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1.
EBioMedicine ; 63: 103195, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33418496

RESUMO

BACKGROUND: Pancreatic cancer (PC) is one of the most lethal solid malignancies in the world due to its excessive cell proliferation and aggressive metastatic features. Emerging evidences revealed the importance of posttranscriptional modifications of RNAs in PC progression. However, knowledge about the 5-methylcytosine (m5C) RNA modification in PC is still extremely limited. In this study, we attempted to explore the expression changes and clinical significances of 12 known m5C-related genes among PC patients. METHODS: A total of 362 normal and 382 tumor specimens from PC patients were examined for candidate m5C-related gene and protein expression by using quantitative PCR (qPCR) and immunohistochemistry (IHC). The proliferation rate of PC cells was detected by MTS assay. Xenograft mouse models were used to assess the role of NSUN6 in PC tumor formation. FINDINGS: Through analyzing the four Gene Expression Omnibus (GEO) databases, six m5C-related genes shown significant and consistent alterations were selected for further examination in our 3 independent PC cohorts. Finally, we identified the reduction of NSUN6 as a common feature of all PC sample sets examined. NSUN6 expression correlated with clinicopathologic parameters including T stage, and Ki67+ cell rate. Further assessing the transcriptional profiles of 50 PC tissues, we found biological processes associated with cell proliferation like cell cycle and G2M checkpoint were enriched in NSUN6 lower expression group. Helped by in vitro PC cell lines and in vivo xenograft mouse models, we confirmed the role of NSUN6 in regulating cell proliferation and PC tumor growth. Last but also importantly, we also show the good performance of NSUN6 in evaluating tumor recurrence and survival among PC patients. INTERPRETATION: Our data suggested that NSUN6 is an important factor involved in regulating cell proliferation of PC, and highlights the potential of novel m5C-based clinical modalities as a therapeutic approach in PC patients. FUNDING: This study was supported by the National Natural Science Foundation of China (Grant Nos. 81803014, 81802424, and 81802911).

2.
Nat Commun ; 12(1): 174, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33420030

RESUMO

The immunosuppressive microenvironment that is shaped by hepatic metastatic pancreatic ductal adenocarcinoma (PDAC) is essential for tumor cell evasion of immune destruction. Neutrophils are important components of the metastatic tumor microenvironment and exhibit heterogeneity. However, the specific phenotypes, functions and regulatory mechanisms of neutrophils in PDAC liver metastases remain unknown. Here, we show that a subset of P2RX1-negative neutrophils accumulate in clinical and murine PDAC liver metastases. RNA sequencing of murine PDAC liver metastasis-infiltrated neutrophils show that P2RX1-deficient neutrophils express increased levels of immunosuppressive molecules, including PD-L1, and have enhanced mitochondrial metabolism. Mechanistically, the transcription factor Nrf2 is upregulated in P2RX1-deficient neutrophils and associated with PD-L1 expression and metabolic reprogramming. An anti-PD-1 neutralizing antibody is sufficient to compromise the immunosuppressive effects of P2RX1-deficient neutrophils on OVA-activated OT1 CD8+ T cells. Therefore, our study uncovers a mechanism by which metastatic PDAC tumors evade antitumor immunity by accumulating a subset of immunosuppressive P2RX1-negative neutrophils.


Assuntos
Imunossupressores/farmacologia , Neoplasias Hepáticas/imunologia , Neutrófilos/metabolismo , Neoplasias Pancreáticas/imunologia , Microambiente Tumoral/imunologia , Animais , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/imunologia , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/patologia , Modelos Animais de Doenças , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Pâncreas/imunologia , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Receptores Purinérgicos P2X/genética , Receptores Purinérgicos P2X/imunologia , Receptores Purinérgicos P2X/metabolismo
3.
Int J Biol Sci ; 17(1): 107-118, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33390837

RESUMO

Aerobic glycolysis, also known as the Warburg effect, is emerged as a hallmark of most cancer cells. Increased aerobic glycolysis is closely associated with tumor aggressiveness and predicts a poor prognosis. Pancreatic ductal adenocarcinoma (PDAC) is characterized by prominent genomic aberrations and increased glycolytic phenotype. However, the detailed molecular events implicated in aerobic glycolysis of PDAC are not well understood. In this study, we performed a comprehensive molecular characterization using multidimensional ''omic'' data from The Cancer Genome Atlas (TCGA). Detailed analysis of 89 informative PDAC tumors identified substantial copy number variations (MYC, GATA6, FGFR1, IDO1, and SMAD4) and mutations (KRAS, SMAD4, and RNF43) related to aerobic glycolysis. Moreover, integrated analysis of transcriptional profiles revealed many differentially expressed long non-coding RNAs involved in PDAC aerobic glycolysis. Loss-of-function studies showed that LINC01559 and UNC5B-AS1 knockdown significantly inhibited the glycolytic capacity of PDAC cells as revealed by reduced glucose uptake, lactate production, and extracellular acidification rate. Moreover, genetic silencing of LINC01559 and UNC5B-AS1 suppressed tumor growth and resulted in alterations in several signaling pathways, such as TNF signaling pathway, IL-17 signaling pathway, and transcriptional misregulation in cancer. Notably, high expression of LINC01559 and UNC5B-AS1 predicted poor patient prognosis and correlated with the maximum standard uptakevalue (SUVmax) in PDAC patients who received preoperative 18F-FDG PET/CT. Taken together, our results decipher the glycolysis-associated copy number variations, mutations, and lncRNA landscapes in PDAC. These findings improve our knowledge of the molecular mechanism of PDAC aerobic glycolysis and may have practical implications for precision cancer therapy.

4.
Genome Biol ; 22(1): 4, 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33397441

RESUMO

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers due to its high metastasis rate in the liver. However, little is known about the molecular features of hepatic metastases due to difficulty in obtaining fresh tissues and low tumor cellularity. RESULTS: We conduct exome sequencing and RNA sequencing for synchronous surgically resected primary tumors and the paired hepatic metastases from 17 hepatic oligometastatic pancreatic ductal adenocarcinoma and validate our findings in specimens from 35 of such cases. The comprehensive analysis of somatic mutations, copy number alterations, and gene expressions show high similarity between primary tumors and hepatic metastases. However, hepatic metastases also show unique characteristics, such as a higher degree of 3p21.1 loss, stronger abilities of proliferation, downregulation of epithelial to mesenchymal transition activity, and metabolic rewiring. More interesting, altered tumor microenvironments are observed in hepatic metastases, especially a higher proportion of tumor infiltrating M2 macrophage and upregulation of complement cascade. Further experiments demonstrate that expression of C1q increases in primary tumors and hepatic metastases, C1q is mainly produced by M2 macrophage, and C1q promotes migration and invasion of PDAC cells. CONCLUSION: Taken together, we find potential factors that contribute to different stages of PDAC metastasis. Our study broadens the understanding of molecular mechanisms driving PDAC metastasis.

5.
Plant Biotechnol J ; 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33236499

RESUMO

Foods high in amylose content and resistant starch (RS) offer great potential to improve human health and lower the risk of serious noninfectious diseases. Common wheat (Triticum aestivum L.) is a major staple food crop globally. However, the RS contents in the grains of modern wheat varieties are low. Here, we report the generation of high-amylose wheat through targeted mutagenesis of TaSBEIIa in a modern winter wheat cv Zhengmai 7698 (ZM) and a spring wheat cv Bobwhite by CRISPR/Cas9, respectively. We generated a series of transgene-free mutant lines either with partial or triple null TasbeIIa alleles in ZM and Bobwhite, respectively. Analyses of starch composition, structure and properties revealed that the effects of partial or triple null alleles were dosage dependent with triple null lines demonstrated more profound impacts on starch composition, fine structures of amylopectin, and physiochemical and nutritional properties. The flours of triple null lines possessed significantly increased amylose, RS, protein and soluble pentosan contents which benefit human health. Baking quality analyses indicated that the high-amylose flours may be used as additives or for making cookies. Collectively, we successfully modified the starch composition, structure and properties through targeted mutagenesis of TaSBEIIa by CRISPR/Cas9 in both winter and spring wheat varieties, and generated transgene-free high-amylose wheat. Our finding provides deep insights on the role of TaSBEIIa in determining starch composition, structure, properties and end-use quality in different genetic backgrounds, and improving RS content with multiple breeding and end-use applications in cereal crop species through genome editing for health benefits.

6.
Oncol Lett ; 20(4): 5, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32774479

RESUMO

Perineural invasion (PNI) is a prominent characteristic of pancreatic ductal adenocarcinoma (PDAC). PNI is associated with tumor progression, local recurrence and neuropathic pain; therefore, the identification of biomarkers associated with PNI may be beneficial in assessing the prognosis for patients with PDAC. Using an in vivo model of PNI, five pancreatic cancer cell lines (PANC-1, CFPAC-1, CAPAN-2, SW1990 and ASPC-1) were divided into two groups: High-(comprising PANC-1, CFPAC-1 and CAPAN-2) and low PNI (comprising SW1990 and ASPC-1). Differentially expressed genes (DEGs) between the two groups were identified using the GSE26088 dataset, and were regarded as PNI-associated genes. A total of 445 DEGs associated with PNI (fold change >1.5 or <0.66; P<0.05) were identified, which included 176 up- and 269 downregulated genes. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis and function annotation were performed, and the NetworkAnalyst database was used for protein-protein interaction network analysis to identify hub genes. A total of 20 hub genes (gene degree, ≥6) were identified. PNI was associated with the function 'chemokine signaling pathway'. The DEGs and hub genes were validated using the GSE102238 dataset and clinical tissue microarrays. Fibroblast growth factor 2 (FGF2) and catenin α 2 were demonstrated to be associated with PNI using the GSE102238 dataset. Furthermore, clinical tissue microarray analysis demonstrated that FGF2 was associated with PNI and poor prognosis. The present study provided a potential method for the reliable identification of PNI-associated genes, although further investigation is required to validate these results.

7.
J Plant Physiol ; 252: 153209, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32791445

RESUMO

Intracellular Ca2+ plays an essential role in plant cellular sensing of various environmental stress signals by modulating the activity of Ca2+-binding proteins. Leymus chinensis is a dominant forage grass widely distributed in the Eurasian Steppe that is well adapted to drought and salty soils common in the region. Through transcript profiling of L. chinensis roots, we identified a transcript predicted to encode histidine-rich calcium-binding protein (HRC), a protein recently characterized in wheat. L. chinensis HRC (LcH RC) localized in the nucleus, as demonstrated using a transient gene expression method that we developed for this species. Different regions of LcHRC showed affinity for either Ca2+ or Zn2+, but not Mg2+ and Mn2+. Arabidopsis thaliana seedlings heterologously overexpressing LcHRC showed greater sensitivity to abscisic acid (ABA), along with decreased expression of some ABA-induced marker genes, but no increase in ABA content. Screening a Arabidopsis cDNA yeast library identified a Tudor/PWWP/MBT-domain-containing protein (AtPWWP3) that interacts with LcHRC. AtPWWP3 also localized in the nucleus and is predicted to mediate gene expression by modifying histone deacetylation. Based on these results, we propose a functional model of LcHRC action.

8.
Theranostics ; 10(18): 8400-8414, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32724477

RESUMO

Rationale: Endoplasmic reticulum oxidoreductase 1 alpha (ERO1L) is an endoplasmic reticulum (ER) luminal glycoprotein that has a role in the formation of disulfide bonds of secreted proteins and membrane proteins. Emerging data identify ERO1L as a tumor promoter in a wide spectrum of human malignancies. However, its molecular basis of oncogenic activities remains largely unknown. Methods: Pan-cancer analysis was performed to determine the expression profile and prognostic value of ERO1L in human cancers. The mechanism by which ERO1L promotes tumor growth and glycolysis in pancreatic ductal adenocarcinoma (PDAC) was investigated by cell biological, molecular, and biochemical approaches. Results: ERO1L was highly expressed in PDAC and its precursor pancreatic intraepithelial neoplasia and acts as an independent prognostic factor for patient survival. Hypoxia and ER stress contributed to the overexpression pattern of ERO1L in PDAC. ERO1L knockdown or pharmacological inhibition with EN460 suppressed PDAC cell proliferation in vitro and slowed tumor growth in vivo. Ectopic expression of wild type ERO1L but not its inactive mutant form EROL-C394A promoted tumor growth. Bioinformatics analyses and functional analyses confirmed a regulatory role of ERO1L on the Warburg effect. Notably, inhibition of tumor glycolysis partially abrogated the growth-promoting activity of ERO1L. Mechanistically, ERO1L-mediated ROS generation was essential for its oncogenic activities. In clinical samples, ERO1L expression was correlated with the maximum standard uptake value (SUVmax) in PDAC patients who received 18F-FDG PET/CT imaging preoperatively. Analysis of TCGA cohort revealed a specific glycolysis gene expression signature that is highly correlated with unfolded protein response-related gene signature. Conclusion: Our findings uncover a key function for ERO1L in Warburg metabolism and indicate that targeting this pathway may offer alternative therapeutic strategies for PDAC.

9.
Surg Infect (Larchmt) ; 21(9): 793-798, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32186972

RESUMO

Background: Infection by multi-drug-resistant (MDR) bacteria is a high-risk factor for poor clinical results. Pancreatoduodenectomy (PD) has been associated with a high rate of complications, including intra-abdominal infections. However, there are few data available regarding MDR infection in patients undergoing PD. This study evaluated the present situation of risk factors for and clinical impact of MDR infection on patients who received PD. Methods: A total of 357 consecutive patients who underwent PD in our department from January 2016 to June 2018 were analyzed retrospectively. They were grouped into those with MDR infection (observation group) and those without MDR infection (control group). Univariable and multivariable analyses were used to identify risk factors for MDR infection in the two groups and the relations between MDR infection and clinical outcome. Results: Infections by MDR bacteria occurred in 38 patients (10.6%), and a total of 49 MDR bacterial strains were detected. Carbapenem-resistant Acinetobacter baumannii and MDR Pseudomonas aeruginosa were the most common strains. Multivariable analysis suggested that pancreatic fistula (p = 0.001) and post-operative use of quinolones (p = 0.000) were risk factors for MDR infection. At the same time, MDR infection was an independent risk factor for an increase in the 30-day in-hospital mortality rate (p = 0.005). Conclusions: Intensive intra-operative management to reduce the incidence of pancreatic fistula as well as curtailing empirical use of antibiotics, especially quinolones, may help to reduce the incidence of MDR infection and thus in-hospital deaths.

10.
Biomed Pharmacother ; 125: 109999, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32070876

RESUMO

The underlying molecular mechanisms of chronic pancreatitis (CP) developing into pancreatic ductal adenocarcinoma (PDAC) remain largely unknown. Here we show that the level of serotonin in mouse pancreatic tissues is upregulated in caerulein-induced CP mice. In vitro study demonstrates that serotonin promotes the formation of acinar-to-ductal metaplasia (ADM) and the activation of pancreatic stellate cells (PSCs), which results from the activation of RhoA/ROCK signaling cascade. Activation of this signaling cascade increases NF-κB nuclear translocation and α-SMA expression, which further enhance the inflammatory responses and fibrosis in pancreatic tissues. Intriguingly, quercetin inhibits both ADM lesion and PSCs activation in vitro and in vivo via its inhibitory effect on serotonin release. Our findings underscore the instrumental role of serotonin-mediated activation of RhoA/ROCK signaling pathway in development of PDAC from CP and highlight a potential to impede PDAC development by disrupting tumor-promoting functions of serotonin.

11.
Cancer Res ; 80(10): 1991-2003, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32098780

RESUMO

Perineural invasion is a common feature of pancreatic ductal adenocarcinoma (PDAC). Here, we investigated the effect of perineural invasion on the microenvironment and how this affects PDAC progression. Transcriptome expression profiles of PDAC tissues with different perineural invasion status were compared, and the intratumoral T-cell density and levels of neurotransmitters in these tissues were assessed. Perineural invasion was associated with impaired immune responses characterized by decreased CD8+ T and Th1 cells, and increased Th2 cells. Acetylcholine levels were elevated in severe perineural invasion. Acetylcholine impaired the ability of PDAC cells to recruit CD8+ T cells via HDAC1-mediated suppression of CCL5. Moreover, acetylcholine directly inhibited IFNγ production by CD8+ T cells in a dose-dependent manner and favored Th2 over Th1 differentiation. Furthermore, hyperactivation of cholinergic signaling enhanced tumor growth by suppressing the intratumoral T-cell response in an orthotopic PDAC model. Conversely, blocking perineural invasion with bilateral subdiaphragmatic vagotomy in tumor-bearing mice was associated with an increase in CD8+ T cells, an elevated Th1/Th2 ratio, and improved survival. In conclusion, perineural invasion-triggered cholinergic signaling favors tumor growth by promoting an immune-suppressive microenvironment characterized by impaired CD8+ T-cell infiltration and a reduced Th1/Th2 ratio. SIGNIFICANCE: These findings provide a promising therapeutic strategy to modulate the immunosuppressive microenvironment of pancreatic ductal adenocarcinoma with severe perineural invasion.


Assuntos
Acetilcolina/metabolismo , Carcinoma Ductal Pancreático/patologia , Invasividade Neoplásica/imunologia , Neoplasias Pancreáticas/patologia , Microambiente Tumoral/imunologia , Animais , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/metabolismo , Humanos , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Invasividade Neoplásica/patologia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/metabolismo , Transdução de Sinais/fisiologia
12.
FASEB J ; 34(3): 3943-3955, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31944405

RESUMO

Mangrove-derived actinobacteria strains are well-known for producing novel secondary metabolites. The polycyclic tetramate macrolactam (PTM), ikarugamycin (IKA) isolated from Streptomyces xiamenensis 318, exhibits antiproliferative activities against pancreatic ductal adenocarcinoma (PDAC) in vitro. However, the protein target for bioactive IKA is unclear. In this study, whole transcriptome-based profiling revealed that the glycolysis pathway is significantly affected by IKA. Metabolomic studies demonstrated that IKA treatment induces a significant drop in glucose-6-phosphate and a slight increase in intracellular glucose level. Analysis of glucose consumption, lactate production, and the extracellular acidification rate confirmed the inhibitory role of IKA on the glycolytic flux in PDAC cells. Surface plasmon resonance (SPR) experiments and docking studies identified the key enzyme of glycolysis, hexokinase 2 (HK2), as a molecular target of IKA. Moreover, IKA reduced tumor size without overt cytotoxicity in mice with PDAC xenografts and increased chemotherapy response to gemcitabine in PDAC cells in vitro. Taken together, IKA can block glycolysis in pancreatic cancer by targeting HK2, which may be a potential drug candidate for PDAC treatment.

13.
HPB (Oxford) ; 22(1): 91-101, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31262486

RESUMO

BACKGROUND: Synchronous resection of primary pancreatic ductal adenocarcinoma (PDAC) and liver metastases in highly selective patients is being accepted based on oncology research progress showing safe surgical outcomes with low morbidity and mortality. We also tried to determine patients who would benefit from the operation. METHODS: From January 2012 to October 2017, 48 patients who underwent synchronous resection of primary PDAC and liver metastases were retrospectively evaluated. Twenty-three of them underwent oligometastatic synchronous resection. RESULTS: The majority of synchronous resection PDAC patients underwent hepatic wedge resection, and no oligometastatic patient was treated with hemihepatectomy. The median overall survival (OS) of the synchronous resection patients was 7.8 months. Hepatic oligometastatic PDAC patients had a longer OS than that of non-oligometastatic synchronous resection patients, systemic chemotherapy patients and palliative patients (16.1 vs 6.4 months, P = 0.02; 16.1 vs 7.6 months, P = 0.02; 16.1 vs 4.3 months, P < 0.0001; respectively). Further analysis showed that localized pancreatic body/tail PDAC had a better OS in oligometastatic patients than in non-oligometastatic synchronous resection patients (16.8 months vs 7.05 months, P = 0.0004) and systemic chemotherapy patients (16.8 months vs 8 months, P = 0.003). CONCLUSION: Patients with pancreatic body/tail PDAC with liver oligometastases can benefit from synchronous resection.

14.
Gut ; 69(4): 715-726, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31300513

RESUMO

OBJECTIVE: SETD2, the sole histone H3K36 trimethyltransferase, is frequently mutated or deleted in human cancer, including pancreatic ductal adenocarcinoma (PDAC). However, whether SETD2/H3K36me3 alteration results in PDAC remains largely unknown. DESIGN: TCGA(PAAD) public database and PDAC tissue array with SETD2/H3K36me3 staining were used to investigate the clinical relevance of SETD2 in PDAC. Furthermore, to define the role of SETD2 in the carcinogenesis of PDAC, we crossed conditional Setd2 knockout mice (Pdx cre Setd2 flox/flox) together with Kras G12D mice. Moreover, to examine the role of SETD2 after ductal metaplasia, Crisp/cas9 was used to deplete Setd2 in PDAC cells. RNA-seq and H3K36me3 ChIP-seq were performed to uncover the mechanism. RESULTS: SETD2 mutant/low expression was correlated with poor prognosis in patients with PDAC. Next, we found that Setd2 acted as a putative tumour suppressor in Kras-driven pancreatic carcinogenesis. Mechanistically, Setd2 loss in acinar cells facilitated Kras-induced acinar-to-ductal reprogramming, mainly through epigenetic dysregulation of Fbxw7. Moreover, Setd2 ablation in pancreatic cancer cells enhanced epithelia-mesenchymal transition (EMT) through impaired epigenetic regulation of Ctnna1. In addition, Setd2 deficiency led to sustained Akt activation via inherent extracellular matrix (ECM) production, which would favour their metastasis. CONCLUSION: Together, our findings highlight the function of SETD2 during pancreatic carcinogenesis, which would advance our understanding of epigenetic dysregulation in PDAC. Moreover, it may also pave the way for development of targeted, patients-tailored therapies for PDAC patients with SETD2 deficiency.


Assuntos
Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Histona-Lisina N-Metiltransferase/genética , Mutação/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Células Acinares/patologia , Animais , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/genética , Metaplasia/genética , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas p21(ras)/fisiologia
15.
Cell Death Dis ; 10(12): 948, 2019 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-31827081

RESUMO

Hypoxia and the hypovascular tumor microenvironment are major hallmarks of pancreatic ductal adenocarcinoma (PDAC), in which glycolysis is of great importance to tumor survival and proliferation. There is little research regarding the role of Nuclear Factor of Activated T Cells 5 (NFAT5) in relation to carcinoma. Here, we explored the impact of NFAT5 on the biological behavior of PDAC and the underlying mechanism. We demonstrated that NFAT5 was highly expressed in PDAC and was related to poorer prognosis. Knockdown of NFAT5 lead to impaired proliferation of tumor cells caused by an aberrant Warburg effect. Mechanically, phosphoglycerate kinase 1 (PGK-1), which is the first enzyme generating ATP in glycolysis, was verified as a target gene of NFAT5. Over-expression of PGK1 compromised the aberrant oncological behavior caused by knockdown of NFAT5 both in vitro and in vivo. Clinical samples underwent positron emission tomography-computed tomography (PET-CT) examination and KrasG12D/+/Trp53R172H/+/Pdx1-Cre (KPC) mice were collected to support our conclusion.


Assuntos
Adenocarcinoma/genética , Carcinoma Ductal Pancreático/genética , Fosfoglicerato Quinase/genética , Fatores de Transcrição/genética , Transcrição Genética , Adenocarcinoma/patologia , Idoso , Animais , Carcinoma Ductal Pancreático/diagnóstico por imagem , Carcinoma Ductal Pancreático/patologia , Proliferação de Células/genética , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Glicólise/genética , Xenoenxertos , Proteínas de Homeodomínio/genética , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Fenótipo , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Proteínas Proto-Oncogênicas p21(ras)/genética , Transdução de Sinais/genética , Transativadores/genética , Hipóxia Tumoral/genética , Microambiente Tumoral/genética , Proteína Supressora de Tumor p53/genética
16.
J Immunol Res ; 2019: 8656282, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31583260

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most devastating cancer types despite the improvement of modern medicine. In our present study, we found that dickkopf-related protein 2 (DKK2) shares a higher expression in PDAC compared with adjacent pancreas tissue in tissue microarray. In addition, an elevated expression of DKK2 predicts poorer prognosis of patients and positively correlated with poor tumor differentiation. Multivariate Cox regression analysis was also performed and confirmed that the expression of DKK2 is an independent prognostic factor in PDAC. A high expression of DKK2 correlates with cell migration and epithelial mesenchymal transition based on gene set enrichment analysis (GSEA) while knockdown of DKK2 in PDAC cells resulted in impaired cellular migration. Furthermore, GSEA predicts negative correlation between tumor immunity invasion and DKK2 expression. We then confirmed these results and demonstrated that a higher expression of DKK2 imparts the recruitment of CD8+ T cells. Our work suggested that DKK2 imparts tumor immune evasion and is associated with poor prognosis in pancreatic ductal adenocarcinoma.


Assuntos
Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Adulto , Idoso , Biomarcadores Tumorais , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Prognóstico , Análise de Sobrevida , Via de Sinalização Wnt
17.
Chin Clin Oncol ; 8(2): 20, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31070040

RESUMO

Pancreatic neuroendocrine neoplasms (P-NENs) are a group of pathologically and clinically heterogeneous tumors. In the past several decades, the incidence has been increasing. In 2010, the WHO presented a new classification dividing P-NENs into well-differentiated neuroendocrine tumors (NETs) and poorly-differentiated neuroendocrine carcinomas (NECs). Surgery is the primary and most important treatment for P-NENs, and is also the only possible curative procedure. By the 2018 NCCN guideline, observation can be considered for <1 cm, low-grade asymptomatic nonfunctional P-NETs. And for patients who are not suitable for surgery, somatostatin analogues, targeted therapy, radionuclides, ablation therapies, (chemo)embolisation and chemotherapy should be considered to improve and maintain a good quality of life. More than one hundred years has passed since termed, and in recent years, more and more molecule mechanism about P-NENs have been discovered. With the addition of several new agents, survival improved over the time. All this made P-NENs great promise.


Assuntos
Tumores Neuroendócrinos/terapia , Neoplasias Pancreáticas/terapia , Qualidade de Vida , Terapia Combinada , Humanos , Prognóstico
18.
Cancer Lett ; 453: 158-169, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30954649

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with no effective treatment. Cancer cells, especially cancer stem cells (CSCs), redirect immune cells to evade immune surveillance and even coopt these immune cells to support their growth and metastasis. However, the identification of CSCs and how CSCs interact with immune cells in PDAC remain uncharacterized. Here, we report that CD90 is expressed on both stromal and tumor cells and that high expression of CD90 is related to a poor prognosis in patients with PDAC. The CD90 highly expressed (CD90hi) population in PDAC cells harbors high stemness features and tumorigenicity. Notably, CD90 acts as an anchor for monocyte/macrophage adhesion, providing a physical interaction between CD90hi cells and monocytes/macrophages. In response, the crosstalk between CD90hi cells and monocytes/macrophages promotes immunosuppressive features of immune cells, which enhance the stemness and epithelial-mesenchymal transition (EMT) of PDAC cells. Moreover, PD-L1 is dominantly expressed in the CD90hi population, providing another strategy for these cells to evade immune surveillance. These findings provide an understanding of the biological significance of CD90 expression in PDAC cells and uncover a novel mechanism for how "stem-like" PDAC cells evade immune surveillance.


Assuntos
Carcinoma Ductal Pancreático/imunologia , Células-Tronco Neoplásicas/imunologia , Neoplasias Pancreáticas/imunologia , Antígenos Thy-1/imunologia , Animais , Antígeno B7-H1/biossíntese , Antígeno B7-H1/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Xenoenxertos , Humanos , Tolerância Imunológica , Macrófagos/imunologia , Camundongos , Camundongos Nus , Monitorização Imunológica , Monócitos/imunologia , Neoplasias Pancreáticas/patologia , Células Estromais/imunologia , Células Estromais/patologia , Antígenos Thy-1/biossíntese
19.
World J Gastroenterol ; 25(14): 1684-1696, 2019 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-31011254

RESUMO

BACKGROUND: Recently, more and more studies have demonstrated the pivotal role of programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway in the immune evasion of tumors from the host immune system. However, the role of PD-1/PD-L1 pathway in gastric neuroendocrine carcinomas (G-NECs) remains unknown. AIM: To investigate the expression of PD-1/PD-L1 and role of PD-1/PD-L1 pathway in G-NECs, which occur rarely but are highly malignant and clinically defiant. METHODS: We investigated the expression of PD-L1 on tumor cells and PD-1+, CD8+, and FOXP3+ T cell infiltration by immunohistochemistry in 43 resected G-NEC tissue specimens. The copy number alterations of PD-L1 were assessed by qRT-PCR. RESULTS: Most of the G-NECs tumor cells exhibited a near-uniform expression pattern of PD-L1, while some showed a tumor-stromal interface enhanced pattern. Of the 43 G-NECs, 21 (48.8%) were classified as a high PD-L1 expression group, and the high expression of PD-L1 was associated with poor overall survival (OS). The high expression of PD-L1 was correlated with abundant PD-1+ tumor infiltrating lymphocytes (TILs) instead of CD8+ TILs and FOXP3+ regulatory T cells (Tregs). Our analysis also suggested that the infiltration of CD8+ TILs tended to be a favorable factor for OS, although the difference did not reach the statistical significance (P = 0.065). Meanwhile, PD-L1 was significantly overexpressed in cases with copy number gain as compared with those without. CONCLUSION: Our data demonstrated for the first time that high expression of PD-L1 in G-NECs is associated with a poor prognosis, while the high expression may be due to the copy number variation of PD-L1 gene or stimulation of TILs. These results provide a basis for the immunotherapy targeting PD-1/PD-L1 pathway in G-NECs.


Assuntos
Antígeno B7-H1/metabolismo , Carcinoma Neuroendócrino/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Transdução de Sinais/imunologia , Neoplasias Gástricas/imunologia , Idoso , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/mortalidade , Carcinoma Neuroendócrino/patologia , Variações do Número de Cópias de DNA , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Imunoterapia/métodos , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Transdução de Sinais/efeitos dos fármacos , Estômago/patologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Evasão Tumoral/imunologia
20.
Am J Cancer Res ; 9(2): 363-377, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30906634

RESUMO

Secreted Frizzled-Related Protein 4 (SFRP4), a member of secreted frizzled-related protein family, has been found as a vital modulator in cell proliferation, cell self-renew and apoptosis through Wnt signaling transduction pathway. In the present study, we re-analyzed the expression pattern of SFRPs in Gene Expression Omnibus (GEO) datasets and evaluated the expression of SFRP4 at protein level in both KrasG12D/+; Trp53R172H/+; Pdx1-Cre; (KPC) mice and human pancreatic ductal adenocarcinoma (PDAC) tissue. We found that the expression of SFRP4 increased gradually in PanINs and PDAC lesions in KPC mice and high expression of SFRP4 was much more common in tumor lesions compared to the adjacent non-tumor tissues. Then we performed Kaplan-Meier survival and Cox regression analysis and found that high expression of SFRP4 in the serum and tumor lesions predicted poor prognosis for pancreatic cancer patients. Furthermore, we demonstrated that SFRP4 positively correlated with FOXP3+ Treg cells infiltration while the down-regulation of SFRP4 in tumor cells impaired the production of cytokines and the recruitments of T cells. This study suggested that SFRP4 can be a novel prognostic biomarker and potential therapeutic target for pancreatic cancer.

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