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1.
World J Gastroenterol ; 27(31): 5171-5180, 2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34497442

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) represents a challenging pathology with very poor outcomes and is increasing in incidence within the general population. The majority of patients are diagnosed incidentally with insidious symptoms and hence present late in the disease process. This significantly affects patient outcomes: the only cure is surgical resection but only up to 20% of patients present with resectable disease at the time of clinical presentation. The use of "omic" technology is expanding rapidly in the field of personalised medicine - using genomic, proteomic and metabolomic approaches allows researchers and clinicians to delve deep into the core molecular processes of this difficult disease. This review gives an overview of the current findings in PDAC using these "omic" approaches and summarises useful markers in aiding clinicians treating PDAC. Future strategies incorporating these findings and potential application of these methods are presented in this review article.


Assuntos
Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/genética , Humanos , Metabolômica , Neoplasias Pancreáticas/genética , Proteômica
2.
BMJ Case Rep ; 14(9)2021 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-34511423

RESUMO

We report a case of a frail 68-year-old woman with stage 4 pancreatic carcinoma harbouring a fibroblastic growth factor receptor 2 (FGFR2) fusion who achieved a durable complete response after treatment with erdafitinib a pan-FGFR inhibitor. The FGFR2-TACC2 fusion was detected on comprehensive tumour somatic mutation profiling. There is ongoing complete response at 10 months after initiation of erdafitinib. Transient central serous retinopathy, grade 2 hyperphosphataemia and diarrhoea were the adverse events encountered.


Assuntos
Adenocarcinoma , Neoplasias Pancreáticas , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Idoso , Proteínas de Transporte , Feminino , Humanos , Mutação , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Pirazóis , Quinoxalinas , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Proteínas Supressoras de Tumor
3.
J Transl Med ; 19(1): 373, 2021 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-34461940

RESUMO

BACKGROUND: Pancreatic cancer is one of the most serious digestive malignancies. At present, there is an extreme lack of effective strategies in clinical treatment. The purpose of this study is to identify key genes and pathways in the development of pancreatic cancer and provide targets for the treatment of pancreatic cancer. METHODS: GSE15471 and GSE62165 were used to screen differentially expressed genes by GEO2R tool. Hub genes prognostic potential assessed using the GEPIA and Kaplan-Meier plotter databases. The drug susceptibility data of pan-cancer cell lines is provided by The Genomics of Drug Sensitivity in Cancer Project (GDSC). Finally, the effects of PI3K-Akt signaling pathway inhibitors on cell viability of pancreatic cancer cells were detected by cell proliferation and invasion assays. RESULTS: A total of 609 differentially expressed genes were screened and enriched in the focal adhesion, phagosome and PI3K-Akt signaling pathway. Of the 15 hub genes we found, four were primarily associated with the PI3K-Akt signaling pathway, including COL3A1, EGF, FN1 and ITGA2. GDSC analysis showed that mTOR inhibitors are very sensitive to pancreatic cancer cells with mutations in EWSR1.FLI1 and RNF43. Cell proliferation and invasion results showed that mTOR inhibitors (GSK2126458) can inhibit the proliferation of pancreatic cancer cells. CONCLUSIONS: This study suggested that the PI3K-Akt signaling pathway may be a key pathway for pancreatic cancer, our study uncovered the potential therapeutic potential of GSK2126458, a specific mTOR inhibitor, for pancreatic cancer.


Assuntos
Biologia Computacional , Neoplasias Pancreáticas , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Fosfatidilinositol 3-Quinases , Piridazinas , Quinolinas , Sulfonamidas
4.
World J Gastroenterol ; 27(27): 4371-4382, 2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34366610

RESUMO

Pancreatic ductal adenocarcinoma is an aggressive tumor with poor long-term outcomes. Chronic pancreatitis (CP) is considered a risk factor for the development of pancreatic cancer (PC). Persistent pancreatic inflammation and activation of pancreatic stellate cells play a crucial role in the pathogenesis of CP-related PC by activating the oncogene pathway. While genetic mutations increase the possibility of recurrent and persistent pancreatic inflammation, they are not directly associated with the development of PC. Recent studies suggest that early surgical intervention for CP might have a protective role in the development of CP-related PC. Hence, the physician faces the clinical question of whether early surgical intervention should be recommended in patients with CP to prevent the development of PC. However, the varying relative risk of PC in different subsets of CP underlines the complex gene-environment interactions in the disease pathogenesis. Hence, it is essential to stratify the risk of PC in each individual patient. This review focuses on the complex relationship between CP and PC and the impact of surgical intervention on PC risk. The proposed risk stratification based on the genetic and environmental factors could guide future research and select patients for prophylactic surgery.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Pancreatite Crônica , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/cirurgia , Humanos , Oncogenes , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/cirurgia , Pancreatite Crônica/genética , Pancreatite Crônica/cirurgia , Fatores de Risco
5.
Free Radic Biol Med ; 174: 202-210, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34364982

RESUMO

The intrinsic chemoresistance of pancreatic ductal adenocarcinoma (PDAC) represents the main obstacle in treating this aggressive malignancy. It has been observed that high antioxidant levels and upregulated Nrf2 and the YAP protein expression can be involved in PDAC chemoresistance. The mechanisms of Nrf2 and YAP increase need to be clarified. We chose a panel of PDAC cell lines with diverse sensitivity to cisplatin and gemcitabine. In PANC-1 chemoresistant cells, we found a low level of oxidative stress and high levels of Nrf2 and YAP protein expressions and their respective targets. On the contrary, in CFPAC-1 chemosensitive cells, we found high levels of oxidative stress and low level of these two proteins, as well as their respective targets. In MiaPaCa-2 cells with a middle chemoresistance, we observed intermediate features. When Nrf2 and YAP were inhibited in PANC-1 cells by Ailanthone, a plant extract, we observed a reduction of viability, thus sustaining the role of these two proteins in maintaining the PDAC chemoresistance. We then delved into the mechanisms of the Nrf2 and YAP protein upregulation in chemoresistance, discovering that it was at a post-translational level since the mRNA expressions did not match the protein levels. Treatments of PANC-1 cells with the proteasome inhibitor MG-132 and the protein synthesis inhibitor cycloheximide further confirmed this observation. The expression of DUB3 and OTUD1 deubiquitinases, involved in the control of Nrf2 and YAP protein level, respectively, was also investigated. Both protein expressions were higher in PANC-1 cells, intermediate in MiaPaCa-2 cells, and lower in CFPAC-1 cells. When DUB3 or OTUD1 were silenced, both Nrf2 and YAP expressions were downregulated. Importantly, in deubiquitinase-silenced cells, we observed a great reduction of proliferation and a higher sensitivity to gemcitabine treatment, suggesting that DUB3 and OTUD1 can represent a suitable target to overcome chemoresistance in PDAC cells.


Assuntos
Fator 2 Relacionado a NF-E2 , Neoplasias Pancreáticas , Linhagem Celular Tumoral , Enzimas Desubiquitinantes , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Proteases Específicas de Ubiquitina
6.
J Transl Med ; 19(1): 332, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34353343

RESUMO

BACKGROUND: Pancreatic cancer (PC) is one of the most fatal digestive system cancers. tripartite motif-29 (TRIM29) has been reported as oncogene in several human cancers. However, the precise role and underlying signal cascade of TRIM29 in PC progression remain unclear. METHODS: Western blot, qRT-PCR and immunohistochemistry were used to analyze TRIM29 and Yes-associated protein 1 (YAP1) levels. CCK8 assays, EdU assays and flow cytometry were designed to explore the function and potential mechanism of TRIM29 and YAP1 in the proliferation of PC. Next, a nude mouse model of PC was established for validating the roles of TRIM29 and YAP1 in vivo. The relationship among TRIM29 and YAP1 was explored by co-immunoprecipitation and in vitro ubiquitination assay. RESULTS: TRIM29 and YAP1 was significantly upregulated in PC patient samples, and TRIM29 expression was closely related to a malignant phenotype and poorer overall survival (OS) of PC patients. Functional assays revealed that TRIM29 knockdown suppresses cell growth, arrests cell cycle progression and promotes cell apoptosis of PC cells in vivo and in vitro. Furthermore, the rescue experiments demonstrated that TRIM29-induced proliferation is dependent on YAP1 in PC cells. Mechanistically, TRIM29 regulates YAP1 expression by directly binding to YAP1, and reduced its ubiquitination and degradation. CONCLUSION: Taken together, these results identify a novel mechanism used by PC growth, and provide insight regarding the role of TRIM29 in PC.


Assuntos
Proteínas de Ligação a DNA , Neoplasias Pancreáticas , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Neoplasias Pancreáticas/genética , Fatores de Transcrição , Ubiquitina-Proteína Ligases
7.
Pathologe ; 42(5): 464-471, 2021 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-34402977

RESUMO

Ductal adenocarcinoma is the most common tumor of the pancreas. Although relatively rare, it poses one of the greatest oncological challenges because of its poor prognosis, which has so far only slightly improved. Progress has been made in the more precise classification and standardization of the morphological assessment. In the current WHO classification, prognostically relevant subtypes are clearly delimited among themselves and from ductal adenocarcinoma not otherwise specified (NOS). In the recent TNM classification, a size-based T­category was introduced. Diagnostically, the histological assessment of the resection specimen is relatively easy; on the other hand, assessment of the fine-needle biopsy from the primary tumor or a liver metastasis is still difficult. The molecular stratification of ductal adenocarcinoma and the other pancreatic neoplasms has made great progress. This not only defined the genetics of tumor entities, but also identified the prognosis and biology of tumor groups on the basis of RNA expression patterns. The range of treatment could be expanded by targeted molecular therapies (especially for patients with BRCA1/2 germline mutations, NTRK- or NRG1-fusions, or oncogenic BRAF and PIK3CA mutations as well as tumors with microsatellite instability (MSI)), even if targeted therapies are currently only available for a minority of patients (<10%).


Assuntos
Neoplasias da Mama , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/genética , Feminino , Humanos , Pâncreas , Neoplasias Pancreáticas/genética , Patologia Molecular , Prognóstico
8.
World J Gastroenterol ; 27(24): 3568-3580, 2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34239270

RESUMO

Pancreatic cancer is one of the highest and in fact, unchanged mortality-associated tumor, with an exceptionally low survival rate due to its challenging diagnostic approach. So far, its treatment is based on a combination of approaches (such as surgical resection with or rarely without chemotherapeutic agents), but with finite limits. Thus, looking for additional space to improve pancreatic tumorigenesis therapeutic approach, research has focused on gene therapy with unexpectedly growing horizons not only for the treatment of inoperable pancreatic disease, but also for its early stages. In vivo gene delivery viral vectors, despite few disadvantages (possible immunogenicity, toxicity, mutagenicity, or high cost), could be one of the most efficient cancer gene therapeutic strategies for clinical application due to their superiority compared with other systems (ex vivo delivery strategies). Their dominance consists of simple preparation, easy operation and a wide range of functions. Adenoviruses are one of the most common used vectors, inducing strong immune as well as inflammatory reactions. Oncolytic virotherapy, using the above mentioned in vivo viral vectors, is one of the most promising non-pathogenic, highly-selective cytotoxic anti-cancer therapy using anti-cancer agents with high anti-tumor potency and strong oncolytic effect. There have been a variety of targeted therapeutic and pre-clinical strategies tested for gene therapy in pancreatic cancer such as gene-editing systems (e.g., clustered regularly interspaced palindromic repeats-Cas9), RNA interference technology (e.g., microRNAs, short hairpin RNA or small interfering RNA), adoptive immunotherapy and vaccination (e.g., chimeric antigen receptor T-cell therapy) with encouraging results.


Assuntos
Terapia Viral Oncolítica , Neoplasias Pancreáticas , Edição de Genes , Técnicas de Transferência de Genes , Terapia Genética , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia
9.
J Transl Med ; 19(1): 323, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34330301

RESUMO

BACKGROUND: Pancreatic cancer is a fatal malignancy of the digestive system and the 5-year survival rate remains low. Therefore, new molecular therapeutic targets are required to improve treatments, prognosis, and the survival of patients. N6-methyladenosine (m6A) is the most prevalent reversible methylation in mammalian messenger RNA (mRNA) and has critical roles in the tumorigenesis and metastasis of various malignancies. However, the role of m6A in pancreatic cancer is still unclear. Exploring genetic alterations and functional networks of m6A regulators in pancreatic cancer may provide new strategies for its treatment. METHODS: In this study, we used data from the Cancer Genome Atlas (TCGA) database and other public databases through cBioPortal, LinkedOmics, UALCAN, GEPIA, STRING, and the database for annotation, visualization, and integrated discovery (DAVID) to systematically analyze the molecular alterations and functions of 20 main m6A regulators in pancreatic cancer. RESULTS: We found that m6A regulators had widespread genetic alterations, and that their expression levels were significantly correlated with pancreatic cancer malignancy. Moreover, m6A regulators were associated with the prognosis of pancreatic cancer patients. CONCLUSIONS: m6A regulators play a crucial part in the occurrence and development of pancreatic cancer. Our study will guide further studies of m6A RNA modification in pancreatic cancer and could potentially provide new strategies for pancreatic cancer treatment.


Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias Pancreáticas , Animais , Mineração de Dados , Humanos , Metilação , Neoplasias Pancreáticas/genética , RNA Mensageiro/metabolismo
10.
Molecules ; 26(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207840

RESUMO

Statins have been widely used for the treatment of hypercholesterolemia due to their ability to inhibit HMG-CoA reductase, the rate-limiting enzyme of de novo cholesterol synthesis, via the so-called mevalonate pathway. However, their inhibitory action also causes depletion of downstream intermediates of the pathway, resulting in the pleiotropic effects of statins, including the beneficial impact in the treatment of cancer. In our study, we compared the effect of all eight existing statins on the expression of genes, the products of which are implicated in cancer inhibition and suggested the molecular mechanisms of their action in epigenetic and posttranslational regulation, and in cell-cycle arrest, death, migration, or invasion of the cancer cells.


Assuntos
Antineoplásicos/farmacologia , Biologia Computacional/métodos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Ácido Mevalônico/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Transcriptoma/efeitos dos fármacos , Morte Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Epigênese Genética , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia
11.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34208964

RESUMO

Gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) are rare diseases occurring in the gastrointestinal tract and pancreas. They are characterized by the loss of epithelial tubular gland elements, and by the increased expression of neuroendocrine markers. GEP-NENs are subdivided into two histo-pathological types, gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) and gastro-entero-pancreatic neuroendocrine carcinomas (GEP-NECs). According to WHO 2017 and 2019 classification criteria are graded and staged in four categories, NET-G1, NET-G2, NET-G3, and NEC-G3. The molecular characterization of these tumors can be fundamental for the identification of new diagnostic, prognostic and predictive biomarkers. The main purpose of this study was to analyze the expression of the paralogous 13 HOX genes, normally involved in embryogenic development and frequently deregulated in human cancers, and of the HOX regulating lncRNA HOTAIR in GEP-NENs. The expression of HOX genes is gradually lost in the transition from GEP NET G1 to NET/NEC G3 tumors, while HOTAIR expression, inversely correlated with HOX genes expression and weakly expressed in low-grade GEP NENs, becomes aberrant in NET G3 and NEC G3 categories. Our data highlights their potential role in the molecular stratification of GEP-NENs by suggesting new prognostic markers and potential therapeutic targets.


Assuntos
Genes Homeobox , Neoplasias Intestinais/patologia , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , RNA Longo não Codificante/genética , Neoplasias Gástricas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Intestinais/genética , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Tumores Neuroendócrinos/genética , Neoplasias Pancreáticas/genética , Neoplasias Gástricas/genética , Regulação para Cima
12.
Nat Commun ; 12(1): 4536, 2021 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-34315872

RESUMO

Despite the substantial impact of post-translational modifications on programmed cell death 1 ligand 1 (PD-L1), its importance in therapeutic resistance in pancreatic cancer remains poorly defined. Here, we demonstrate that never in mitosis gene A-related kinase 2 (NEK2) phosphorylates PD-L1 to maintain its stability, causing PD-L1-targeted pancreatic cancer immunotherapy to have poor efficacy. We identify NEK2 as a prognostic factor in immunologically "hot" pancreatic cancer, involved in the onset and development of pancreatic tumors in an immune-dependent manner. NEK2 deficiency results in the suppression of PD-L1 expression and enhancement of lymphocyte infiltration. A NEK binding motif (F/LXXS/T) is identified in the glycosylation-rich region of PD-L1. NEK2 interacts with PD-L1, phosphorylating the T194/T210 residues and preventing ubiquitin-proteasome pathway-mediated degradation of PD-L1 in ER lumen. NEK2 inhibition thereby sensitizes PD-L1 blockade, synergically enhancing the anti-pancreatic cancer immune response. Together, the present study proposes a promising strategy for improving the effectiveness of pancreatic cancer immunotherapy.


Assuntos
Antígeno B7-H1/metabolismo , Imunidade , Quinases Relacionadas a NIMA/antagonistas & inibidores , Neoplasias Pancreáticas/imunologia , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Modelos Biológicos , Quinases Relacionadas a NIMA/deficiência , Quinases Relacionadas a NIMA/genética , Quinases Relacionadas a NIMA/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Fosforilação , Fosfosserina/metabolismo , Prognóstico , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica , Estabilidade Proteica , Proteólise , Ubiquitinação
13.
Zhonghua Zhong Liu Za Zhi ; 43(6): 646-656, 2021 Jun 23.
Artigo em Chinês | MEDLINE | ID: mdl-34289556

RESUMO

Objective: To investigate the role of CUL4B-RING E3 ubiquitin ligase (CRL4B) complex in pancreatic tumorigenesis and the molecular mechanism. Methods: Pancreatic cells were divided into control group (transfected with negative control lentivirus), shCUL4B group (transfected with CUL4B lentivirus), shDDB1 group [transfected with DNA damage binding protein 1 (DDB1) lentivirus], and shCUL4B+ siSFRP1 group (transfected with CUL4B lentivirus and SFRP1-siRNA). RNA-seq was performed in pancreatic cancer cell lines with CUL4B and DDB1 knocked down respectively, to identify the target genes regulated by CRL4B complex. Real-time fluorescent quantitative polymerase chain reaction (qRT-PCR) was used to detect the mRNA expression levels of target genes. Chromatin immunoprecipitation (ChIP) assay was used to identify the target genes directly regulated by CUL4B and DDB1. Western blot was used to detect the protein expression levels of the epithelial-mesenchymal transition (EMT) markers. The EdU cell proliferation test was used to detect cell proliferation ability. The scratch repair test and Transwell cell invasion test were used to detect cell migration and invasion ability. Finally, the sequencing data of pancreatic cancer-related tumor samples and normal samples in GEO, TCGA and GTEx databases were used to analyze the expression correlations of CUL4B, DDB1 and their downstream target genes. Results: RNA-seq results showed that target genes regulated by CRL4B complex involved in a number of malignant tumor-related signaling pathways. qRT-PCR results verified that the mRNA expression levels of the target genes of CUL4B or DDB1 knockdown groups were higher than those of the control group, and the difference was statistically significant (P<0.05). ChIP-PCR results showed that CRL4B complex directly bound to the promoter regions of the target genes, NME1 and SFRP1, and the enrichment of monoubiquitination of lysine at 119 of histone H2A (H2AK119ub1) in the promoter region of target gene was reduced after CUL4B knockdown. The proliferation rate in PANC-1 cell line of the control group was (32.10±3.58)%, higher than (13.95±1.66)% in the shCUL4B group and (22.38±0.77)% in the shCUL4B+ siSFRP1 group (P<0.05). The proliferation rate in AsPC-1 cell line of the control group was (35.47±7.80)%, higher than (19.60±3.58)% in the shCUL4B group and (30.09±0.81)% in the shCUL4B+ siSFRP1 group (P<0.05). The scratch repair experiment showed that the migration rate of PANC-1 cell line control group was (53.18±3.70)%, higher than that (17.46±2.62)% in the shCUL4B group and (44.99±9.18)% in the shCUL4B + siSFRP1 group (P<0.05). Western blot showed the expression levels of epithelial markers including α-catenin and γ-catenin in the control group were 1.00±0.03 and 1.01±0.11, respectively, lower than 1.44±0.01 and 1.21±0.06 in the shCUL4B group (P<0.05). The expression levels of mesenchymal markers including fibronectin and vimentin in the control group were 1.01±0.14 and 1.02±0.18, respectively, higher than 1.53±0.13 and 1.22±0.07 in the shCUL4B+ siSFRP1 group (P<0.05). The cell metastasis rate of the control group was (100.00±3.96)%, higher than the (35.49±0.34)% in the shCUL4B group and (107.06±2.77)% in the shCUL4B+ siSFRP1 group, the difference was statistically significant (P<0.05). The expressions of CUL4B and DDB1 were significantly upregulated in the pancreatic cancer tissues, and were negatively correlated with the expression of SFRP1 (r=-0.342 and r=-0.264, respectively). Conclusions: CRL4B complex inhibits the transcription of target gene SFRP1 and promotes the development of pancreatic cancer. Moreover, CRL4B complex is upregulated in pancreatic cancer, which provide a potential of therapeutic target for pancreatic cancer.


Assuntos
Proteínas Culina , Neoplasias Pancreáticas , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Proteínas Culina/genética , Proteínas Culina/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Neoplasias Pancreáticas/genética
14.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201897

RESUMO

Intraductal papillary mucinous neoplasms (IPMN) are common and one of the main precursor lesions of pancreatic ductal adenocarcinoma (PDAC). PDAC derived from an IPMN is called intraductal papillary mucinous carcinoma (IPMC) and defines a subgroup of patients with ill-defined specificities. As compared to conventional PDAC, IPMCs have been associated to clinical particularities and favorable pathological features, as well as debated outcomes. However, IPMNs and IPMCs include distinct subtypes of precursor (gastric, pancreato-biliary, intestinal) and invasive (tubular, colloid) lesions, also associated to specific characteristics. Notably, consistent data have shown intestinal IPMNs and associated colloid carcinomas, defining the "intestinal pathway", to be associated with less aggressive features. Genomic specificities have also been uncovered, such as mutations of the GNAS gene, and recent data provide more insights into the mechanisms involved in IPMCs carcinogenesis. This review synthetizes available data on clinical-pathological features and outcomes associated with IPMCs and their subtypes. We also describe known genomic hallmarks of these lesions and summarize the latest data about molecular processes involved in IPMNs initiation and progression to IPMCs. Finally, potential implications for clinical practice and future research strategies are discussed.


Assuntos
Carcinoma Ductal Pancreático/patologia , Neoplasias Intraductais Pancreáticas/patologia , Neoplasias Pancreáticas/patologia , Animais , Carcinoma Ductal Pancreático/classificação , Carcinoma Ductal Pancreático/genética , Cromograninas/genética , Progressão da Doença , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Humanos , Camundongos , Modelos Biológicos , Mutação , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Neoplasias Intraductais Pancreáticas/classificação , Neoplasias Intraductais Pancreáticas/genética , Neoplasias Pancreáticas/classificação , Neoplasias Pancreáticas/genética , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)/genética
15.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203589

RESUMO

Pancreatic ductal adenocarcinoma is one of the deadliest tumors. This neoplasia is characterized by an important cellular and phenotypic heterogeneity. In particular, it has been shown that at least two subtypes can be found: basal-like, which presents stem-like properties, and classical. Cancer stem cells have been isolated and characterized from these tumors, showing their dependance on general and tissue-specific stem transcription factors and signaling pathways. Nevertheless, little is known about their tissue microenvironment and cell non-autonomous regulators, such as long-non-coding RNAs. (lncRNAs). In this review, we summarize the current knowledge about the positive and negative effects of lncRNAs in the stemness phenotype of pancreatic ductal adenocarcinoma cancer (PDAC).


Assuntos
Adenocarcinoma/genética , Carcinoma Ductal Pancreático/genética , Células-Tronco Neoplásicas/patologia , Neoplasias Pancreáticas/genética , RNA Longo não Codificante/metabolismo , Adenocarcinoma/patologia , Animais , Carcinoma Ductal Pancreático/patologia , Humanos , Células-Tronco Neoplásicas/metabolismo , Neoplasias Pancreáticas/patologia , Fenótipo , RNA Longo não Codificante/genética
16.
Biomater Sci ; 9(16): 5599-5611, 2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34250995

RESUMO

Pancreatic carcinoma elevates quickly and thus has a high mortality rate. Therefore, early treatment is essential for treating pancreatic carcinoma. KRAS is the most frequently identified and one of the earliest mutations in pancreatic tumorigenesis. Thus, the KRAS-mutant cell is an ideal target for the treatment of pancreatic carcinoma, especially at the early stage. KRAS mutation increases macropinocytosis in pancreatic cancer cells, enhancing the internalization of exosomes. Because acquiring natural exosomes could be laborious and their encapsulation efficiency is often unsatisfactory, we aimed to develop a delivery system that mimics the Kras-mutant cell targeting capability of exosomes but is easier to generate and has better loading efficiency. For this purpose, we constructed a hybrid nanoplatform by fusing CLT (Celastrol)-Loaded PEGylated lipids with the DC2.4 cell membrane (M-LIP-CLT) to achieve targeted treatment of Kras-mutant pancreatic cancer. This hybrid nanoplatform improved CLT tumor accumulation and showed excellent anti-cancer efficiency both in vitro and in vivo with increased safety. These results suggest that M-LIP-CLT is an effective drug delivery system for targeted therapy against pancreatic carcinoma, and the fusion strategy showed attractive potential for further development.


Assuntos
Exossomos , Neoplasias Pancreáticas , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Exossomos/genética , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética
17.
J Transl Med ; 19(1): 301, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34247626

RESUMO

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with molecular heterogeneity, inducing differences in biological behavior, and therapeutic strategy. NGS profiles of pathogenic alterations in the Chinese PDAC population are limited. We conducted a retrospective study to investigate the predictive role of DNA damage repair (DDR) mutations in precision medicine. METHODS: The NGS profiles were performed on resected tissues from 195 Chinese PDAC patients. Baseline clinical or genetic characteristics and survival status were collected. The Kaplan-Meier survival analyses were performed by the R version 3.6.1. RESULTS: The main driver genes were KRAS, TP53, CDKN2A, and SMAD4. Advanced patients with KRAS mutation showed a worse OS than KRAS wild-type (p = 0.048). DDR pathogenic deficiency was identified in 30 (15.38%) of overall patients, mainly involving BRCA2 (n = 9, 4.62%), ATM (n = 8, 4.10%) and RAD50 genes (n = 3, 1.54%). No significance of OS between patients with or without DDR mutations (p = 0.88). But DDR mutation was an independent prognostic factor for survival analysis of advanced PDAC patients (p = 0.032). For DDR mutant patients, treatment with platinum-based chemotherapy (p = 0.0096) or olaparib (p = 0.018) respectively improved the overall survival. No statistical difference between tumor mutation burden (TMB) and DDR mutations was identified. Treatment of PD-1 blockades did not bring significantly improved OS to DDR-mutated patients than the naive DDR group (p = 0.14). CONCLUSIONS: In this retrospective study, we showed the role of germline and somatic DDR mutation in predicting the efficacy of olaparib and platinum-based chemotherapy in Chinese patients. However, the value of DDR mutation in the prediction of hypermutation status and the sensitivity to the PD-1 blockade needed further investigation.


Assuntos
Adenocarcinoma , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , China , Dano ao DNA/genética , Células Germinativas , Humanos , Mutação/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Estudos Retrospectivos
18.
Can J Gastroenterol Hepatol ; 2021: 8882129, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34222137

RESUMO

Background: One of the microRNAs (miRNAs) known to be associated with cancer development is miR-607. The aim of this study is to investigate the clinical significance and diagnostic and prognostic value of miR-607 and to explore its potential role in pancreatic ductal adenocarcinoma (PDAC). Methods: The expression levels of miR-607 were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). The correlation between miR-607 expression and clinical characteristics was analyzed by the Chi-square test. Overall survival (OS) and progression-free survival (PFS) were evaluated via the Kaplan-Meier method, and the association between miR-607 expression and OS was investigated by the Cox proportional hazard analysis. The diagnostic value was estimated via receiver operating characteristic (ROC) curve analysis. The effect of miR-607 overexpression on cell migration, invasion, and epithelial-mesenchymal transition (EMT) was determined by wound-healing, Transwell invasion, and Western blotting assays. Results: miR-607 levels were downregulated in PDAC tumor tissues compared with normal tissues. Also, low miR-607 levels were observed in serum samples from PDAC patients than that in healthy controls. The miR-607 level was found to be closely correlated with lymphatic metastasis and liver metastasis, perineural invasion, and OS and PFS, and the low miR-607 level was an independent prognostic factor for the poor OS of PDAC patients. Furthermore, the area under the curve (AUC) of serum miR-607 for discriminating PDAC patients was 0.785 with a sensitivity of 0.647 and a specificity of 0.772, which was better than those for CA19-9 (AUC: 0.702, sensitivity: 0.607, specificity: 0.736) and CEA (AUC: 0.648, sensitivity: 0.542, specificity: 0.670). The AUC (0.863), sensitivity (0.766), and specificity (0.831) of their combination in the diagnosis of PDAC were better than those for alone. Moreover, ectopic overexpression of miR-607 could inhibit cell migration and invasion of BxPc-3 and PANC-1 cells by decreasing EMT ability. Conclusions: Low serum miR-607 level may serve as a potential diagnostic and prognostic biomarker through regulation of tumor metastasis in PDAC patients.


Assuntos
Carcinoma Ductal Pancreático , MicroRNAs , Neoplasias Pancreáticas , Biomarcadores Tumorais/sangue , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/sangue , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Prognóstico
19.
Nat Commun ; 12(1): 4626, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34330913

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that has remained clinically challenging to manage. Here we employ an RNAi-based in vivo functional genomics platform to determine epigenetic vulnerabilities across a panel of patient-derived PDAC models. Through this, we identify protein arginine methyltransferase 1 (PRMT1) as a critical dependency required for PDAC maintenance. Genetic and pharmacological studies validate the role of PRMT1 in maintaining PDAC growth. Mechanistically, using proteomic and transcriptomic analyses, we demonstrate that global inhibition of asymmetric arginine methylation impairs RNA metabolism, which includes RNA splicing, alternative polyadenylation, and transcription termination. This triggers a robust downregulation of multiple pathways involved in the DNA damage response, thereby promoting genomic instability and inhibiting tumor growth. Taken together, our data support PRMT1 as a compelling target in PDAC and informs a mechanism-based translational strategy for future therapeutic development.Statement of significancePDAC is a highly lethal cancer with limited therapeutic options. This study identified and characterized PRMT1-dependent regulation of RNA metabolism and coordination of key cellular processes required for PDAC tumor growth, defining a mechanism-based translational hypothesis for PRMT1 inhibitors.


Assuntos
Carcinoma Ductal Pancreático/genética , Dano ao DNA , Neoplasias Pancreáticas/genética , Proteína-Arginina N-Metiltransferases/genética , RNA/genética , Proteínas Repressoras/genética , Animais , Biocatálise/efeitos dos fármacos , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/prevenção & controle , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/prevenção & controle , Proteína-Arginina N-Metiltransferases/metabolismo , RNA/metabolismo , Interferência de RNA , Proteínas Repressoras/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
20.
Aging (Albany NY) ; 13(12): 16471-16484, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-34230221

RESUMO

BACKGROUND: Increasing reports have revealed that dysregulated expression of long non-coding RNAs (lncRNAs) is involved in pancreatic carcinoma progression. This study intends to explore the function and molecular mechanism of lncRNA HLA complex group 11 (HCG11) in pancreatic carcinoma. METHODS: The expression profiles of HCG11 in pancreatic carcinoma samples were detected by qPCR. Bioinformatics analysis was applied to detect the associations among HCG11/miR-579-3p/MDM2. The malignant properties of pancreatic carcinoma cells were measured by numerous biological assays. Xenograft model was exploited to detect the effect of HCG11 on tumor growth. RESULTS: A significant increase of HCG11 was occurred in pancreatic carcinoma samples. Knockdown of HCG11 suppressed the progression of pancreatic carcinoma cells. Bioinformatics analysis revealed that HCG11 upregulated MDM2 expression by competitively targeting miR-579-3p. The rescue assays showed that miR-579-3p reversed cell behaviors caused by HCG11, and MDM2 reversed cell properties induced by miR-579-3p. The Notch1 intracellular domain (NICD) and Hes1 protein levels were increased by overexpression of HCG11/MDM2. The tumor growth was suppressed after depletion of HCG11, followed by suppressing Ki67, PCNA and Vimentin expression, increasing TUNEL-positive cells and E-cadherin expression. CONCLUSIONS: Our observations highlighted that HCG11 contributed to the progression of pancreatic carcinoma by promoting growth and aggressiveness, and inhibiting apoptosis via miR-579-3p/MDM2/Notch/Hes1 axis.


Assuntos
MicroRNAs/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , RNA Longo não Codificante/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais , Fatores de Transcrição HES-1/metabolismo , Animais , Apoptose/genética , Sequência de Bases , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , MicroRNAs/genética , RNA Longo não Codificante/genética , Reprodutibilidade dos Testes , Ensaios Antitumorais Modelo de Xenoenxerto
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