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1.
Nat Commun ; 11(1): 4611, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929072

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) and cancer-associated cachexia (CAC) are multifactorial and characterized by dysregulated inflammatory networks. Whether the proinflammatory cytokine IL-20 is involved in the complex networks of PDAC and CAC remains unclear. Here, we report that elevated IL-20 levels in tumor tissue correlate with poor overall survival in 72 patients with PDAC. In vivo, we establish a transgenic mouse model (KPC) and an orthotopic PDAC model and examine the therapeutic efficacy of an anti-IL-20 monoclonal antibody (7E). Targeting IL-20 not only prolongs survival and attenuates PD-L1 expression in both murine models but also inhibits tumor growth and mitigates M2-like polarization in the orthotopic PDAC model. Combination treatment with 7E and an anti-PD-1 antibody shows better efficacy in inhibiting tumor growth than either treatment alone in the orthotopic PDAC model. Finally, 7E mitigates cachexic symptoms in CAC models. Together, we conclude IL-20 is a critical mediator in PDAC progression.


Assuntos
Anticorpos Monoclonais/farmacologia , Antígeno B7-H1/metabolismo , Interleucinas/antagonistas & inibidores , Modelos Biológicos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Caquexia , Carcinoma Pulmonar de Lewis/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Interleucinas/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Neoplasias Pancreáticas/imunologia , Análise de Sobrevida , Resultado do Tratamento , Triglicerídeos/sangue , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Medicine (Baltimore) ; 99(35): e22045, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871962

RESUMO

BACKGROUND: Previous studies have reported that microRNA-21 (mRNA-21) has an effect on the prognosis of pancreatic cancer. However, the conclusion is still unclear. Therefore, this study will try to explore the effect of high expression of mRNA-21 on the prognosis of pancreatic cancer. METHODS: Retrieved the database, including the China National Knowledge Infrastructure (CNKI), Chinese Biomedical literature Database (CBM), Chinese Scientific and Journal Database (VIP), Wan Fang database, PubMed, and EMBASE. Hazard ratios (HRs) and its 95% confidence intervals (CIs) to assess the prognostic effect of miRNA-21 on overall survival (OS) and disease-free survival (DFS). RevMan 5.3 and STATA 16.0 software were used to perform the meta-analysis. RESULTS: This study will comprehensively review and evaluate the available evidence of high expression of miRNA-21 on the prognosis of patients with pancreatic cancer. CONCLUSION: Our findings will show the effect of high expression of miRNA-21 on the prognosis of patients with pancreatic cancer. Such studies may find a new prognostic marker for patients with pancreatic cancer and help clinicians and health professionals make clinical decisions. ETHICS AND DISSEMINATION: The private information from individuals will not publish. This systematic review also will not involve endangering participant rights. Ethical approval is not available. The results may be published in a peer- reviewed journal or disseminated in relevant conferences. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/2A6KJ.


Assuntos
MicroRNAs/metabolismo , Neoplasias Pancreáticas/metabolismo , Humanos , Metanálise como Assunto , Neoplasias Pancreáticas/diagnóstico , Prognóstico , Revisões Sistemáticas como Assunto
3.
Nat Commun ; 11(1): 4055, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32792504

RESUMO

Although metastasis is the most common cause of cancer deaths, metastasis-intrinsic dependencies remain largely uncharacterized. We previously reported that metastatic pancreatic cancers were dependent on the glucose-metabolizing enzyme phosphogluconate dehydrogenase (PGD). Surprisingly, PGD catalysis was constitutively elevated without activating mutations, suggesting a non-genetic basis for enhanced activity. Here we report a metabolic adaptation that stably activates PGD to reprogram metastatic chromatin. High PGD catalysis prevents transcriptional up-regulation of thioredoxin-interacting protein (TXNIP), a gene that negatively regulates glucose import. This allows glucose consumption rates to rise in support of PGD, while simultaneously facilitating epigenetic reprogramming through a glucose-fueled histone hyperacetylation pathway. Restoring TXNIP normalizes glucose consumption, lowers PGD catalysis, reverses hyperacetylation, represses malignant transcripts, and impairs metastatic tumorigenesis. We propose that PGD-driven suppression of TXNIP allows pancreatic cancers to avidly consume glucose. This renders PGD constitutively activated and enables metaboloepigenetic selection of additional traits that increase fitness along glucose-replete metastatic routes.


Assuntos
Cromatina/metabolismo , Glucose/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Animais , Transporte Biológico/genética , Transporte Biológico/fisiologia , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Reprogramação Celular/genética , Reprogramação Celular/fisiologia , Imunoprecipitação da Cromatina , Epigênese Genética/genética , Camundongos , Camundongos Nus , Neoplasias Pancreáticas/genética , Fosfogluconato Desidrogenase/genética , Fosfogluconato Desidrogenase/metabolismo , Tiorredoxinas/genética , Tiorredoxinas/metabolismo
4.
PLoS One ; 15(7): e0235904, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32663208

RESUMO

Pancreatic ductal adenocarcinoma is one of the most aggressive types of cancer. Certain proteins in the tumor microenvironment have attracted considerable attention owing to their association with tumor invasion and metastasis. Here, we used proteomics to identify proteins associated with lymph-node metastasis, which is one of the prognostic factors. We selected lymph node metastasis-positive and -negative patients (n = 5 each) who underwent pancreatectomy between 2005 and 2015 and subjected to comprehensive proteomic profiling of tumor stroma. A total of 490 proteins were detected by mass spectrometry. Software analysis revealed that nine of these proteins were differentially expressed between the two patient groups. We focused on hemopexin and ferritin light chain based on immunohistochemistry results. We assessed the clinicopathological data of 163 patients and found that hemopexin expression was associated with UICC N2 (p = 0.0399), lymph node ratio (p = 0.0252), venous invasion (p = 0.0096), and lymphatic invasion (p = 0.0232). Notably, in vitro assays showed that hemopexin promotes invasion of the pancreatic cancer cells. Our findings suggest that hemopexin is a lymph node metastasis-associated protein that could potentially serve as a useful therapeutic target or biomarker of pancreatic ductal adenocarcinoma.


Assuntos
Carcinoma Ductal Pancreático/patologia , Hemopexina/metabolismo , Neoplasias Pancreáticas/patologia , Idoso , Apoferritinas/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Imuno-Histoquímica , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias Pancreáticas/metabolismo , Prognóstico , Proteoma/análise , Proteômica/métodos , Espectrometria de Massas em Tandem
5.
Anticancer Res ; 40(8): 4401-4404, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727769

RESUMO

BACKGROUND: The occurrence of lung adenocarcinoma metastasizing to the pancreas is overall rare and can histologically imitate primary pancreatic ductal carcinoma (PDAC). CASE REPORT: This is a case report of a 70-year-old female with a history of surgically resected right lung adenocarcinoma presenting for routine follow up without symptoms. CT scans revealed a pancreatic cystic mass with ductal dilatation that was sampled via endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) and thought to be a primary pancreatic mucinous neoplasm with high grade dysplasia suspicious for carcinoma based on smear cytology. On repeat EUS-FNA and biopsy (FNB) with additional immunohistochemical testing for lung adenocarcinoma markers thyroid transcription factor (TTF1) and Napsin A and molecular testing, the lesion was identified as a metastasis of lung adenocarcinoma with an epidermal growth factor receptor (EGFR L858R) mutation; subsequently, the patient underwent targeted therapy that yielded an almost complete response. CONCLUSION: To the best of our knowledge, this is the first documented case in English literature of a lung adenocarcinoma metastasis to the pancreas mimicking a pancreatic primary neoplasm and highlights the potential pitfalls of EUS-FNA for the diagnosis of certain metastases to the pancreas.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pancreáticas/secundário , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Idoso , Biomarcadores/metabolismo , Carcinoma Ductal Pancreático/diagnóstico por imagem , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Diagnóstico Diferencial , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Mutação , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Tomografia Computadorizada por Raios X
6.
Anticancer Res ; 40(8): 4445-4455, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727774

RESUMO

BACKGROUND/AIM: To examine interferon (IFN) signaling pathways in human pancreatic cancer cells and their therapeutic application for pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: We examined the effects of IFNα on cytotoxicity, migration, as well as on the levels of toll-like receptor (TLR) signaling pathway-associated genes expression in pancreatic cancer cells. We also examined the additive effects of IFNα and poly(I-C) on tyrosine kinase inhibitor (TKI)-induced cytotoxicity. We performed transcriptome analysis (RNA-Seq) of clinical samples and compared the profile between pancreatic intraepithelial neoplasias (PanINs) and PDACs. RESULTS: IFNα suppressed cell viability and cell migration, and affected TLR signaling pathways, in pancreatic cancer cells. TLR3 is one of the potential genes involved in IFN-treated pancreatic cancer cells. Furthermore, similar to IFN, extracellular addition of poly(I-C) enhanced TKI-induced cytotoxicity in pancreatic cancer cells. RNA-Seq analysis demonstrated that IFN signaling is one of the potential pathways involved in the progression of PanIN to PDAC. CONCLUSION: IFN signaling may be involved in the development of PDAC. Treatments that target the IFN and TLR3 signaling pathways may be therapeutic options against PDAC.


Assuntos
Carcinoma in Situ/genética , Carcinoma Ductal Pancreático/genética , Perfilação da Expressão Gênica/métodos , Interferons/metabolismo , Neoplasias Pancreáticas/genética , Poli I-C/farmacologia , Receptores Toll-Like/genética , Idoso , Carcinoma in Situ/tratamento farmacológico , Carcinoma in Situ/metabolismo , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Análise de Sequência de RNA , Transdução de Sinais/efeitos dos fármacos
7.
Medicine (Baltimore) ; 99(29): e21287, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32702921

RESUMO

The potential association between the prognosis of the pancreatic adenocarcinoma (PAAD) and its microenvironment is unclear. This study aims to construct a prognostic index (PI) model of the PAAD microenvironment to predict PAAD patient survival outcomes.The mRNA sequencing and the clinical parameters data were obtained from The Cancer Genome Atlas. Immune and stromal scores were computed using the expression data algorithm to capture infiltration of immune and stromal cells in the PAAD tissue, where patients were categorized as high and low score groups according to these scores. Differentially expressed genes were identified using the R package LIMMA. Univariate and multivariate Cox regression analysis were conducted to select candidate survival-correlated gene signatures from the tumor microenvironment for constructing a model. The Kaplan-Meier method was used to access overall survival of the primary and validation cohorts. The immunological features of the PI model was explored using the Tumor Immune Estimation Resource (TIMER) database. Bioinformatic analyses were conducted based on the DAVID database.A total of 1266 overlapping differentially expressed genes and 49 prognosis-associated genes were identified. A 7-mRNA signature (GBP5, BICC1, SLC7A14, CYSLTR1, P2RY6, VENTX, and RAB39B) was screened for the construction of a PI model (area under the curve = 0.791). In both the primary and validation cohorts, Kaplan Meier analysis revealed that the overall survival of the high-risk group was significantly worse compared to the low-risk group (P < .0001, P = .0028 respectively). The TIMER database described that the 7 signature genes were correlated with immune infiltrating cells and tumor purity. Bioinformatic analyses revealed that these prognosis-associated genes were significantly enriched during inflammation, the defense response, would response, calcium ion transport, and plasma membrane part.A list of the prognosis-correlated genes was generated based on the PAAD microenvironment. A 7-mRNA PI model may be used for predicting the prognosis of PAAD patients.


Assuntos
Adenocarcinoma/metabolismo , Neoplasias Pancreáticas/metabolismo , RNA Mensageiro/metabolismo , RNA Neoplásico/metabolismo , Microambiente Tumoral , Adenocarcinoma/diagnóstico , Adenocarcinoma/mortalidade , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Transcriptoma
8.
Toxicol Appl Pharmacol ; 401: 115118, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32619553

RESUMO

Glucocorticoid receptor (GR) modulates extensive biological and pathological processes including tumor progression through diverse mechanisms. The regulatory effects of dexamethasone (DEX), a synthetic glucocorticoid, as well as its interaction with GR have been recognized beyond hematologic cancers. In the present study, we investigated the anti-cancer efficacy of DEX and the correlation with GR in pancreatic cancer, a most aggressive malignancy threatening human health. The differential levels of GR expression were examined in two human pancreatic cancer cell lines, PANC-1 and SW1990, as well as in xenografts and patient tumor tissues. DEX significantly inhibited colony formation, migration, and tumor growth of PANC-1 cells expressing abundant GR. The underlying mechanisms involved suppression of nuclear factor κB (NF-κB) phosphorylation and down-regulation of epithelial-to-mesenchymal transition (EMT), interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF). The anti-cancer effects of DEX were partially reversed by GR silencing or combinational administration of GR antagonist, RU486. The dose-dependent efficacy of DEX in tumor growth inhibition was also demonstrated in a GR-positive patient-derived xenograft model along with safety in mice. DEX was less potent, however, in SW1990 cells with poor GR expression. Our findings suggest that DEX effectively inhibits pancreatic tumor growth partially through GR activation. The potential correlation between GR expression and anti-cancer efficacy of DEX may have some clinical implications.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Dexametasona/uso terapêutico , Neoplasias Pancreáticas/metabolismo , Receptores de Glucocorticoides/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Células A549 , Animais , Antineoplásicos Hormonais/farmacologia , Dexametasona/farmacologia , Relação Dose-Resposta a Droga , Feminino , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Pancreáticas/tratamento farmacológico , Carga Tumoral/fisiologia
9.
Nat Commun ; 11(1): 3303, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620742

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) lethality is due to metastatic dissemination. Characterization of rare, heterogeneous circulating tumor cells (CTCs) can provide insight into metastasis and guide development of novel therapies. Using the CTC-iChip to purify CTCs from PDAC patients for RNA-seq characterization, we identify three major correlated gene sets, with stemness genes LIN28B/KLF4, WNT5A, and LGALS3 enriched in each correlated gene set; only LIN28B CTC expression was prognostic. CRISPR knockout of LIN28B-an oncofetal RNA-binding protein exerting diverse effects via negative regulation of let-7 miRNAs and other RNA targets-in cell and animal models confers a less aggressive/metastatic phenotype. This correlates with de-repression of let-7 miRNAs and is mimicked by silencing of downstream let-7 target HMGA2 or chemical inhibition of LIN28B/let-7 binding. Molecular characterization of CTCs provides a unique opportunity to correlated gene set metastatic profiles, identify drivers of dissemination, and develop therapies targeting the "seeds" of metastasis.


Assuntos
Carcinoma Ductal Pancreático/genética , Proteína HMGA2/genética , MicroRNAs/genética , Células Neoplásicas Circulantes/metabolismo , Neoplasias Pancreáticas/genética , Proteínas de Ligação a RNA/genética , Adulto , Idoso , Animais , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Proteína HMGA2/metabolismo , Humanos , Estimativa de Kaplan-Meier , Masculino , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Proteínas de Ligação a RNA/metabolismo
10.
Nat Commun ; 11(1): 3409, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32641778

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is associated with high mortality and therapy resistance. Here, we show that low expression of κB-Ras GTPases is frequently detected in PDAC and correlates with higher histologic grade. In a model of KRasG12D-driven PDAC, loss of κB-Ras accelerates tumour development and shortens median survival. κB-Ras deficiency promotes acinar-to-ductal metaplasia (ADM) during tumour initiation as well as tumour progression through intrinsic effects on proliferation and invasion. κB-Ras proteins are also required for acinar regeneration after pancreatitis, demonstrating a general role in control of plasticity. Molecularly, upregulation of Ral GTPase activity and Sox9 expression underlies the observed phenotypes, identifying a previously unrecognized function of Ral signalling in ADM. Our results provide evidence for a tumour suppressive role of κB-Ras proteins and highlight low κB-Ras levels and consequent loss of Ral control as risk factors, thus emphasizing the necessity for therapeutic options that allow interference with Ral-driven signalling.


Assuntos
Células Acinares/metabolismo , Carcinoma Ductal Pancreático/genética , GTP Fosfo-Hidrolases/genética , Neoplasias Pancreáticas/genética , Pancreatite/genética , Proteínas/genética , Células Acinares/patologia , Idoso , Animais , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Feminino , GTP Fosfo-Hidrolases/metabolismo , Regulação da Expressão Gênica , Humanos , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Estimativa de Kaplan-Meier , Masculino , Metaplasia/genética , Metaplasia/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Pancreatite/metabolismo , Proteínas/metabolismo , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Proteínas ral de Ligação ao GTP/genética , Proteínas ral de Ligação ao GTP/metabolismo , Proteínas ras/genética , Proteínas ras/metabolismo
11.
PLoS One ; 15(7): e0235573, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32609742

RESUMO

Diabetes mellitus is a well-known risk factor for pancreatic cancer. We focused on hyperglycemia, a main feature of diabetes mellitus, and uncovered its effect on precancerous pancreatic intraepithelial neoplasia (PanIN) progression. In vivo induction of hyperglycemia with 100 mg/kg streptozotocin in KrasLSL G12D Pdx1Cre (KP) mice promoted the PanIN formation and progression. Preconditioning with a high- or low-glucose medium for 28 days showed that a high-glucose environment increased cell viability and sphere formation in PANC-1, a Kras-mutant human pancreatic ductal adenocarcinoma cell line, and mPKC1, a Kras-mutant murine pancreatic cancer cell line. In contrast, no changes were observed in BxPC3, a Kras-wild-type human pancreatic cancer cell line. Orthotopic injection of mPKC1 into the pancreatic tails of BL6/J mice showed that cells maintained in high-glucose medium grew into larger tumors than did those maintained in low-glucose medium. Hyperglycemia strengthened the STAT3 phosphorylation, which was accompanied by elevated MYC expression in Kras-mutant cells. Immunohistochemistry showed stronger phosphorylated STAT3 (pSTAT3) and MYC staining in PanINs from diabetic KP mice than in those from euglycemic counterparts. STAT3 inhibition with 1 µM STAT3 inhibitor STATTIC in Kras-mutant pancreatic cell lines blocked the cell viability- and sphere formation-enhancing effects of the hyperglycemic environment and reversed the elevated pSTAT3 and MYC expression. MYC knockdown did not affect cell viability but did reduce sphere formation. No decrease in pSTAT3 expression was observed upon siMYC treatment. In conclusion, hyperglycemia, on a Kras-mutant background, aggravates the PanIN progression, which is accompanied by elevated pSTAT3 and MYC expression.


Assuntos
Progressão da Doença , Hiperglicemia/complicações , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Regulação Neoplásica da Expressão Gênica , Glucose/metabolismo , Humanos , Camundongos , Mutação , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Fosforilação , Proteínas Proto-Oncogênicas p21(ras)/genética
12.
Cancer Sci ; 111(9): 3111-3121, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32639661

RESUMO

Cancer cells are often characterized by abnormalities in DNA damage response including defects in cell cycle checkpoints and/or DNA repair. Synthetic lethality between DNA damage repair (DDR) pathways has provided a paradigm for cancer therapy by targeting DDR. The successful example is that cancer cells with BRCA1/2 mutations are sensitized to poly(adenosine diphosphate [ADP]-ribose)polymerase (PARP) inhibitors. Beyond the narrow scope of defects in the BRCA pathway, "BRCAness" provides more opportunities for synthetic lethality strategy. In human pancreatic cancer, frequent mutations were found in cell cycle and DDR genes, including P16, P73, APC, MLH1, ATM, PALB2, and MGMT. Combined DDR inhibitors and chemotherapeutic agents are under preclinical or clinical trials. Promoter region methylation was found frequently in cell cycle and DDR genes. Epigenetics joins the Knudson's "hit" theory and "BRCAness." Aberrant epigenetic changes in cell cycle or DDR regulators may serve as a new avenue for synthetic lethality strategy in pancreatic cancer.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias Pancreáticas/etiologia , Mutações Sintéticas Letais , Animais , Ciclo Celular/genética , Quimiorradioterapia , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Suscetibilidade a Doenças , Epigênese Genética/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Transdução de Sinais
13.
Cancer Sci ; 111(9): 3292-3302, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32644283

RESUMO

EphA10 (erythropoietin-producing hepatocellular carcinoma receptor A10) is a catalytically defective receptor protein tyrosine kinase in the ephrin receptor family. Although EphA10 is involved in the malignancy of some types of cancer, its role as an oncogene has not been extensively studied. Here, we investigated the influence of EphA10 on the tumorigenic potential of pancreatic cancer cells. Analysis of expression profiles from The Cancer Genome Atlas confirmed that EphA10 was elevated and higher in tumor tissues than in normal tissues in some cancer types, including pancreatic cancer. EphA10 silencing reduced the proliferation, migration, and adhesion of MIA PaCa-2 and AsPC-1 pancreatic cancer cells. These effects were reversed by overexpression of EphA10 in MIA PaCa-2 cells. Importantly, overexpression and silencing of EphA10 respectively increased and decreased the weight, volume, and number of Ki-67-positive proliferating cells in MIA PaCa-2 xenograft tumors. Further, EphA10 expression was positively correlated with invasion and gelatin degradation in MIA PaCa-2 cells. Moreover, overexpression of EphA10 enhanced the expression and secretion of MMP-9 in MIA PaCa-2 cells and increased the expression of MMP-9 and the vascular density in xenograft tumors. Finally, expression of EphA10 increased the phosphorylation of ERK, JNK, AKT, FAK, and NF-κB, which are important for cell proliferation, survival, adhesion, migration, and invasion. Therefore, we suggest that EphA10 plays a pivotal role in the tumorigenesis of pancreatic epithelial cells and is a novel therapeutic target for pancreatic cancer.


Assuntos
Carcinogênese/genética , Carcinogênese/metabolismo , Suscetibilidade a Doenças , Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/metabolismo , Receptores da Família Eph/genética , Receptores da Família Eph/metabolismo , Animais , Adesão Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Neoplasias Pancreáticas/patologia , Transdução de Sinais
14.
Anticancer Res ; 40(6): 3571-3577, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487660

RESUMO

BACKGROUND/AIM: We evaluated urinary levels of porphyrin metabolites, such as uroporphyrin (UP) and coproporphyrin (CP), after 5-Aminolevulinic acid (ALA) administration in patients with or without pancreatic cancer (PaC). PATIENTS AND METHODS: Sixty-seven subjects with PaC, 11 with pancreatitis, and 9 with normal pancreas (NP) were enrolled. Urine samples from all subjects were collected prior to ALA administration and at more than 4 hours after ALA administration. We measured the urinary levels of UP and CP by high-performance liquid chromatography analysis. RESULTS: The PaC group showed significantly higher UP levels compared to NP groups (104.9 nmol/g Cre vs. 53.4 nmol/g Cre, p=0.014). Moreover, PaC patients with long-term survival had significantly lower urinary levels of UP at diagnosis (98.8 nmol/gCre) than the short-term survival group (125.2 nmol/gCre) (p=0.042). CONCLUSION: The urinary levels of UP after ALA administration might serve as a promising biomarker for diagnosis and prognosis prediction of PaC.


Assuntos
Ácidos Levulínicos , Luz , Imagem Molecular , Neoplasias Pancreáticas/diagnóstico , Fármacos Fotossensibilizantes , Idoso , Biomarcadores , Biomarcadores Tumorais , Detecção Precoce de Câncer , Feminino , Humanos , Ácidos Levulínicos/metabolismo , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Imagem Molecular/métodos , Imagem Molecular/normas , Neoplasias Pancreáticas/metabolismo , Fármacos Fotossensibilizantes/metabolismo , Porfirinas , Sensibilidade e Especificidade
15.
Anticancer Res ; 40(6): 3109-3118, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487605

RESUMO

BACKGROUND/AIM: Pancreatic cancer is one of the deadliest forms of cancer and ranks among the leading causes of cancer-related death worldwide. The most common histological type is ductal adenocarcinoma (PDAC), accounting for approximately 95% of cases. Deregulation of protein synthesis has been found to be closely related to cancer. The rate-limiting step of translation is initiation, which is regulated by a broad range of eukaryotic translation initiation factors (eIFs). PATIENTS AND METHODS: Human PDAC samples were biochemically analyzed for the expression of various eIF subunits on the protein level (immunohistochemistry, immunoblot analyses) in 174 cases of PDAC in comparison with non-neoplastic pancreatic tissue (n=10). RESULTS: Our investigation revealed a significant down-regulation of four specific eIF subunits, namely eIF1, eIF2D, eIF3C and eIF6. Concomitantly, the protein (immunoblot) levels of eIF1, eIF2D, eIF3C and eIF6 were reduced in PDAC samples as compared with non-neoplastic pancreatic tissue. CONCLUSION: Members of the eIF family are of relevance in pancreatic tumor biology and may play a major role in translational control in PDAC. Consequently, they might be useful as potential new biomarkers and therapeutic targets in PDAC.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/genética , Fatores de Iniciação em Eucariotos/genética , Neoplasias Pancreáticas/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Regulação para Baixo , Fatores de Iniciação em Eucariotos/biossíntese , Fatores de Iniciação em Eucariotos/metabolismo , Humanos , Imuno-Histoquímica , Neoplasias Pancreáticas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Taxa de Sobrevida , Serina-Treonina Quinases TOR/metabolismo , Análise Serial de Tecidos
16.
Am J Pathol ; 190(9): 1931-1942, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32526166

RESUMO

Pancreatic cancer has a dismal prognosis, and there is no targeted therapy against this malignancy. The neuronal membrane protein sortilin is emerging as a regulator of cancer cell development, but its expression and impact in pancreatic cancer are unknown. This study found that sortilin expression was higher in pancreatic cell lines versus normal pancreatic ductal epithelial cells, as shown by Western blot analysis and mass spectrometry. The increased sortilin level in pancreatic cancer cells was confirmed by immunohistochemistry in a series of 99 human pancreatic adenocarcinomas versus 48 normal pancreatic tissues (P = 0.0014). Sortilin inhibition by siRNA and the pharmacologic inhibitor AF38469 strongly reduced the adhesion and invasion of pancreatic cancer cells without affecting cell survival and viability. Sortilin inhibition also decreased the phosphorylation of the focal adhesion kinase in Tyr925. Together, these data show that sortilin contributes to pancreatic cancer invasion and could eventually be targeted in therapy.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Neoplasias Pancreáticas/patologia , Adesão Celular/fisiologia , Movimento Celular/fisiologia , Humanos , Invasividade Neoplásica/patologia , Neoplasias Pancreáticas/metabolismo
17.
Tumour Biol ; 42(6): 1010428320936410, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32586207

RESUMO

Pancreatic ductal adenocarcinoma is the most common and aggressive type of pancreatic cancer, with a 5-year survival rate that is less than 10%. New biomarkers to aid in predicting the prognosis of pancreatic ductal adenocarcinoma patients are needed. Previous proteomic studies have to a great extent focused on finding proteins of value for the diagnosis of pancreatic ductal adenocarcinoma. There is a lack of studies that have profiled the serum or plasma proteome in order to discover candidates for new prognostic biomarkers. In this study, we have used ultra-performance liquid chromatography-ultra-definition mass spectrometry to analyze the serum samples of 21 pancreatic ductal adenocarcinoma patients with short or long survival. Statistical analysis discovered 31 proteins whose expression differed significantly between pancreatic ductal adenocarcinoma patients with short or long survival. Pathway analysis discovered multiple canonical pathways enriched in this data set, with several pathways having roles in inflammation and lipid metabolism. The serum proteins identified here, which include complement components and several enzymes, could be of value as candidates for new noninvasive prognostic markers.


Assuntos
Adenocarcinoma/mortalidade , Biomarcadores Tumorais/metabolismo , Proteínas Sanguíneas/metabolismo , Carcinoma Ductal Pancreático/mortalidade , Neoplasias Pancreáticas/mortalidade , Proteoma/metabolismo , Proteômica/métodos , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Idoso , Biomarcadores Tumorais/análise , Proteínas Sanguíneas/análise , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Projetos Piloto , Prognóstico , Mapas de Interação de Proteínas , Proteoma/análise , Taxa de Sobrevida
18.
J Cancer Res Clin Oncol ; 146(9): 2219-2229, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32507974

RESUMO

PURPOSE: Pancreatic cancer is a lethal form of cancer that can be triggered by prolonged or acute inflammation of the pancreas. Inflammation have been shown to be regulated by a group of key protein molecules known as the inflammasomes. The NLRP3 inflammasome is the most studied inflammasome and have been strongly implicated to regulate cancer cell proliferation. Therefore, this study aimed to examine the regulation of NLRP3 inflammasome under LPS-induced inflammation and its role in modulating cell proliferation in a panel of pancreatic cancer cells. METHODS: The effects of LPS-induced NLRP3 activation in the presence or absence of MCC950, NLRP3-specific inhibitor, was tested on a panel of three pancreatic cancer cell lines (SW1990, PANC1 and Panc10.05). Western blotting, cell viability kits and ELISA kits were used to examine the effects of LPS-induced NLRP3 activation and inhibition by MCC950 on NLRP3 expression, cell viability, caspase-1 activity and cytokine IL-1ß, respectively. RESULTS: LPS-induced inflammation in the presence of ATP activates NLRP3 that subsequently increases pancreatic cancer cell proliferation by increasing caspase-1 activity leading to overall production of IL-1ß. The inhibition of the NLRP3 inflammasome activation via the specific NLRP3 antagonist MCC950 was able to reduce the cell viability of pancreatic cancer cells. However, the efficacy of MCC950 varies between cell types which is most probably due to the difference in ASC expressions which have a different role in inflammasome activation. CONCLUSION: There is a dynamic interaction between inflammasome that regulates inflammasome-mediated inflammation in pancreatic adenocarcinoma cells.


Assuntos
Adenocarcinoma/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Inflamassomos/efeitos dos fármacos , Inflamação/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Sulfonas/farmacologia , Adenocarcinoma/induzido quimicamente , Adenocarcinoma/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Humanos , Inflamassomos/metabolismo , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Neoplasias Pancreáticas/induzido quimicamente , Neoplasias Pancreáticas/metabolismo
19.
Nat Commun ; 11(1): 3018, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32541668

RESUMO

Chronic pancreatitis represents a risk factor for the development of pancreatic cancer. We find that heterozygous loss of histone H2A lysine 119 deubiquitinase BAP1 (BRCA1 Associated Protein-1) associates with a history of chronic pancreatitis and occurs in 25% of pancreatic ductal adenocarcinomas and 40% of acinar cell carcinomas. Deletion or heterozygous loss of Bap1 in murine pancreata causes genomic instability, tissue damage, and pancreatitis with full penetrance. Concomitant expression of KrasG12D leads to predominantly intraductal papillary mucinous neoplasms and mucinous cystic neoplasms, while pancreatic intraepithelial neoplasias are rarely detected. These lesions progress to metastatic pancreatic cancer with high frequency. Lesions with histological features mimicking Acinar Cell Carcinomas are also observed in some tumors. Heterozygous mice also develop pancreatic cancer suggesting a haploinsufficient tumor suppressor role for BAP1. Mechanistically, BAP1 regulates genomic stability, in a catalytic independent manner, and its loss confers sensitivity to irradiation and platinum-based chemotherapy in pancreatic cancer.


Assuntos
Neoplasias Pancreáticas/metabolismo , Pancreatite Crônica/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina Tiolesterase/metabolismo , Animais , Estudos de Coortes , Regulação Neoplásica da Expressão Gênica , Haploinsuficiência , Humanos , Camundongos , Neoplasias Pancreáticas/genética , Pancreatite Crônica/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética
20.
Life Sci ; 256: 117936, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32531376

RESUMO

AIMS: The regulation of the Ras-ERK pathway is the crucial point in pancreatic carcinogenesis, and the Ras kinase is an essential regulatory upstream signal molecule of the ERK1/2 pathway. H3K9ac is a vital histone modification, but its specific role in pancreatic cancer remains unclear. This research aims to study whether the modification level of H3K9ac can regulate the characteristic phenotype of the pancreatic cancer cells by affecting the downstream expression, proliferation, migration, and other related genes. MAIN METHODS: The RasG12V/T35S were used to transfect pancreatic cancer cells, and the levels of phosphorylated ERK1/2 and H3K9ac were detected by western blotting. The colony formation assay, transwell assay, and chromatin immunoprecipitation assay were used to study cell viability, migration, and the downstream genes of the ERK1/2 pathway. KEY FINDINGS: The results showed that Ras ERK1/2 reduced H3K9ac expression in ASPC-1 cells, and H3K9ac significantly repressed the viability of cells, colony formation, and ASPC-1 cell movement induced by Ras ERK1/2. Besides, HDAC1 silencing increased H3K9ac expression, and changed the effect of Ras ERK1/2 on ASPC-1 cells proliferation, its movement, and mRNAs of ERK1/2 downstream genes. Moreover, Ras ERK1/2 inhibited H3K9ac expression by the degradation of PCAF via MDM2. SIGNIFICANCE: Ras ERK1/2 promotes pancreatic carcinogenesis cell movement, through down-regulating H3K9ac via MDM2 mediated PCAF degradation.


Assuntos
Carcinogênese/patologia , Histonas/metabolismo , Lisina/metabolismo , Sistema de Sinalização das MAP Quinases , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Fatores de Transcrição de p300-CBP/metabolismo , Proteínas ras/metabolismo , Acetilação , Carcinogênese/genética , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Histona Desacetilase 1/metabolismo , Humanos , Neoplasias Pancreáticas/genética , Fenótipo , Proteólise , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Transdução de Sinais , Transcrição Genética
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