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1.
Anticancer Res ; 39(10): 5449-5459, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570439

RESUMO

BACKGROUND/AIM: Epigenetic abnormalities in microRNAs (miRNAs) have not been analyzed in samples other than pancreaticobiliary tissues in patients with pancreaticobiliary cancer (PBC). To identify miRNAs specific for PBC, the present study analyzed the methylation of tumor-suppressive miRNAs in bile from patients with pancreaticobiliary diseases. MATERIALS AND METHODS: Bile was collected endoscopically or percutaneously from 52 patients with pancreatic cancer, 26 with biliary tract cancer, and 20 with benign pancreaticobiliary diseases. Sequences encoding 16 tumor-suppressive miRNAs were amplified by polymerase chain reaction and sequenced, and their methylation rates were determined. RESULTS: The methylation rates of miR-1247 and miR-200a were significantly higher in patients with pancreatic cancer, and biliary tract cancer than in those with benign diseases, and the methylation rate of miR-200b was significantly higher in patients with pancreatic cancer than in those with benign diseases. CONCLUSION: Methylation of miR-1247, miR-200a, and miR-200b in bile may be useful for distinguishing PBC from benign diseases.


Assuntos
Neoplasias do Sistema Biliar/genética , Metilação de DNA/genética , MicroRNAs/genética , Neoplasias Pancreáticas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Bile/metabolismo , Epigenômica/métodos , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Genes Supressores de Tumor/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade
2.
Medicine (Baltimore) ; 98(40): e17443, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31577767

RESUMO

RATIONALE: Pancreatic cancer (PC) is considered as one of the deadliest cancers all over the world. Germline and somatic BRCA1/2 mutations have been widely studied in breast and ovarian carcinomas as they have been found to enhance the risk for disease progression. Olaparib, an oral poly(adenosine diphosphate-ribose)polymerase (PARP) inhibitor, has been approved for the treatment strategy of ovarian cancer with any BRCA1/2 mutations. There is a lack of studies which focus on the treatment of other cancer with BRCA-Mutation. PATIENT CONCERNS: This report describes a patient whose presenting complaints were "Physical examination showed that the pancreas was occupied for one month." He initially was diagnosed with stage IV PC based on conventional imaging and pathologic assessment. He had a known germline BRCA 2 mutation, which exhibited a good response to PARP inhibitor therapy. DIAGNOSIS: Through the biopsy histopathological examination, imaging examination, and genetic testing, the patient was diagnosed as metastatic PC with BRCA2 mutation. INTERVENTIONS: He received gemcitabine and albumin-bound paclitaxel chemotherapy from March 15, 2017 to June 30, 2017, and Nivolumab immunotherapy as the maintenance therapy. After serum CA-199 level increased, Olaparib was orally administered from August 17, 2017 to March. After tumor relapsed, he received multiple lines of chemotherapy, including Trametinib Oxaliplatin, S-1, bevacizumab, and irinotecan liposome injection till July 17, 2018. OUTCOMES: We observed the patient had a good progression-free survival (7.4 months); the lesion of the pancreas was classified as partial disease through Olaparib treatment, which indicated significant shrinkage. But it is difficult to conclude whether such therapy could help prolong the overall survival for such patients. LESSONS: The targeted therapy Olaparib showed early signs of potential in treating PC in patients with mutations of the BRCA genes. With emerging therapeutic modalities and next-generation sequencing development, it is increasingly relevant to consider mutation screenings of patients with PC.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Genes BRCA2 , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Adenocarcinoma/genética , Adenocarcinoma/secundário , Idoso , Mutação em Linhagem Germinativa/genética , Humanos , Masculino , Neoplasias Pancreáticas/genética
3.
Anticancer Res ; 39(9): 4721-4728, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519571

RESUMO

BACKGROUND/AIM: Recent research has identified the transcription factors NFATc2 and Sp1 as key regulators in the carcinogenesis of pancreatic carcinoma. This study aimed to examine the effect of clinically achievable dosages of analgesics including ketamine, s-ketamine, metamizole, and paracetamol as well as that of sufentanil, ropicavaine, and lidocaine on pancreatic carcinoma cells and the expression of NFATc2 and Sp1. MATERIALS AND METHODS: The effects of analgesics on the expression of NFATc2 and Sp1 were investigated with immunoblotting. Cell proliferation was measured with the ELISA BrdU assay. RESULTS: In PaTu8988t pancreatic carcinoma cells, 48 h stimulation with ketamine and s-ketamine significantly inhibited proliferation and decreased expression of NFATc2 in the nucleus. The addition of metamizole and lidocaine reduced proliferation of PaTu8988t cells after 48 h. CONCLUSION: New treatment concepts target specific signaling and transcription pathways. The extent to which drugs influence these mechanisms in pancreatic carcinoma cells needs to be investigated in future studies.


Assuntos
Analgésicos/farmacologia , Anestésicos Locais/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fatores de Transcrição NFATC/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Fator de Transcrição Sp1/metabolismo , Biomarcadores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias Pancreáticas/patologia , Transcrição Genética
4.
Zhonghua Wai Ke Za Zhi ; 57(9): 691-697, 2019 Sep 01.
Artigo em Chinês | MEDLINE | ID: mdl-31474062

RESUMO

Objectives: To examine the expression of the long coding RNA GSTM3TV2 in pancreatic cancer tissues and to examine its role and mechanism in chemoresistance of pancreatic cancer cells. Methods: The expression of lncRNA GSTM3TV2 in 15 pancreatic cancer specimens and corresponding adjacent to cancer tissue samples diagnosed by Department of Pathology, Peking Union Medical College Hospital was detected by real-time PCR.And the expressions of GSTM3TV2 in pancreatic cancer cell AsPC-1, BxPC-3, MIAPaCa-2, PanC-1, SU86.86, T3M4, and chemoresistant cells AsPC-1/GR and MIAPaCa-2/GR, and human pancreatic nestin-expressing cells hTERT-HPNE were detected. Pancreatic cancer cell lines were transfected with GSTM3TV2-pcDNA3.1(+)in order to get cells with GSTM3TV2 overexpression.GSTM3TV2-siRNA was transfected into pancreatic cancer cells to knock down GSTM3TV2. The cell chemoresistance was measured by CCK-8 and flow cytometry assay when incubated with nab-paclitaxel. At the same time, subcutaneous xenograft tumor models were established in nude mice to observe the effect of GSTM3TV2 on chemoresistance of tumor growth in nude mice.Western blot assay was also performed to detect the molecular mechanism of chemoresistance of GSTM3TV2. Results: Comparing toadjacent tissues(0.084±0.019), GSTM3TV2 expression was significantly upregulated in the pancreatic cancer tissues(0.493±0.084) (t=5.146, P<0.05). GSTM3TV2 expression were higher in the chemotherapy resistance pancreatic cancer cells AsPC-1/GR(210.799±19.788) and MIAPaCa-2/GR(122.408±23.419) than that in the AsPC-1(3.793±0.615) and the MIAPaCa-2(5.179±1.095)(t=21.800,P<0.05;t=-18.490,P<0.05). The results of in vivo experiments showed that the volume of subcutaneously transplanted tumors in the overexpressing GSTM3TV2 group ((1 059.609±102.498)mm(3)) was significantly larger than that in the control group((566.414±81.087) mm(3)) by treated with nab-paclitaxel(t=4.230,P<0.05).Meanwhile, GSTM3TV2 could promote the expression of Cyclin D1, CDK6, Cyclin E1, Vimentin, N-cadherin, ZEB1, Snail and Slug; but decrease cleaved caspase-3, cleaved PARP in pancreatic cancer cells. Conclusions: The expression level of GSTM3TV2 in pancreatic canceris higher than that in paired adjacent tissues. GSTM3TV2 may act as an oncogene to promote chemoresistance in pancreatic cancer through regulation of cell proliferation, apoptosis, and epithelial-mesenchymal transition.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Glutationa Transferase/genética , Oncogenes/genética , Neoplasias Pancreáticas/genética , RNA não Traduzido/genética , Animais , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/genética , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Camundongos Nus , Neoplasias Pancreáticas/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Medicine (Baltimore) ; 98(32): e16541, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31393355

RESUMO

BACKGROUNDS: Previous investigations yielded inconsistent results for the associations between pancreatic cancer (PC) risk and genetic polymorphisms. The study aimed to perform a systematic review and meta-analysis of studies exploring association of some genetic polymorphisms and PC risk. METHODS: We systematically searched on PubMed and Web of Science for association of genetic polymorphisms and PC risk published from 1969 to January 2019. We computed the multivariate odd ratio (OR) and 95% confidence intervals (CI), comparing different genetic types. RESULTS: The present meta-analysis showed significant associations between deoxyribonucleic acid (DNA) repair gene (X-ray repair cross-complementing group 1 (XRCC1) Arg399GIn and Arg194Trp, excision repair cross complementation 1 (ERCC1) rs11615 and rs3212986, ERCC2 rs13181) polymorphisms and PC risk. CONCLUSIONS: Because of the limited sample size and ethnicity enrolled in the present meta-analysis, further larger scaled studies should be performed to demonstrate the association.


Assuntos
Neoplasias Pancreáticas/genética , DNA Glicosilases/genética , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética , Proteína Grupo D do Xeroderma Pigmentoso/genética
7.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 44(7): 749-756, 2019 Jul 28.
Artigo em Chinês | MEDLINE | ID: mdl-31413212

RESUMO

OBJECTIVE: To conduct genetic analysis of pancreatic ductal adenocarcinoma tissues and analyze the correlation between targeted microRNA (miRNA) and pathways in pancreatic ductal adenocarcinoma.
 Methods: We collected 19 samples of peripheral venous blood serum from patients with pancreatic ductal adenocarcinoma in Hainan Provincial Hospital of Chinese Medicine, and also collected 21 blood serum samples as a control group of non-pancreatic ductal adenocarcinoma. We used the bioinformatics analysis of literature GCBI data platform for screening and analyzing the genetics of pancreatic ductal adenocarcinoma samples. Through GCBI data platform of hierarchy clustering analysis and the enrichment of gene function analysis, the relevant miRNA was screened as a research object in patients with pancreatic ductal adenocarcinoma. The miRNA was screened by literature analysis and pancreatic cancer gene analysis. Real-time PCR and Western blotting were carried out to study the relationship between the selected miRNA and TGF-ß1 by overexpression and suppression of the gene in pancreatic ductal adenocarcinoma cells.
 Results: MiRNA-21 was screened as a gene associated with pancreatic ductal carcinoma via hierarchy clustering analysis and gene function analysis. MiRNA-21 was highly expressed in the pancreatic ductal carcinoma patients. Expressions of TGF-ß1 were inhibired in miRNA-21 overexpressed PANC-1. While the expression of miRNA-21 was inhibited, TGF-ß1 expression increased obviously.
 Conclusion: MiRNA-21 is highly expressed in patients with pancreatic ductal adenocarcinoma, can regulate the expression of TGF-ß1, which may be a mechanism of miRNA-21 in pancreatic ductal adenocarcinoma.


Assuntos
Carcinoma Ductal Pancreático , MicroRNAs/genética , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/genética , Humanos , Neoplasias Pancreáticas/genética , Fator de Crescimento Transformador beta1
8.
Anticancer Res ; 39(8): 4055-4060, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366487

RESUMO

BACKGROUND/AIM: Tumor-derived exosomes play important roles in tumor metastases. In this report, we observed the fate of tumor-derived exosomes in pancreatic cancer metastatic nude-mouse models using color-coded imaging. MATERIALS AND METHODS: Mia-PaCa-2 human pancreatic cancer cells expressing red fluorescent protein (RFP) were transduced by exosome-specific pCT-CD63-green fluorescent protein (GFP) and injected in the spleen of nude mice. RESULTS: Four weeks after injection of these cells into the spleen, liver metastases developed and tumor-derived exosomes were observed within the metastatic cancer cells and in Kupffer cells. Furthermore, tumor-derived exosomes diffused to bone marrow and lung cells, especially macrophages, without any metastases present. CONCLUSION: In the present study, we visualized the distribution of cancer-derived exosomes for the first time at the cellular level, in a pancreatic-cancer metastatic model.


Assuntos
Linhagem da Célula/genética , Exossomos/genética , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Pancreáticas/diagnóstico por imagem , Animais , Modelos Animais de Doenças , Proteínas de Fluorescência Verde/química , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Proteínas Luminescentes/química , Camundongos , Metástase Neoplásica , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
9.
J Cancer Res Clin Oncol ; 145(10): 2481-2493, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31451931

RESUMO

PURPOSE: Pancreatic adenocarcinoma (PAC) represents one of the most fatal types of cancer with an exceptionally poor prognosis, underscoring the need for improved diagnostic and treatment approaches. An over-expression of somatostatin receptors (SST) as well as of the chemokine receptor CXCR4 has been shown for many tumour entities. Respective expression data for PAC, however, are scarce and contradictory. METHODS: Overall, 137 tumour samples from 70 patients, 26 of whom were diagnosed with PAC and 44 with pancreatic neuroendocrine tumour (PanNET), were compared in terms of SST and CXCR4 expression by immunohistochemical analysis using well-characterized rabbit monoclonal antibodies. RESULTS: Only SST1 and CXCR4 expression was detected in PAC tumours, with SST1 present in 42.3% and CXCR4 in 7.7% of cases. However, the overall staining intensity was very weak. In contrast to the tumour cells, in many PAC cases, tumour capillaries exhibited strong SST3, SST5, or CXCR4 expression. In PanNETs, SST2 was the most-prominently expressed receptor, observed in 75.0% of the tumours at medium-strong intensity. SST5, SST1, and CXCR4 expression was detected in 20.5%, 15.9%, and 11.4% of PanNET cases, respectively, but the staining intensity was only weak. SST2 positivity in PanNET, but not in PAC, was associated with favourable patient outcomes. CONCLUSIONS: SST or CXCR4 expression in PAC is clearly of no therapeutic relevance. However, indirect targeting of these tumours via SST3, SST5, or CXCR4 on tumour microvessels may represent a promising additional therapeutic strategy.


Assuntos
Adenocarcinoma/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Intestinais/genética , Tumores Neuroendócrinos/genética , Neoplasias Pancreáticas/genética , Receptores CXCR4/genética , Somatostatina/genética , Neoplasias Gástricas/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Biomarcadores , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Neoplasias Intestinais/metabolismo , Neoplasias Intestinais/mortalidade , Neoplasias Intestinais/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Receptores CXCR4/metabolismo , Somatostatina/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia
11.
JAMA ; 322(5): 445-454, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31386140

RESUMO

Importance: Pancreatic adenocarcinoma is the third most common cause of cancer death among men and women in the United States. Objective: To systematically review benefits and harms of screening for pancreatic adenocarcinoma to inform the US Preventive Services Task Force. Data Sources: MEDLINE, PubMed, and the Cochrane Collaboration Registry of Controlled Trials, from January 2002 through April 27, 2018; surveillance through March 22, 2019. Study Selection: Studies of adults with or without risk factors for pancreatic adenocarcinoma (eg, family history of pancreatic cancer, personal history of new-onset diabetes) undergoing imaging-based screening; studies of treatment for adults with screen-detected or asymptomatic pancreatic adenocarcinoma. Included study designs were randomized clinical trials, nonrandomized controlled intervention studies, diagnostic accuracy studies with a reference standard, cohort studies, and case-control studies (for evaluation of harms only). Studies consisting entirely of populations with known genetic syndromes associated with pancreatic cancer were excluded. Data Extraction and Synthesis: Two investigators independently reviewed abstracts and full-text articles and rated included studies for quality; data were quantitatively analyzed to calculate a pooled diagnostic yield and narratively synthesized. Main Outcomes and Measures: Mortality, morbidity, or quality of life; diagnostic accuracy of screening tests; any harm of screening or treatment. Results: Thirteen fair-quality prospective cohort screening studies (N = 1317) conducted predominantly in populations at high familial risk for pancreatic adenocarcinoma were included. No studies reported on the effect of screening on morbidity or mortality or on the effectiveness of treatment for screen-detected pancreatic adenocarcinoma. Although no studies evaluated the diagnostic accuracy of screening tests, all 13 studies reported the diagnostic yield. Yields ranged from 0 to 75 cases per 1000 persons in studies using endoscopic ultrasound, magnetic resonance imaging, and/or computed tomography-based screening. In total, 18 cases of pancreatic adenocarcinoma were detected in 1156 adults at increased familial risk and 0 cases were detected in 161 average-risk adults. In 8 studies (n = 675) assessing procedural harms of screening, no serious harms from initial screening were reported. Two studies (n = 271) found no evidence of psychosocial harms related to screening. Evidence of surgical harms was limited. Conclusions and Relevance: Imaging-based screening in groups at high familial risk can detect pancreatic adenocarcinoma with limited evidence of minimal harms. However, the effect of screening on morbidity and mortality in groups at high familial risk has not been studied, and no data are available in average-risk populations. There is limited evidence to assess benefits or harms of surgical intervention for screen-detected pancreatic adenocarcinoma.


Assuntos
Adenocarcinoma/diagnóstico por imagem , Detecção Precoce de Câncer , Neoplasias Pancreáticas/diagnóstico , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/cirurgia , Adulto , Detecção Precoce de Câncer/efeitos adversos , Feminino , Humanos , Masculino , Programas de Rastreamento/efeitos adversos , Pâncreas/diagnóstico por imagem , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/cirurgia , Complicações Pós-Operatórias , Qualidade de Vida , Fatores de Risco , Sensibilidade e Especificidade
12.
JAMA ; 322(5): 438-444, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31386141

RESUMO

Importance: Pancreatic cancer is an uncommon cancer with an age-adjusted annual incidence of 12.9 cases per 100 000 person-years. However, the death rate is 11.0 deaths per 100 000 person-years because the prognosis of pancreatic cancer is poor. Although its incidence is low, pancreatic cancer is the third most common cause of cancer death in the United States. Because of the increasing incidence of pancreatic cancer, along with improvements in early detection and treatment of other types of cancer, it is estimated that pancreatic cancer may soon become the second-leading cause of cancer death in the United States. Objective: To update the 2004 US Preventive Services Task Force (USPSTF) recommendation on screening for pancreatic cancer. Evidence Review: The USPSTF reviewed the evidence on the benefits and harms of screening for pancreatic cancer, the diagnostic accuracy of screening tests for pancreatic cancer, and the benefits and harms of treatment of screen-detected or asymptomatic pancreatic cancer. Findings: The USPSTF found no evidence that screening for pancreatic cancer or treatment of screen-detected pancreatic cancer improves disease-specific morbidity or mortality, or all-cause mortality. The USPSTF found adequate evidence that the magnitude of the benefits of screening for pancreatic cancer in asymptomatic adults can be bounded as no greater than small. The USPSTF found adequate evidence that the magnitude of the harms of screening for pancreatic cancer and treatment of screen-detected pancreatic cancer can be bounded as at least moderate. The USPSTF reaffirms its previous conclusion that the potential benefits of screening for pancreatic cancer in asymptomatic adults do not outweigh the potential harms. Conclusions and Recommendation: The USPSTF recommends against screening for pancreatic cancer in asymptomatic adults. (D recommendation).


Assuntos
Carcinoma Ductal Pancreático/diagnóstico , Detecção Precoce de Câncer/normas , Neoplasias Pancreáticas/diagnóstico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/cirurgia , Efeitos Psicossociais da Doença , Detecção Precoce de Câncer/efeitos adversos , Feminino , Humanos , Masculino , Programas de Rastreamento/normas , Pâncreas/diagnóstico por imagem , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/cirurgia , Medição de Risco , Fatores de Risco , Sensibilidade e Especificidade
13.
Anticancer Res ; 39(8): 4575-4580, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366562

RESUMO

BACKGROUND/AIM: The aim of this study was to examine the clinicopathological features of pancreatic adenosquamous carcinoma (PASC). PATIENTS AND METHODS: Our study included seven patients who underwent resection of PASC. RESULTS: PASC is characterized by large tumors and strong infiltration into the major blood vessels and other organs, forcing many patients to undergo extended resections. In addition, all patients experienced liver metastasis recurrence following surgery, with a very poor prognosis. Histopathologically, a poorly differentiated sarcomatous component existed in all patients in addition to an adenocarcinoma component and squamous carcinoma component. Although P40 staining for the sarcomatous component was positive along with squamous carcinoma, E-cadherin expression disappeared while vimentin was expressed. It has been suggested that it is highly likely that these sarcomatous components are derived from squamous carcinoma and have an impact on prognosis. CONCLUSION: The sarcomatous component may be related to the biological malignancy of PASC.


Assuntos
Carcinoma Adenoescamoso/cirurgia , Neoplasias Pancreáticas/cirurgia , Prognóstico , Idoso , Caderinas/genética , Carcinoma Adenoescamoso/genética , Carcinoma Adenoescamoso/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia
14.
J Surg Oncol ; 120(5): 851-857, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31309569

RESUMO

Pancreatic cancer remains leading cause of cancer-related death in the United States. Patients with familial pancreas cancer, hereditary pancreatitis, known genetic mutations, and syndromes are deemed high risk for the development of pancreas cancer. Guidelines exist to help facilitate early diagnosis and treatment and these will be reviewed. Pancreatic cancer remains a leading cause of cancer-related death in the United States. Patients with familial pancreatic cancer, hereditary pancreatitis, known genetic mutations, and syndromes are deemed high risk for the development of pancreas cancer. Guidelines have been made to help facilitate early diagnosis and treatment for these patients and these will be reviewed. The exact timing of initial screening depends not only on the individual risk factors but consists of endoscopic ultrasound and magnetic resonance cholangiopancreatography. The frequency of screening depends largely on the findings of initial imaging and the patient's clinical status. We suggest that providers make themselves knowledgeable of current screening recommendations and appropriately apply them. Further critical evaluation of ongoing research is necessary to amend these recommendations as more data and genetic testing becomes available.


Assuntos
Detecção Precoce de Câncer/métodos , Predisposição Genética para Doença , Neoplasias Pancreáticas/diagnóstico , Humanos , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/genética , Prevalência , Fatores de Risco
15.
Cancer Sci ; 110(9): 2760-2772, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31325400

RESUMO

Long noncoding RNAs (lncRNAs) are emerging as key regulators in cancer initiation and progression. TP53TG1 is a recently identified lncRNA and several studies have shown that TP53TG1 may play the role of tumor suppressor gene or oncogene in different tumors. Nevertheless, the involvement of TP53TG1 in carcinogenesis of pancreatic ductal adenocarcinoma (PDAC) has not been characterized. In our studies, we identified that TP53TG1 was highly expressed in PDAC and was a novel regulator of PDAC development. Knockdown of TP53TG1 inhibited proliferation, induced apoptosis, and decreased migration and invasion in PDAC cells, whereas enhanced expression of TP53TG1 had the opposite effects. Mechanistically, TP53TG1 could directly bind to microRNA (miR)-96 and effectively function as a sponge for miR-96, thus antagonizing the functions of miR-96 and leading to derepression of its endogenous target KRAS, which is a core oncogene in the initiation and maintenance of PDAC. Taken together, these observations imply that TP53TG1 contributes to the growth and progression of PDAC by acting as a competing endogenous RNA (ceRNA) to competitively bind to miR-96 and regulate KRAS expression, which highlights the importance of the complicated miRNA-lncRNA network in modulating the progression of PDAC.


Assuntos
Carcinoma Ductal Pancreático/genética , Proteínas de Ligação a DNA/metabolismo , MicroRNAs/antagonistas & inibidores , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA Longo não Codificante/metabolismo , Carcinogênese/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/metabolismo , Invasividade Neoplásica/genética , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , RNA Longo não Codificante/genética
17.
Anticancer Res ; 39(7): 3493-3498, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262873

RESUMO

BACKGROUND/AIM: Pancreatic cancer is the most lethal cancer of the digestive system. IL-29 is a new member of the IFNλ family and well-known for its strong antiviral activity. However, its direct effect on pancreatic cancer is still unclear. This study was performed to investigate if IL-29 has any direct effect on Pan-48 pancreatic cancer cells. MATERIALS AND METHODS: Clonogenic survival assay, cell proliferation, and caspase-3 activity kits were used to evaluate the effects of IL-29 on cell survival, proliferation, and apoptosis of Pan-48 pancreatic cancer cells. RT-PCR and IHC were subsequently performed to explore IL-29's potential molecular mechanisms. RESULTS: The percentage of colonies of Pan-48 cells was decreased following the addition of IL-29. This was consistent with a decreased optical density (OD) value of cancer cells. Furthermore, the relative caspase-3 activity in cancer cells was increased after the addition of IL-29, indicating increased apoptosis of cancer cells. The anti-proliferative effect of IL-29 on cancer cells correlated with increased expression of the anti-proliferative molecule p21. The pro-apoptotic effect of IL-29 on cancer cells correlated with an increased expression of the pro-apoptotic molecule Bax. CONCLUSION: IL-29 constrains Pan-48 pancreatic cell growth via up-regulation of p21 and Bax. Our study suggests a potential use of IL-29 in immunotherapy for pancreatic cancer treatment.


Assuntos
Antineoplásicos/farmacologia , Inibidor de Quinase Dependente de Ciclina p21/genética , Interleucinas/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Proteína X Associada a bcl-2/genética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , RNA Mensageiro/metabolismo , Regulação para Cima , Proteína X Associada a bcl-2/metabolismo
18.
BMC Bioinformatics ; 20(1): 393, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311505

RESUMO

BACKGROUND: MicroRNAs (miRNAs) are small RNAs that regulate gene expression at a post-transcriptional level and are emerging as potentially important biomarkers for various disease states, including pancreatic cancer. In silico-based functional analysis of miRNAs usually consists of miRNA target prediction and functional enrichment analysis of miRNA targets. Since miRNA target prediction methods generate a large number of false positive target genes, further validation to narrow down interesting candidate miRNA targets is needed. One commonly used method correlates miRNA and mRNA expression to assess the regulatory effect of a particular miRNA. The aim of this study was to build a bioinformatics pipeline in R for miRNA functional analysis including correlation analyses between miRNA expression levels and its targets on mRNA and protein expression levels available from the cancer genome atlas (TCGA) and the cancer proteome atlas (TCPA). TCGA-derived expression data of specific mature miRNA isoforms from pancreatic cancer tissue was used. RESULTS: Fifteen circulating miRNAs with significantly altered expression levels detected in pancreatic cancer patients were queried separately in the pipeline. The pipeline generated predicted miRNA target genes, enriched gene ontology (GO) terms and Kyoto encyclopedia of genes and genomes (KEGG) pathways. Predicted miRNA targets were evaluated by correlation analyses between each miRNA and its predicted targets. MiRNA functional analysis in combination with Kaplan-Meier survival analysis suggest that hsa-miR-885-5p could act as a tumor suppressor and should be validated as a potential prognostic biomarker in pancreatic cancer. CONCLUSIONS: Our miRNA functional analysis (miRFA) pipeline can serve as a valuable tool in biomarker discovery involving mature miRNAs associated with pancreatic cancer and could be developed to cover additional cancer types. Results for all mature miRNAs in TCGA pancreatic adenocarcinoma dataset can be studied and downloaded through a shiny web application at https://emmbor.shinyapps.io/mirfa/ .


Assuntos
MicroRNAs/metabolismo , Neoplasias Pancreáticas/genética , Proteínas/genética , Interface Usuário-Computador , Automação , Humanos , Estimativa de Kaplan-Meier , MicroRNAs/genética , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Mapas de Interação de Proteínas , Proteínas/metabolismo , RNA Mensageiro/metabolismo
19.
Nat Commun ; 10(1): 3055, 2019 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-31296870

RESUMO

KRAS mutations are present in over 90% of pancreatic ductal adenocarcinomas (PDAC), and drive their poor outcomes and failure to respond to targeted therapies. Here we show that Leukemia Inhibitory Factor (LIF) expression is induced specifically by oncogenic KRAS in PDAC and that LIF depletion by genetic means or by neutralizing antibodies prevents engraftment in pancreatic xenograft models. Moreover, LIF-neutralizing antibodies synergize with gemcitabine to eradicate established pancreatic tumors in a syngeneic, KrasG12D-driven, PDAC mouse model. The related cytokine IL-6 cannot substitute for LIF, suggesting that LIF mediates KRAS-driven malignancies through a non-STAT-signaling pathway. Unlike IL-6, LIF inhibits the activity of the Hippo-signaling pathway in PDACs. Depletion of YAP inhibits the function of LIF in human PDAC cells. Our data suggest a crucial role of LIF in KRAS-driven pancreatic cancer and that blockade of LIF by neutralizing antibodies represents an attractive approach to improving therapeutic outcomes.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Fator Inibidor de Leucemia/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Feminino , Técnicas de Inativação de Genes , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Fator Inibidor de Leucemia/antagonistas & inibidores , Fator Inibidor de Leucemia/genética , Camundongos , Mutação , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Anticancer Res ; 39(7): 3609-3614, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262886

RESUMO

BACKGROUND/AIM: The novel cytidine analog RX-3117, which is activated by uridine-cytidine kinase 2 (UCK2), shows encouraging activity in pancreatic and bladder cancer Phase IIa studies. In this study we highlight the potential role of UCK2 as a biomarker for selecting patients for RX-3117 treatment. PATIENTS AND METHODS: The online genomics analysis and visualization platform, R2, developed by the Oncogenomics department at the AMC (Amsterdam, The Netherlands) was used for in silico UCK2-mRNA correlation with overall survival of pancreatic cancer patients, while UCK2 protein expression was evaluated by immunohistochemistry on pancreatic tumor formalin-fixed-paraffin-embedded sections from independent pancreatic cancer patients. mRNA expression was also determined for SUIT-2, PANC-1 and PDAC-3. Lastly, the drug sensitivity to RX-3117 was investigated using the Sulforhodamine-B cytotoxicity assay. RESULTS: The in silico data showed that a high UCK2-mRNA expression was correlated with a shorter overall survival in pancreatic cancer patients. Moreover, UCK2 protein expression was high in 21/25 patients, showing a significantly shorter mean. Overall Survival (8.4 versus 34.3 months, p=0.045). Sensitivity to RX-3117 varied between 0.6 and 11 µM. CONCLUSION: Pancreatic cancer cells are sensitive to pharmacologically achievable RX-3117 concentrations and UCK2 might be exploited as a biomarker for patient treatment selection.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/farmacologia , Biomarcadores Tumorais/metabolismo , Citidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Uridina Quinase/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Idoso , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Citidina/farmacologia , Feminino , Humanos , Masculino , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , RNA Mensageiro/metabolismo , Uridina Quinase/genética
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