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1.
Adv Sci (Weinh) ; : e2402954, 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-38962952

RESUMO

Genetic and epigenetic alterations occur in many physiological and pathological processes. The existing knowledge regarding the association of PIWI-interacting RNAs (piRNAs) and their genetic variants on risk and progression of prostate cancer (PCa) is limited. In this study, three genome-wide association study datasets are combined, including 85,707 PCa cases and 166,247 controls, to uncover genetic variants in piRNAs. Functional investigations involved manipulating piRNA expression in cellular and mouse models to study its oncogenetic role in PCa. A specific genetic variant, rs17201241 is identified, associated with increased expression of PROPER (piRNA overexpressed in prostate cancer) in tumors and are located within the gene, conferring an increased risk and malignant progression of PCa. Mechanistically, PROPER coupled with YTHDF2 to recognize N6-methyladenosine (m6A) and facilitated RNA-binding protein interactions between EIF2S3 at 5'-untranslated region (UTR) and YTHDF2/YBX3 at 3'-UTR to promote DUSP1 circularization. This m6A-dependent mRNA-looping pattern enhanced DUSP1 degradation and inhibited DUSP1 translation, ultimately reducing DUSP1 expression and promoting PCa metastasis via the p38 mitogen-activated protein kinase (MAPK) signaling pathway. Inhibition of PROPER expression using antagoPROPER effectively suppressed xenograft growth, suggesting its potential as a therapeutic target. Thus, targeting piRNA PROPER-mediated genetic and epigenetic fine control is a promising strategy for the concurrent prevention and treatment of PCa.

2.
J Phys Chem A ; 128(27): 5253-5259, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38937133

RESUMO

Metal oxide clusters with atomic oxygen radical anions are important model systems to study the mechanisms of activating and transforming very stable alkane molecules under ambient conditions. It is extremely challenging to characterize the activation and conversion of methane, the most stable alkane molecule, by metal oxide cluster anions due to the low reactivity of the anionic species. In this study, using a ship-lock type reactor that could be run at relatively high pressure conditions to provide a high number of collisions in ion-molecule reactions, the rate constants of the reactions between (MoO3)NO- (N = 1-21) cluster anions and the light alkanes (C1-C4) were measured under thermal collision conditions. The relationships among the reaction rates of different alkanes were obtained to establish a model to predict the low rate constants with methane from the high rate constants with C2-C4 alkanes. The model was tested by using available experimental results in literature. This study provides a new method to estimate the relatively low reactivity of atomic oxygen radical anions with methane on metal oxide clusters.

3.
Adv Sci (Weinh) ; : e2401492, 2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-38932472

RESUMO

Genetic and epigenetic alterations are cancer hallmark characteristics. However, the role of inherited cancer predisposition alleles in co-opting lineage factor epigenetic reprogramming and tumor progression remains elusive. Here the FinnGen cohort phenome-wide analysis, along with multiple genome-wide association studies, has consistently identified the rs339331-RFX6/6q22 locus associated with prostate cancer (PCa) risk across diverse populations. It is uncovered that rs339331 resides in a reprogrammed androgen receptor (AR) binding site in PCa tumors, with the T risk allele enhancing AR chromatin occupancy. RFX6, an AR-regulated gene linked to rs339331, exhibits synergistic prognostic value for PCa recurrence and metastasis. This comprehensive in vitro and in vivo studies demonstrate the oncogenic functions of RFX6 in promoting PCa cell proliferation and metastasis. Mechanistically, RFX6 upregulates HOXA10 that profoundly correlates with adverse PCa outcomes and is pivotal in RFX6-mediated PCa progression, facilitating the epithelial-mesenchymal transition (EMT) and modulating the TGFß/SMAD signaling axis. Clinically, HOXA10 elevation is associated with increased EMT scores, tumor advancement and PCa recurrence. Remarkably, reducing RFX6 expression restores enzalutamide sensitivity in resistant PCa cells and tumors. This findings reveal a complex interplay of genetic and epigenetic mechanisms in PCa pathogenesis and drug resistance, centered around disrupted prostate lineage AR signaling and abnormal RFX6 expression.

4.
BMC Cancer ; 24(1): 744, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38890593

RESUMO

BACKGROUND: Tumor hypoxia is associated with prostate cancer (PCa) treatment resistance and poor prognosis. Pimonidazole (PIMO) is an investigational hypoxia probe used in clinical trials. A better understanding of the clinical significance and molecular alterations underpinning PIMO-labeled tumor hypoxia is needed for future clinical application. Here, we investigated the clinical significance and molecular alterations underpinning PIMO-labeled tumor hypoxia in patients with localized PCa, in order to apply PIMO as a prognostic tool and to identify potential biomarkers for future clinical translation. METHODS: A total of 39 patients with localized PCa were recruited and administered oral PIMO before undergoing radical prostatectomy (RadP). Immunohistochemical staining for PIMO was performed on 37 prostatectomy specimens with staining patterns evaluated and clinical association analyzed. Whole genome bisulfite sequencing was performed using laser-capture of microdissected specimen sections comparing PIMO positive and negative tumor areas. A hypoxia related methylation molecular signature was generated by integrating the differentially methylated regions with previously established RNA-seq datasets. RESULTS: Three PIMO staining patterns were distinguished: diffuse, focal, and comedo-like. The comedo-like staining pattern was more commonly associated with adverse pathology. PIMO-defined hypoxia intensity was positively correlated with advanced pathologic stage, tumor invasion, and cribriform and intraductal carcinoma morphology. The generated DNA methylation signature was found to be a robust hypoxia biomarker, which could risk-stratify PCa patients across multiple clinical datasets, as well as be applicable in other cancer types. CONCLUSIONS: Oral PIMO unveiled clinicopathologic features of disease aggressiveness in localized PCa. The generated DNA methylation signature is a novel and robust hypoxia biomarker that has the potential for future clinical translation.


Assuntos
Metilação de DNA , Epigênese Genética , Nitroimidazóis , Prostatectomia , Neoplasias da Próstata , Humanos , Masculino , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Neoplasias da Próstata/metabolismo , Idoso , Pessoa de Meia-Idade , Hipóxia Tumoral/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Prognóstico , Administração Oral
5.
Cancer Sci ; 115(7): 2269-2285, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38720175

RESUMO

Dysregulation of long noncoding RNA (lncRNA) expression plays a pivotal role in the initiation and progression of gastric cancer (GC). However, the regulation of lncRNA SNHG15 in GC has not been well studied. Mechanisms for ferroptosis by SNHG15 have not been revealed. Here, we aimed to explore SNHG15-mediated biological functions and underlying molecular mechanisms in GC. The novel SNHG15 was identified by analyzing RNA-sequencing (RNA-seq) data of GC tissues from our cohort and TCGA dataset, and further validated by qRT-PCR in GC cells and tissues. Gain- and loss-of-function assays were performed to examine the role of SNHG15 on GC both in vitro and in vivo. SNHG15 was highly expressed in GC. The enhanced SNHG15 was positively correlated with malignant stage and poor prognosis in GC patients. Gain- and loss-of-function studies showed that SNHG15 was required to affect GC cell growth, migration and invasion both in vitro and in vivo. Mechanistically, the oncogenic transcription factors E2F1 and MYC could bind to the SNHG15 promoter and enhance its expression. Meanwhile, SNHG15 increased E2F1 and MYC mRNA expression by sponging miR-24-3p. Notably, SNHG15 could also enhance the stability of SLC7A11 in the cytoplasm by competitively binding HNRNPA1. In addition, SNHG15 inhibited ferroptosis through an HNRNPA1-dependent regulation of SLC7A11/GPX4 axis. Our results support a novel model in which E2F1- and MYC-activated SNHG15 regulates ferroptosis via an HNRNPA1-dependent modulation of the SLC7A11/GPX4 axis, which serves as the critical effectors in GC progression, and provides a new therapeutic direction in the treatment of GC.


Assuntos
Sistema y+ de Transporte de Aminoácidos , Progressão da Doença , Ferroptose , Regulação Neoplásica da Expressão Gênica , Ribonucleoproteína Nuclear Heterogênea A1 , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , RNA Longo não Codificante , Neoplasias Gástricas , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Neoplasias Gástricas/metabolismo , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Ribonucleoproteína Nuclear Heterogênea A1/metabolismo , Ribonucleoproteína Nuclear Heterogênea A1/genética , Animais , Linhagem Celular Tumoral , Camundongos , Ferroptose/genética , Masculino , Sistema y+ de Transporte de Aminoácidos/genética , Sistema y+ de Transporte de Aminoácidos/metabolismo , Feminino , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Proliferação de Células/genética , Fator de Transcrição E2F1/metabolismo , Fator de Transcrição E2F1/genética , Movimento Celular/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Pessoa de Meia-Idade , Prognóstico , Camundongos Nus , Transdução de Sinais/genética , Retroalimentação Fisiológica
6.
Res Sq ; 2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-38645058

RESUMO

Genome wide association studies (GWASs) have identified numerous risk loci associated with prostate cancer, yet unraveling their functional significance remains elusive. Leveraging our high-throughput SNPs-seq method, we pinpointed rs4519489 within the multi-ancestry GWAS-discovered 2p25 locus as a potential functional SNP due to its significant allelic differences in protein binding. Here, we conduct a comprehensive analysis of rs4519489 and its associated gene, NOL10, employing diverse cohort data and experimental models. Clinical findings reveal a synergistic effect between rs4519489 genotype and NOL10 expression on prostate cancer prognosis and severity. Through unbiased proteomics screening, we reveal that the risk allele A of rs4519489 exhibits enhanced binding to USF1, a novel oncogenic transcription factor (TF) implicated in prostate cancer progression and prognosis, resulting in elevated NOL10 expression. Furthermore, we elucidate that NOL10 regulates cell cycle pathways, fostering prostate cancer progression. The concurrent expression of NOL10 and USF1 correlates with aggressive prostate cancer characteristics and poorer prognosis. Collectively, our study offers a robust strategy for functional SNP screening and TF identification through high-throughput SNPs-seq and unbiased proteomics, highlighting the rs4519489-USF1-NOL10 regulatory axis as a promising biomarker or therapeutic target for clinical diagnosis and treatment of prostate cancer.

7.
Nat Commun ; 15(1): 1729, 2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38409266

RESUMO

Alternative polyadenylation plays an important role in cancer initiation and progression; however, current transcriptome-wide association studies mostly ignore alternative polyadenylation when identifying putative cancer susceptibility genes. Here, we perform a pan-cancer 3' untranslated region alternative polyadenylation transcriptome-wide association analysis by integrating 55 well-powered (n > 50,000) genome-wide association studies datasets across 22 major cancer types with alternative polyadenylation quantification from 23,955 RNA sequencing samples across 7,574 individuals. We find that genetic variants associated with alternative polyadenylation are co-localized with 28.57% of cancer loci and contribute a significant portion of cancer heritability. We further identify 642 significant cancer susceptibility genes predicted to modulate cancer risk via alternative polyadenylation, 62.46% of which have been overlooked by traditional expression- and splicing- studies. As proof of principle validation, we show that alternative alleles facilitate 3' untranslated region lengthening of CRLS1 gene leading to increased protein abundance and promoted proliferation of breast cancer cells. Together, our study highlights the significant role of alternative polyadenylation in discovering new cancer susceptibility genes and provides a strong foundational framework for enhancing our understanding of the etiology underlying human cancers.


Assuntos
Neoplasias , Transcriptoma , Humanos , Poliadenilação/genética , Estudo de Associação Genômica Ampla , Regiões 3' não Traduzidas/genética , Perfilação da Expressão Gênica , Neoplasias/genética
8.
J Phys Chem A ; 128(7): 1218-1225, 2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38340065

RESUMO

Investigation of the reactivity of heteronuclear metal oxide clusters is an important way to uncover the molecular-level mechanisms of the doping effect. Herein, we performed a comparative study on the reactions of CH4 with NiAl3O6+ and Al4O6+ cluster cations at room temperature to understand the role of Ni during the activation and transformation of methane. Mass spectrometric experiments identify that both NiAl3O6+ and Al4O6+ could bring about hydrogen atom abstraction reaction to generate CH3• radical; however, only NiAl3O6+ has the potential to stabilize [CH3] moiety and then transform [CH3] to CH2O. Density functional theory calculations demonstrate that the terminal oxygen radicals (Ot-•) bound to Al act as the reactive sites for the two clusters to activate the first C-H bond. Although the Ni atom cannot directly participate in methane activation, it can manipulate the electronic environment of the surrounding bridging oxygen atoms (Ob) and enable such Ob to function as an electron reservoir to help Ot-• oxidize CH4 to [H-O-CH3]. The facile reduction of Ni3+ to Ni+ also facilitates the subsequent step of activating the second C-H bond by the bridging "lattice oxygen" (Ob2-), finally enabling the oxidation of methane into formaldehyde. The important role of the dopant Ni played in improving the product selectivity of CH2O for methane conversion discovered in this study allows us to have a possible molecule-level understanding of the excellent performance of the catalysts doping with nickel.

9.
EMBO Rep ; 25(3): 1589-1622, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38297188

RESUMO

Embryonic genome activation (EGA) occurs during preimplantation development and is characterized by the initiation of de novo transcription from the embryonic genome. Despite its importance, the regulation of EGA and the transcription factors involved in this process are poorly understood. Paired-like homeobox (PRDL) family proteins are implicated as potential transcriptional regulators of EGA, yet the PRDL-mediated gene regulatory networks remain uncharacterized. To investigate the function of PRDL proteins, we are identifying the molecular interactions and the functions of a subset family of the Eutherian Totipotent Cell Homeobox (ETCHbox) proteins, seven PRDL family proteins and six other transcription factors (TFs), all suggested to participate in transcriptional regulation during preimplantation. Using mass spectrometry-based interactomics methods, AP-MS and proximity-dependent biotin labeling, and chromatin immunoprecipitation sequencing we derive the comprehensive regulatory networks of these preimplantation TFs. By these interactomics tools we identify more than a thousand high-confidence interactions for the 21 studied bait proteins with more than 300 interacting proteins. We also establish that TPRX2, currently assigned as pseudogene, is a transcriptional activator.


Assuntos
Proteínas de Homeodomínio , Fatores de Transcrição , Humanos , Fatores de Transcrição/metabolismo , Proteínas de Homeodomínio/genética , Genes Homeobox , Genoma
10.
Adv Sci (Weinh) ; 11(11): e2305547, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38169150

RESUMO

The extracellular matrix (ECM) undergoes substantial changes during prostate cancer (PCa) progression, thereby regulating PCa growth and invasion. Herein, a meta-analysis of multiple PCa cohorts is performed which revealed that downregulation or genomic loss of ITGA1 and ITGA2 integrin genes is associated with tumor progression and worse prognosis. Genomic deletion of both ITGA1 and ITGA2 activated epithelial-to-mesenchymal transition (EMT) in benign prostate epithelial cells, thereby enhancing their invasive potential in vitro and converting them into tumorigenic cells in vivo. Mechanistically, EMT is induced by enhanced secretion and autocrine activation of TGFß1 and nuclear targeting of YAP1. An unbiased genome-wide co-expression analysis of large PCa cohort datasets identified the transcription factor TEAD1 as a key regulator of ITGA1 and ITGA2 expression in PCa cells while TEAD1 loss phenocopied the dual loss of α1- and α2-integrins in vitro and in vivo. Remarkably, clinical data analysis revealed that TEAD1 downregulation or genomic loss is associated with aggressive PCa and together with low ITGA1 and ITGA2 expression synergistically impacted PCa prognosis and progression. This study thus demonstrated that loss of α1- and α2-integrins, either via deletion/inactivation of the ITGA1/ITGA2 locus or via loss of TEAD1, contributes to PCa progression by inducing TGFß1-driven EMT.


Assuntos
Próstata , Neoplasias da Próstata , Masculino , Humanos , Próstata/metabolismo , Próstata/patologia , Linhagem Celular Tumoral , Neoplasias da Próstata/genética , Transdução de Sinais/genética , Integrina alfa2/genética , Integrina alfa2/metabolismo , Fatores de Transcrição de Domínio TEA
11.
China Pharmacy ; (12): 762-766, 2024.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-1013116

RESUMO

OBJECTIVE To analyze the prevalence of potentially inappropriate medication (PIM) in elderly patients with femoral neck fractures at admission and compare the concordance of 3 evaluation criteria. METHODS A retrospective study was conducted to review the data of elderly patients with femoral neck fractures admitted to the Department of Orthopedics in Northern Jiangsu People’s Hospital from July 2022 to June 2023. The PIMs were identified according to the Criteria of Potentially Inappropriate Medications for Older Adults in China:2017 edition (hereinafter referred to as Chinese criteria), American Geriatrics Society 2023 Updated AGS Beers Criteria® for Potentially Inappropriate Medication in Older Adults (hereinafter referred to as 2023 Beers criteria), third version criteria for screening tool of older people’s prescriptions for potentially inappropriate medication (hereinafter referred to as STOPP criteria version 3). The concordance of the 3 evaluation criteria was compared by using Kappa statistics. RESULTS A total of 246 patients were included in this study; 49 patients (19.92%) with 77 PIMs were detected by the Chinese criteria, 64 patients (26.02%) with 118 PIMs were detected by the 2023 Beers criteria, and 41 patients (16.67%) with 67 PIMs were detected by the STOPP criteria version 3; 22 patients met all three criteria simultaneously. The concordance among the three criteria showed moderate agreement (0.417≤Kappa≤0.486) when compared in pairs. CONCLUSIONS There are certain differences in the PIM evaluated by the three criteria, but the prevalence of PIMs is below 30% according to the different H202134) criteria. Benzodiazepines, antipsychotics, antidepressants, and other drugs may increase the risk of patients falling again.

12.
Genome Biol ; 24(1): 285, 2023 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-38066556

RESUMO

BACKGROUND: Expression quantitative trait locus (eQTL) analysis has emerged as an important tool in elucidating the link between genetic variants and gene expression, thereby bridging the gap between risk SNPs and associated diseases. We recently identified and validated a specific case where the methylation of a CpG site influences the relationship between the genetic variant and gene expression. RESULTS: Here, to systematically evaluate this regulatory mechanism, we develop an extended eQTL mapping method, termed DNA methylation modulated eQTL (memo-eQTL). Applying this memo-eQTL mapping method to 128 normal prostate samples enables identification of 1063 memo-eQTLs, the majority of which are not recognized as conventional eQTLs in the same cohort. We observe that the methylation of the memo-eQTL CpG sites can either enhance or insulate the interaction between SNP and gene expression by altering CTCF-based chromatin 3D structure. CONCLUSIONS: This study demonstrates the prevalence of memo-eQTLs paving the way to identify novel causal genes for traits or diseases associated with genetic variations.


Assuntos
Metilação de DNA , Regulação da Expressão Gênica , Masculino , Humanos , Mapeamento Cromossômico , Locos de Características Quantitativas , Polimorfismo de Nucleotídeo Único , Estudo de Associação Genômica Ampla/métodos
13.
J Clin Invest ; 133(24)2023 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-38099500

RESUMO

Strategies for patient stratification and early intervention are required to improve clinical benefits for patients with prostate cancer. Here, we found that active DHEA utilization in the prostate gland correlated with tumor aggressiveness at early disease stages, and 3ßHSD1 inhibitors were promising for early intervention. [3H]-labeled DHEA consumption was traced in fresh prostatic biopsies ex vivo. Active DHEA utilization was more frequently found in patients with metastatic disease or therapy-resistant disease. Genetic and transcriptomic features associated with the potency of prostatic DHEA utilization were analyzed to generate clinically accessible approaches for patient stratification. UBE3D, by regulating 3ßHSD1 homeostasis, was discovered to be a regulator of patient metabolic heterogeneity. Equilin suppressed DHEA utilization and inhibited tumor growth as a potent 3ßHSD1 antagonist, providing a promising strategy for the early treatment of aggressive prostate cancer. Overall, our findings indicate that patients with active prostatic DHEA utilization might benefit from 3ßHSD1 inhibitors as early intervention.


Assuntos
Próstata , Neoplasias da Próstata , Masculino , Humanos , Próstata/metabolismo , Próstata/patologia , Desidroepiandrosterona , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo
14.
Cell Rep ; 42(9): 113041, 2023 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-37682709

RESUMO

Alternative splicing (AS) has been implicated in cell cycle regulation and cancer, but the underlying mechanisms are poorly understood. The poly(U)-binding splicing factor 60 (PUF60) is essential for embryonic development and is overexpressed in multiple types of cancer. Here, we report that PUF60 promotes mitotic cell cycle and lung cancer progression by controlling AS of the cell division cycle 25C (CDC25C). Systematic analysis of splicing factors deregulated in lung adenocarcinoma (LUAD) identifies that elevated copy number and expression of PUF60 correlate with poor prognosis. PUF60 depletion inhibits LUAD cell-cycle G2/M transition, cell proliferation, and tumor development. Mechanistically, PUF60 knockdown leads to exon skipping enriched in mitotic cell cycle genes, including CDC25C. Exon 3 skipping in the full-length CDC25C results in nonsense-mediated mRNA decay and a decrease of CDC25C protein, thereby inhibiting cell proliferation. This study establishes PUF60 as a cell cycle regulator and an oncogenic splicing factor in lung cancer.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Adenocarcinoma de Pulmão/genética , Processamento Alternativo/genética , Fosfatases cdc25/genética , Fosfatases cdc25/metabolismo , Ciclo Celular/genética , Divisão Celular , Linhagem Celular Tumoral , Neoplasias Pulmonares/genética , Fatores de Processamento de RNA/genética , Fatores de Processamento de RNA/metabolismo
15.
Adv Sci (Weinh) ; 10(27): e2301975, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37526345

RESUMO

The Warburg effect-related metabolic dysfunction of the tricarboxylic acid (TCA) cycle has emerged as a hallmark of various solid tumors, particularly renal cell carcinoma (RCC). RCC is characterized by high immune infiltration and thus recommended for immunotherapeutic interventions at an advanced stage in clinical guidelines. Nevertheless, limited benefits of immunotherapy have prompted investigations into underlying mechanisms, leading to the proposal of metabolic dysregulation-induced immunoevasion as a crucial contributor. In this study, a significant decrease is found in the abundance of alpha-ketoglutarate (αKG), a crucial intermediate metabolite in the TCA cycle, which is correlated with higher grades and a worse prognosis in clinical RCC samples. Elevated levels of αKG promote major histocompatibility complex-I (MHC-I) antigen processing and presentation, as well as the expression of ß2-microglobulin (B2M). While αKG modulates broad-spectrum demethylation activities of histone, the transcriptional upregulation of B2M is dependent on the demethylation of H3K4me1 in its promoter region. Furthermore, the combination of αKG supplementation and PD-1 blockade leads to improved therapeutic efficacy and prolongs survival in murine models when compared to monotherapy. Overall, the findings elucidate the mechanisms of immune evasion in anti-tumor immunotherapies and suggest a potential combinatorial treatment strategy in RCC.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Animais , Camundongos , Carcinoma de Células Renais/terapia , Carcinoma de Células Renais/patologia , Receptor de Morte Celular Programada 1 , Ácidos Cetoglutáricos , Neoplasias Renais/terapia , Imunoterapia
16.
J Exp Clin Cancer Res ; 42(1): 198, 2023 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-37550764

RESUMO

BACKGROUND: Aberrant somatic genomic alteration including copy number amplification is a hallmark of cancer genomes. We previously profiled genomic landscapes of prostate cancer (PCa), yet the underlying causal genes with prognostic potential has not been defined. It remains unclear how a somatic genomic event cooperates with inherited germline variants contribute to cancer predisposition and progression. METHODS: We applied integrated genomic and clinical data, experimental models and bioinformatic analysis to identify GATA2 as a highly prevalent metastasis-associated genomic amplification in PCa. Biological roles of GATA2 in PCa metastasis was determined in vitro and in vivo. Global chromatin co-occupancy and co-regulation of GATA2 and SMAD4 was investigated by coimmunoprecipitation, ChIP-seq and RNA-seq assays. Tumor cellular assays, qRT-PCR, western blot, ChIP, luciferase assays and CRISPR-Cas9 editing methods were performed to mechanistically understand the cooperation of GATA2 with SMAD4 in promoting TGFß1 and AR signaling and mediating inherited PCa risk and progression. RESULTS: In this study, by integrated genomics and experimental analysis, we identified GATA2 as a prevalent metastasis-associated genomic amplification to transcriptionally augment its own expression in PCa. Functional experiments demonstrated that GATA2 physically interacted and cooperated with SMAD4 for genome-wide chromatin co-occupancy and co-regulation of PCa genes and metastasis pathways like TGFß signaling. Mechanistically, GATA2 was cooperative with SMAD4 to enhance TGFß and AR signaling pathways, and activated the expression of TGFß1 via directly binding to a distal enhancer of TGFß1. Strinkingly, GATA2 and SMAD4 globally mediated inherited PCa risk and formed a transcriptional complex with HOXB13 at the PCa risk-associated rs339331/6q22 enhancer, leading to increased expression of the PCa susceptibility gene RFX6. CONCLUSIONS: Our study prioritizes causal genomic amplification genes with prognostic values in PCa and reveals the pivotal roles of GATA2 in transcriptionally activating the expression of its own and TGFß1, thereby co-opting to TGFß1/SMAD4 signaling and RFX6 at 6q22 to modulate PCa predisposition and progression.


Assuntos
Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/patologia , Próstata/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Cromatina , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Proteína Smad4/genética , Proteína Smad4/metabolismo , Fator de Transcrição GATA2/genética , Fator de Transcrição GATA2/metabolismo
17.
Am J Hum Genet ; 110(8): 1289-1303, 2023 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-37541187

RESUMO

Genome-wide association studies along with expression quantitative trait locus (eQTL) mapping have identified hundreds of single-nucleotide polymorphisms (SNPs) and their target genes in prostate cancer (PCa), yet functional characterization of these risk loci remains challenging. To screen for potential regulatory SNPs, we designed a CRISPRi library containing 9,133 guide RNAs (gRNAs) to cover 2,166 candidate SNP loci implicated in PCa and identified 117 SNPs that could regulate 90 genes for PCa cell growth advantage. Among these, rs60464856 was covered by multiple gRNAs significantly depleted in screening (FDR < 0.05). Pooled SNP association analysis in the PRACTICAL and FinnGen cohorts showed significantly higher PCa risk for the rs60464856 G allele (p value = 1.2 × 10-16 and 3.2 × 10-7, respectively). Subsequent eQTL analysis revealed that the G allele is associated with increased RUVBL1 expression in multiple datasets. Further CRISPRi and xCas9 base editing confirmed that the rs60464856 G allele leads to elevated RUVBL1 expression. Furthermore, SILAC-based proteomic analysis demonstrated allelic binding of cohesin subunits at the rs60464856 region, where the HiC dataset showed consistent chromatin interactions in prostate cell lines. RUVBL1 depletion inhibited PCa cell proliferation and tumor growth in a xenograft mouse model. Gene-set enrichment analysis suggested an association of RUVBL1 expression with cell-cycle-related pathways. Increased expression of RUVBL1 and activation of cell-cycle pathways were correlated with poor PCa survival in TCGA datasets. Our CRISPRi screening prioritized about one hundred regulatory SNPs essential for prostate cell proliferation. In combination with proteomics and functional studies, we characterized the mechanistic role of rs60464856 and RUVBL1 in PCa progression.


Assuntos
Próstata , Neoplasias da Próstata , Animais , Humanos , Masculino , Camundongos , Alelos , ATPases Associadas a Diversas Atividades Celulares/genética , Proteínas de Transporte/genética , DNA Helicases/genética , Detecção Precoce de Câncer , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Próstata/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Proteômica , Coesinas
18.
Inorg Chem ; 62(29): 11318-11324, 2023 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-37428555

RESUMO

Inspired by the fact that Mo is a key element in biological nitrogenase, a series of gas-phase MoxSy- cluster anions are prepared and their reactivity toward N2 is investigated by the combination of mass spectrometry, photoelectron imaging spectroscopy, and density functional theory calculations. The Mo5S2- and Mo5S3- cluster anions show remarkable reactivity compared with the anionic species reported previously. The spectroscopic results in conjunction with theoretical analysis reveal that a facile cleavage of N≡N bonds takes place on Mo5S2- and Mo5S3-. The large dissociative adsorption energy of N2 and the favorable entrance channel for initial N2 approaching are proposed as two decisive factors for the superior reactivity of Mo5S2- and Mo5S3-. Besides, the modulation of S ligands on the reactivity of metal centers with N2 is proposed. The highly reactive metal-sulfur species may be obtained by the coordination of two to three sulfur atoms to bare metal clusters so that an appropriate combination of electronic structures and charge distributions can be achieved.

19.
Int J Biol Sci ; 19(11): 3483-3498, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37496999

RESUMO

Gastric cancer (GC) is a common malignancy and remains the fourth-leading cause of cancer-related deaths worldwide. Oncogenic potential of SDC2 has been implicated in multiple types of cancers, yet its role and underlying molecular mechanisms in GC remain unknown. Here, we found that SDC2 was highly expressed in GC and its upregulation correlated with poor prognosis in GC patients. Depletion of SDC2 significantly suppressed the growth and invasive capability of GC cells, while overexpressing SDC2 exerts opposite effects. Combined bioinformatics and experimental analyses substantiated that overexpression of SDC2 activated the AKT signaling pathway in GC, mechanistically through the interaction between SDC2 and PDK1-PH domain, thereby facilitating PDK1 membrane translocation to promote AKT activation. Moreover, SDC2 could also function as a co-receptor for FGF2 and was profoundly involved in the FGF2-AKT signaling axis in GC. Lastly, we revealed a mechanism on the USP14-mediated stabilization of SDC2 that is likely to contribute to SDC2 upregulation in GC tissues. Furthermore, we showed that IU1, a potent USP14 inhibitor, decreased the abundance of SDC2 in GC cells. Our findings indicate that SDC2 functions as a novel GC oncogene and has potential utility as a diagnostic marker and therapeutic target for GC.


Assuntos
Neoplasias Gástricas , Humanos , Linhagem Celular Tumoral , Proliferação de Células/genética , Fator 2 de Crescimento de Fibroblastos/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/genética , Neoplasias Gástricas/metabolismo , Sindecana-2/metabolismo , Ubiquitina Tiolesterase/metabolismo
20.
J Chem Phys ; 158(19)2023 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-37191213

RESUMO

Understanding the properties of small particles working under high-temperature conditions at the atomistic scale is imperative for exact control of related processes, but it is quite challenging to achieve experimentally. Herein, benefitting from state-of-the-art mass spectrometry and by using our newly designed high-temperature reactor, the activity of atomically precise particles of negatively charged vanadium oxide clusters toward hydrogen atom abstraction (HAA) from methane, the most stable alkane molecule, has been measured at elevated temperatures up to 873 K. We discovered the positive correlation between the reaction rate and cluster size that larger clusters possessing greater vibrational degrees of freedom can carry more vibrational energies to enhance the HAA reactivity at high temperature, in contrast with the electronic and geometric issues that control the activity at room temperature. This finding opens up a new dimension, vibrational degrees of freedom, for the simulation or design of particle reactions under high-temperature conditions.

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