. Then, a set of PADI1 co-expressed genes (PCGs) risk-prognosis scores was developed with PADI1 as the core, which could accurately predict the prognosis of CRC (p < 0.05). PCGs risk score can be an independent prognostic factor for CRC. A new set of Norman plot models were developed for clinical characteristics with age, sex, and TNM stage, which can accurately predict CRC 1, 3, and 5 years survival, and calibration curves and decision curve analysis (DCA) validated the accuracy of the models. The risk score assessed the immune microenvironment of CRC and found that the immune score was higher in the low-risk group, and CD4+ T cells, helper T cells, and eosinophils were more infiltrated in the low-risk group (p < 0.05). Immunotherapy efficacy was better in the low-risk group (p < 0.05). The underlying mechanism may be that the high-risk group of PCGs was enriched in some pathways that promote immune escape and immune dysfunction. In conclusion, PCGs may better predict CRC prognosis and immunotherapeutic response.

18.
Lancet Oncol ; 23(11): 1465-1474, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36265503

RESUMO

BACKGROUND: Mosaic chromosomal alterations (mCAs) detected from blood-derived DNA are large structural alterations of clonal haematopoietic origin and are associated with various diseases, such as haematological malignancies, infections, and solid cancers. We aimed to investigate whether mCAs contribute to the risk of lung cancer and modify the effect of polygenic risk score (PRS) on lung cancer risk prediction. METHODS: The blood-derived DNA of patients with lung cancer and cancer-free controls with Chinese ancestry from the Nanjing Lung Cancer Cohort (NJLCC) study were genotyped with a Global Screening Array, and mCAs were detected with the Mosaic Chromosomal Alterations (MoChA) pipeline. mCA call sets of individuals with European ancestry were obtained from the prospective cohort UK Biobank (UKB) study, including documented incident lung cancer. All patients with lung cancer from the NJLCC study (aged 15 years or older at diagnosis) were histopathologically confirmed as new lung cancer cases by at least two pathologists and were free of chemotherapy or radiotherapy before diagnosis. Participants with incident lung cancer (aged 37-73 years at assessment) diagnosed after recruitment to the UKB were identified through linkage to national cancer registries. Logistic regression and Cox proportional hazard models were applied to evaluate associations between mCAs and risk of lung cancer in the NJLCC (logistic regression) and UKB (Cox proportional hazard model) studies. FINDINGS: The NJLCC study included 10 248 individuals (6445 [62·89%] men and 3803 [37·11%] women; median age 60·0 years [IQR 53·0-66·0]) with lung cancer and 9298 individuals (5871 [63·14%] men and 3427 [36·86%] women; median age 60·0 years [52·0-65·0]) without lung cancer recruited from three sub-regions (north, central, and south) across China between April 15, 2003, and Aug 18, 2017. The UKB included 450 821 individuals recruited from 22 centres across the UK between March 13, 2006, and Nov 1, 2010, including 2088 individuals with lung cancer (1075 [51·48%] men and 1013 [48·52%] women; median age 63·0 years [IQR 59·0-66·0]), and 448 733 participants were free of lung cancer (204 713 [45·62%] men and 244 020 [54·38%] women; median age 58·0 years [IQR 50·0-63·0]). Compared with non-carriers of mosaic losses, carriers had a significantly increased risk of lung cancer in the NJLCC (odds ratio [OR] 1·81, 95% CI 1·43-2·28; p=6·69 × 10-7) and UKB (hazard ratio [HR] 1·40, 95% CI 1·00-1·95; p=0·048) studies. This increased risk was even higher in patients with expanded cell fractions of mCAs (ie, cell fractions ≥10% vs cell fractions <10%) in the NJLCC (OR 1·61 [95% CI 1·26-2·08] vs 1·03 [0·83-1·26]; p for heterogeneity test=6·41 × 10-3). A significant multiplicative interaction was observed between PRS and mosaic losses on the risk of lung cancer in both the NJLCC (interaction p value=0·030) and UKB (p=0·043). Compared with non-carriers of mosaic loss abnormalities with low genetic risk, participants with expanded mosaic losses (cell fractions ≥10%) and high genetic risk had around a six-times increased risk of lung cancer in the NJLCC study (OR 6·40 [95% CI 3·22-12·69]), and an almost four-times increased risk of lung cancer (HR 3·75 [95% CI 1·86-7·55]) in the UKB study. The additive interaction also contributed a 3·67 (95% CI 0·49-6·85) relative excess risk of developing lung cancer in the NJLCC study, and a 2·15 (0·12-4·19) relative excess risk in the UKB study. INTERPRETATION: mCAs act as a new endogenous indicator for the risk of lung cancer and might be jointly used with PRS to optimise personalised risk stratification for lung cancer. FUNDING: National Natural Science Foundation of China, Outstanding Youth Foundation of Jiangsu Province, Natural Science Foundation of Jiangsu Province, and Postdoctoral Science Foundation of China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.


Assuntos
Cromossomos Humanos Y , Neoplasias Pulmonares , Adolescente , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Mosaicismo , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Fatores de Risco , Estudos de Coortes , Estudos de Casos e Controles , DNA
19.
Cancer Cell ; 40(10): 1223-1239.e6, 2022 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-36113475

RESUMO

We present the largest whole-genome sequencing (WGS) study of non-small cell lung cancer (NSCLC) to date among 6,004 individuals of Chinese ancestry, coupled with 23,049 individuals genotyped by SNP array. We construct a high-quality haplotype reference panel for imputation and identify 20 common and low-frequency loci (minor allele frequency [MAF] ≥ 0.5%), including five loci that have never been reported before. For rare loss-of-function (LoF) variants (MAF < 0.5%), we identify BRCA2 and 18 other cancer predisposition genes that affect 5.29% of individuals with NSCLC, and 98.91% (181 of 183) of LoF variants have not been linked previously to NSCLC risk. Promoter variants of BRCA2 also have a substantial effect on NSCLC risk, and their prevalence is comparable with BRCA2 LoF variants. The associations are validated in an independent case-control study including 4,410 individuals and a prospective cohort study including 23,826 individuals. Our findings not only provide a high-quality reference panel for future array-based association studies but depict the whole picture of rare pathogenic variants for NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/genética , Estudos de Casos e Controles , China/epidemiologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos
20.
Mol Carcinog ; 61(8): 776-786, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35596703

RESUMO

Super-enhancers (SEs) are important transcriptional regulators in tumorigenesis; however, the functional characterization and clinical significance of SEs in lung adenocarcinoma (LUAD) remain unclear. By using H3K27ac ChIP-seq data of two LUAD cell lines and eight lung tissues, we detected 1045 cancer-specific and 5032 normal-specific SEs. Compared to normal-specific SEs, cancer-specific SEs have different regulatory mechanisms where associated target genes were enriched in critical tumor-related pathways and tended to be regulated by transcription factors of Fos Proto-Oncogene, AP-1 Transcription Factor Subunit and Jun Proto-Oncogene, AP-1 Transcription Factor Subunit families. By using expression data of 513 LUAD and 57 adjacent samples from The Cancer Genome Atlas and 80 tumor-normal paired LUAD samples from the Nanjing Lung Cancer Cohort study, we performed differential expression analysis of target genes for SEs and defined 243 crucial SEs. Unsupervised clustering of crucial SEs revealed two subtypes with different levels of genomic aberrations (i.e., mutation and copy number alteration) and clinical outcomes (progression-free interval: p = 0.030; disease-free interval: p = 0.047). In addition, patients with adverse clinical outcomes were more sensitive to three small molecule inhibitors (bortezomib, doxorubicin, and etoposide), and their targets (PSMB5 and TOP2A) also have elevated expression levels among these patients. Taken together, our findings provided a comprehensive characterization of SEs in LUAD and emphasized their clinical significance in LUAD therapy.


Assuntos
Adenocarcinoma de Pulmão , Adenocarcinoma , Neoplasias Pulmonares , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma de Pulmão/genética , Estudos de Coortes , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Fator de Transcrição AP-1/genética
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