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1.
Sci Adv ; 10(4): eadk6633, 2024 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-38277454

RESUMO

Hyperactivation of the oncogenic transcription reflects the epigenetic plasticity of the cancer cells. Su(var)3-9, enhancer of zeste, Trithorax (SET) was described as a nuclear factor that stimulated transcription from the chromatin template. However, the mechanisms of SET-dependent transcription are unknown. Here, we found that overexpression of SET and CDK9 induced very similar transcriptome signatures in multiple cancer cell lines. SET localized in the transcription start site (TSS)-proximal regions and supported the RNA transcription. SET specifically bound the PP2A-C subunit and induced PP2A-A subunit repulsion from the C subunit, which indicated the role of SET as a PP2A-A/C complex disruptor in the TSS-proximal regions. Through blocking PP2A activity, SET assisted CDK9 to maintain Pol II CTD phosphorylation and activated mRNA transcription. Our findings position SET as a key factor that modulates chromatin PP2A activity, promoting the oncogenic transcription in the pancreatic cancer.


Assuntos
Genes Essenciais , Neoplasias Pancreáticas , Humanos , Cromatina/genética , Neoplasias Pancreáticas/genética , RNA Polimerase II/genética , RNA Polimerase II/metabolismo , Transcrição Gênica
2.
Cell Rep Med ; 4(10): 101234, 2023 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-37852179

RESUMO

The molecular dynamics of pancreatic ductal adenocarcinoma (PDAC) under chemotherapy remain incompletely understood. The widespread use of neoadjuvant chemotherapy (NAC) provides a unique opportunity to investigate PDAC samples post-chemotherapy. Leveraging a cohort from Fudan University Shanghai Cancer Center, encompassing PDAC samples with and without exposure to neoadjuvant albumin-bound paclitaxel and gemcitabine (AG), we have compiled data from single-cell and spatial transcriptomes, proteomes, bulk transcriptomes, and metabolomes, deepening our comprehension of the molecular changes in PDACs in response to chemotherapy. Metabolic flux analysis reveals that NAC induces a reprogramming of PDAC metabolic patterns and enhances immunogenicity. Notably, NAC leads to the downregulation of glycolysis and the upregulation of CD36. Tissue microarray analysis demonstrates that high CD36 expression is linked to poorer survival in patients receiving postoperative AG. Targeting CD36 synergistically improves the PDAC response to AG both in vitro and in vivo, including patient-derived preclinical models.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Terapia Neoadjuvante , Desoxicitidina/farmacologia , China , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas
3.
Gut ; 72(12): 2329-2343, 2023 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-37541772

RESUMO

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is among the most immunosuppressive tumour types. The tumour immune microenvironment (TIME) is largely driven by interactions between immune cells and heterogeneous tumour cells. Here, we aimed to investigate the mechanism of tumour cells in TIME formation and provide potential combination treatment strategies for PDAC patients based on genotypic heterogeneity. DESIGN: Highly multiplexed imaging mass cytometry, RNA sequencing, mass cytometry by time of flight and multiplex immunofluorescence staining were performed to identify the pro-oncogenic proteins associated with low immune activation in PDAC. An in vitro coculture system, an orthotopic PDAC allograft tumour model, flow cytometry and immunohistochemistry were used to explore the biological functions of cysteine-rich intestinal protein 1 (CRIP1) in tumour progression and TIME formation. RNA sequencing, mass spectrometry and chromatin immunoprecipitation were subsequently conducted to investigate the underlying mechanisms of CRIP1. RESULTS: Our results showed that CRIP1 was frequently upregulated in PDAC tissues with low immune activation. Elevated CRIP1 expression induced high levels of myeloid-derived suppressor cell (MDSC) infiltration and fostered an immunosuppressive tumour microenvironment. Mechanistically, we primarily showed that CRIP1 bound to nuclear factor kappa-B (NF-κB)/p65 and facilitated its nuclear translocation in an importin-dependent manner, leading to the transcriptional activation of CXCL1/5. PDAC-derived CXCL1/5 facilitated the chemotactic migration of MDSCs to drive immunosuppression. SX-682, an inhibitor of CXCR1/2, blocked tumour MDSC recruitment and enhanced T-cell activation. The combination of anti-PD-L1 therapy with SX-682 elicited increased CD8+T cell infiltration and potent antitumor activity in tumour-bearing mice with high CRIP1 expression. CONCLUSIONS: The CRIP1/NF-κB/CXCL axis is critical for triggering immune evasion and TIME formation in PDAC. Blockade of this signalling pathway prevents MDSC trafficking and thereby sensitises PDAC to immunotherapy.


Assuntos
Carcinoma Ductal Pancreático , Células Supressoras Mieloides , Neoplasias Pancreáticas , Microambiente Tumoral , Animais , Humanos , Camundongos , Carcinoma Ductal Pancreático/patologia , Proteínas de Transporte , Proteínas com Domínio LIM/metabolismo , NF-kappa B/metabolismo , Neoplasias Pancreáticas/patologia , Fator de Transcrição RelA/metabolismo , Neoplasias Pancreáticas
4.
Sci Adv ; 9(35): eadg7125, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37647391

RESUMO

TERT reactivation occurs frequently in human malignancies, especially advanced cancers. However, in vivo functions of TERT reactivation in cancer progression and the underlying mechanism are not fully understood. In this study, we expressed TERT and/or active BRAF (BRAF V600E) specifically in mouse thyroid epithelium. While BRAF V600E alone induced papillary thyroid cancer (PTC), coexpression of BRAF V600E and TERT resulted in poorly differentiated thyroid carcinoma (PDTC). Spatial transcriptome analysis revealed that tumors from mice coexpressing BRAF V600E and TERT were highly heterogeneous, and cell dedifferentiation was positively correlated with ribosomal biogenesis. Mechanistically, TERT boosted ribosomal RNA (rRNA) expression and protein synthesis by interacting with multiple proteins involved in ribosomal biogenesis. Furthermore, we found that CX-5461, an rRNA transcription inhibitor, effectively blocked proliferation and induced redifferentiation of thyroid cancer. Thus, TERT promotes thyroid cancer progression by inducing cancer cell dedifferentiation, and ribosome inhibition represents a potential strategy to treat TERT-reactivated cancers.


Assuntos
Adenocarcinoma , Telomerase , Neoplasias da Glândula Tireoide , Humanos , Animais , Camundongos , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias da Glândula Tireoide/genética , Desdiferenciação Celular/genética , RNA Ribossômico , Ribossomos/genética , Telomerase/genética
5.
Oncogene ; 41(20): 2860-2872, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35422475

RESUMO

RNA N6-methyladenosine (m6A) is an emerging regulator of mRNA modifications and represents a novel player in tumorigenesis. Although it has functional significance in both pathological and physiological processes, the role of m6A modification in pancreatic ductal cancer (PDAC) remains elusive. Here, we showed that high fat mass and obesity-associated gene (FTO) expression was associated with a poor prognosis in PDAC patients and that suppression of FTO expression inhibited cell proliferation. Here, m6A sequencing (m6A-seq) was performed to screen genes targeted by FTO. The effects of FTO stimulation on the biological characteristics of pancreatic cancer cells, including proliferation and colony formation, were investigated in vitro and in vivo. The results indicate that FTO directly targets platelet-derived growth factor C (PDGFC) and stabilizes its mRNA expression in an m6A-YTHDF2-dependent manner. m6A-methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR), RNA immunoprecipitation (RIP), and luciferase reporter assays were employed to validate the specific binding of FTO to PDGFC. PDGFC upregulation led to reactivation of the Akt signaling pathway, promoting cell growth. Overall, our study reveals that FTO downregulation leads to increased m6A modifications in the 3' UTR of PDGFC and then modulates the degradation of its transcriptional level in an m6A-YTHDF2-dependent manner, highlighting a potential therapeutic target for PDAC treatment and prognostic prediction.


Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato , Neoplasias Pancreáticas , Fator de Crescimento Derivado de Plaquetas , Proteínas de Ligação a RNA , Adenosina/genética , Adenosina/metabolismo , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Humanos , Linfocinas , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Fator de Crescimento Derivado de Plaquetas/genética , Fator de Crescimento Derivado de Plaquetas/metabolismo , RNA , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Neoplasias Pancreáticas
6.
Front Oncol ; 11: 674897, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34367961

RESUMO

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most invasive solid malignancies. Immunotherapy and targeted therapy confirmed an existing certain curative effect in treating PDAC. The aim of this study was to develop an immune-related molecular marker to enhance the ability to predict Stages III and IV PDAC patients. METHOD: In this study, weighted gene co-expression network (WGCNA) analysis and a deconvolution algorithm (CIBERSORT) that evaluated the cellular constituent of immune cells were used to evaluate PDAC expression data from the GEO (Gene Expression Omnibus) datasets, and identify modules related to CD4+ T cells. LASSO Cox regression analysis and Kaplan-Meier curve were applied to select and build prognostic multi-gene signature in TCGA Stages III and IV PDAC patients (N = 126). This was followed by independent Stages III and IV validation of the gene signature in the International Cancer Genome Consortium (ICGC, N = 62) and the Fudan University Shanghai Cancer Center (FUSCC, N = 42) cohort. Inherited germline mutations and tumor immunity exploration were applied to elucidate the molecular mechanisms in PDAC. Univariate and Multivariate Cox regression analyses were applied to verify the independent prognostic factors. Finally, a prognostic nomogram was created according to the TCGA-PDAC dataset. RESULTS: A four-gene signature comprising NAPSB, ZNF831, CXCL9 and PYHIN1 was established to predict overall survival of PDAC. This signature also robustly predicted survival in two independent validation cohorts. The four-gene signature could divide patients into high and low-risk groups with disparity overall survival verified by a Log-rank test. Expression of four genes positively correlated with immunosuppression activity (PD-L1 and PD1). Immune-related genes nomogram and corresponding calibration curves showed significant performance for predicting 3-year survival in TCGA-PDAC dataset. CONCLUSION: We constructed a novel four-gene signature to predict the prognosis of Stages III and IV PDAC patients by applying WGCNA and CIBERSORT algorithm scoring to transcriptome data different from traditional methods of filtrating for differential genes in cancer and healthy tissues. The findings may provide reference to predict survival and was beneficial to individualized management for advanced PDAC patients.

7.
Aging (Albany NY) ; 12(23): 24228-24241, 2020 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-33226369

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies worldwide. Extensive enhancement of glycolysis and reprogramming of lipid metabolism are both associated with the development and progression of PDAC. Previous studies have suggested that various gene signatures could convey prognostic information about PDAC. However, the use of these signatures has some limitations, perhaps because of a lack of knowledge regarding the genetic and energy supply backgrounds of PDAC. Therefore, we conducted multi-mRNA analysis based on metabolic reprogramming to identify novel signatures for accurate prognosis prediction in PDAC patients. In this study, a three-gene signature comprising MET, ENO3 and CD36 was established to predict the overall survival of PDAC patients. The three-gene signature could divide patients into high- and low-risk groups by disparities in overall survival verified by log-rank test in two independent validation cohorts and could differentiate tumors from normal tissues with excellent accuracy in four Gene Expression Omnibus (GEO) cohorts. We also found a positive correlation between the risk score of the gene signature and inherited germline mutations in PDAC predisposition genes. A glycolysis and lipid metabolism-based gene nomogram and corresponding calibration curves showed significant performance for survival prediction in the TCGA-PDAC dataset. The high-risk designation was closely connected with oncological signatures and multiple aggressiveness-related pathways, as determined by gene set enrichment analysis (GSEA). In summary, our study developed a three-gene signature and established a prognostic nomogram that objectively predicted overall survival in PDAC. The findings could provide a reference for the prediction of overall survival and could aid in individualized management for PDAC patients.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/genética , Reprogramação Celular , Técnicas de Apoio para a Decisão , Metabolismo Energético/genética , Perfilação da Expressão Gênica , Nomogramas , Neoplasias Pancreáticas/genética , Transcriptoma , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/terapia , Bases de Dados Genéticas , Feminino , Regulação Neoplásica da Expressão Gênica , Mutação em Linhagem Germinativa , Humanos , Masculino , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/terapia , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Transdução de Sinais
8.
Cancers (Basel) ; 11(12)2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31842285

RESUMO

Damaged DNA-binding protein 1 (DDB1) recruits nucleotide excision pathway proteins to form the UV-damaged DNA-binding protein complex and is required for DNA repair. DDB1 was reported to participate in apoptosis and chemoresistance regulation in several cancers. However, little is known about the function of DDB1 in pancreatic adenocarcinoma (PDAC). In this study, we reported that DDB1 functions as a tumor-promoting factor in PDAC by regulating cancer cell proliferation, epithelial-mesenchymal transition (EMT) and chemoresistance. Compared to normal pancreatic tissues, PDAC tissues had high expression levels of DDB1, and this high expression was positively correlated with poor prognosis. Furthermore, reductions in cell proliferation and EMT were observed in DDB1-deficient PDAC cell lines. Intriguingly, we also found that abrogation of DDB1 expression increased PDAC cell sensitivity to gemcitabine (GEM). Mechanistically, DDB1 knockdown was associated with an increase in deoxycytidine kinase expression in vivo and in vitro. In summary, our work demonstrated that DDB1 promotes PDAC progression and chemoresistance and may serve as a potential predictive marker and therapeutic target for PDAC treatment.

9.
Mol Cancer ; 16(1): 170, 2017 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-29126425

RESUMO

BACKGROUND: Lung cancer is the leading cause of cancer death worldwide. However, the molecular mechanisms underlying lung cancer development have not been fully understood. The functions of histone deacetylases (HDACs), a class of total eighteen proteins (HDAC1-11 and SIRT1-7 in mammals) that deacetylate histones and non-histone proteins, in cancers are largely unknown. METHODS: Hdac7 +/-/K-Ras mice and HDAC7-depleted human lung cancer cell lines were used as models for studying the function of Hdac7 gene in lung cancer. Kaplan-Meier survival analysis was performed to explore the relationship between HDAC7 expression and prognosis of human lung cancers. Recombinant lentivirus-mediated in vivo gene expression or knockdown, Western blotting, and pull-down assay were applied to investigate the underlying molecular mechanism by which Hdac7 promotes lung tumorigenesis. RESULTS: The number and burden of lung tumor were dramatically reduced in Hdac7 +/-/K-Ras mice compared to control K-Ras mice. Also, in Hdac7 +/-/K-Ras mice, cell proliferation was significantly inhibited and apoptosis in lung tumors was greatly enhanced. Similarly, cell proliferation and anchorage-independent growth of human lung cancer cell lines expressing shHDAC7 were also significantly suppressed and apoptosis was dramatically elevated respectively. Mechanistic study revealed that Hdac7 mutation in mouse lung tumors or HDAC7 depletion in human tumor cell lines resulted in significantly enhanced acetylation and tyrosine-phosphorylation of Stat3 and HDAC7 protein directly interacted with and deacetylateed STAT3. The Hdac7 mutant-mediated inhibitory effects on lung tumorigenesis in mice and cell proliferation/soft agar colony formation of human lung cancer cell lines were respectively reversed by expressing dnStat3. Finally, the high HDAC7 mRNA level was found to be correlated with poor prognosis of human lung cancer patients. CONCLUSION: Our study suggests that Hdac7 promotes lung tumorigenesis by inhibiting Stat3 activation via deacetylating Stat3 and may shed a light on the design of new therapeutic strategies for human lung cancer.


Assuntos
Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Neoplasias Pulmonares/metabolismo , Fator de Transcrição STAT3/metabolismo , Células A549 , Acetilação , Animais , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Técnicas de Inativação de Genes , Humanos , Neoplasias Pulmonares/genética , Camundongos , Transplante de Neoplasias , Fosforilação , Prognóstico , Fator de Transcrição STAT3/genética , Análise de Sobrevida , Ativação Transcricional
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