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  • 1
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    Abstract 2860: NOSTRIN-induced inhibition of pancreatic cancer progression involves CCBE1 in an eNOS-independent manner
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2860-2860
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2860-2860
    Abstract: NOSTRIN represses disease aggressiveness in pancreatic cancer by suppressing eNOS-mediated NO production. We have further explored the NOSTRIN-mediated eNOS-independent pathways that contribute to its tumor inhibitory function. Gene expression analysis identified CCBE1 as a target of NOSTRIN. We provide experimental and clinical evidence that NOSTRIN functions a negative regulator in pancreatic cancer progression through inhibiting the expression of CCBE1. Furthermore, CCBE1 expression is regulated by NOSTRIN independent of eNOS. NOSTRIN attenuates protein-protein interaction between ABL1 and PKD2 resulting in the suppression of PKD2 and NFkB p50 activation. Inhibition of PKD2 and NFkB p50 activation results in the suppression of CTCF, which is as a transcription factor of CCBE1. CCBE1 expression is decreased as the down-stream gene of CTCF. Taken together, CCBE1 may be a potential therapeutic target in pancreatic cancer. Citation Format: Lin Zhang, Shouhui Yang, Limin Wang, Peijun He, Ohara Yuuki, Paloma Valenzuela, Wei Tang, Jochen Gaedcke, B. Michael Ghadim, Matthias M. Gaida, Frank Bergmann, H. Richard Alexander, Nader Hanna, Brid M Ryan, S. Perwez Hussain. NOSTRIN-induced inhibition of pancreatic cancer progression involves CCBE1 in an eNOS-independent manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2860.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-2860
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 2
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    Abstract 923: Nitric oxide signaling pathway as a pathogenic driver in pancreatic cancer
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 923-923
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 923-923
    Abstract: Pancreatic Ductal Adenocarcinoma (PDAC) is among the most malignant cancers, with 5-year survival of 6%. Chronic inflammation is associated with increased risk of PDAC. Nitric oxide (NO) is an important mediator of inflammatory responses and plays a role in tumorigenesis. The principal source of an increased and sustained level of NO is inducible nitric oxide synthase (NOS2). In this study, we’ve tested the hypothesis that NO enhances tumor progression in pancreatic cancer. We found that higher NOS2 expression in tumors was associated with poor survival in resected PDAC patients (p = 0.011). We then investigated the role of NO by deleting NOS2 gene in a genetically engineered mouse model of pancreatic cancer (KPC mice) with pancreas-specific activation of mutant KRAS and P53, which faithfully recapitulates the development and progression of human pancreatic cancer. NOS2-deficient KPC mice showed longer survival compared to the KPC littermates with wildtype NOS2 (p & lt;0.01). Compared to tumors from KPC mice, KPC/NOS2−/− tumors were less vascularized (p & lt;0.001) and with less macrophage recruitment (p & lt;0.005), indicated by decreased expression of CD31 and F4/80 respectively. NOS2 deficiency led to attenuated proliferation and invasion, and enhanced apoptosis indicated by high level of cleaved caspase-3 (p = 0.02). Consistent with the less malignant phenotype, NOS2 deficiency reduced nuclear pERK accumulation (P = 0.034) and the subsequent phosphorylation of FOXO3 (p = 0.026). Further investigation showed a positive correlation between NOS2 expression and pFOXO level in human PDAC specimen (p = 0.005). In addition, NOS2 deficiency reduced the expression of a well known oncogenic microRNA, miR21 (p = 0.001). In summary, NOS2 gene expression in tumors is a candidate prognostic marker in resected pancreatic cancer patients, and NOS2/NO signaling may contribute to the pancreatic tumor progression by inactivating FOXO3 in KPC mice. In this ongoing study, we are further investigating the mechanistic role of NO in disease progression. Citation Format: Jian Wang, Peijun He, Matthias M. Gaida, Shouhui Yang, Aaron Schetter, Jochen Gaedcke, Michael Ghadimi, Thomas Ried, Harris G. Yfantis, Dong H. Lee, Jonathan M. Weiss, Nadar Hanna, H. Richard Alexander, S. Perwez Hussain. Nitric oxide signaling pathway as a pathogenic driver in pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 923. doi:10.1158/1538-7445.AM2015-923
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-923
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 3
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    Endothelial Nitric Oxide Synthase Traffic Inducer (NOSTRIN) is a Negative Regulator of Disease Aggressiveness in Pancreatic Cancer
    American Association for Cancer Research (AACR) ; 2016
    In:  Clinical Cancer Research Vol. 22, No. 24 ( 2016-12-15), p. 5992-6001
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 22, No. 24 ( 2016-12-15), p. 5992-6001
    Abstract: Purpose: Pancreatic ductal adenocarcinoma (PDAC) is refractory to available treatments. Delineating critical pathways, responsible for disease aggressiveness and therapeutic resistance, may identify effective therapeutic targets. We aimed to identify key pathways contributing to disease aggressiveness by comparing gene expression profiles of tumors from early-stage PDAC cases with extremely poor survival (≤7 months) and those surviving 2 years or more following surgical resection. Experimental Design: Gene expression profiling was performed in tumors in a test cohort of PDAC (N = 50), which included short (≤7 months, N = 11) and long surviving (≥2 years, N = 14) patients, using affymetrix GeneChip Human 1.0 ST array. Key genes associated with disease aggressiveness were identified, using Cox regression, Kaplan–Meier, and pathway analyses with validations in independent cohorts for mechanistic and functional analyses. Results: Gene expression profiling identified 1,820 differentially expressed genes between short and long survival groups with inflammatory gene network ranking first. Lower expression of endothelial nitric oxide synthase traffic inducer (NOSTRIN) was associated with worst survival indicating its potential inhibitory role in disease progression. NOSTRIN overexpression suppressed migration and invasion of pancreatic cancer cells and enhanced sensitivity to chemotherapeutic drug gemcitabine. NOSTRIN inhibited production of nitric oxide (NO) by suppressing the activation of endothelial nitric oxide synthase (eNOS). Furthermore, miR-221, bound to the 3′UTR of NOSTRIN and suppressed its expression, and an increased miR-221 expression associated with poor survival in PDAC. Conclusions: Our findings showed that NOSTRIN is a potential negative regulator of disease aggressiveness, which may be targeted for designing improved treatment strategy in PDAC. Clin Cancer Res; 22(24); 5992–6001. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-16-0511
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 4
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    Abstract C61: Dysregulation of HNF1B/Clusterin axis enhances disease progression in a highly aggressive subset of pancreatic cancer
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 24_Supplement ( 2019-12-15), p. C61-C61
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 24_Supplement ( 2019-12-15), p. C61-C61
    Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy and is largely refractory to available treatments with heterogenous chemotherapeutic response in subsets of patients. Identifying key pathways associated with disease aggressiveness and therapeutic resistance may characterize candidate targets to improve patient outcome. We used a strategy of examining the molecular subset of PDAC patients with worst survival to understand the underlying mechanisms of disease progression and to identify candidate molecular targets with potential therapeutic significance. Non-negative matrix factorization (NMF) clustering using gene expression profile revealed three patient subsets. A 142-gene signature specific to the subset with the worst patient survival predicted prognosis and stratified patients in two clusters in a test (N=126) and validation (N=176) cohorts with significantly different survival. Gene-network and pathway analysis of the 142-gene signature revealed dysregulation of hepatocyte nuclear factor 1-B (HNF1B)/Clusterin (CLU) axis in the highly aggressive patient subset. HNF1B positively regulated CLU and a lower expression of HNF1B and CLU was associated with poor patient survival. Mechanistic and functional analyses revealed that CLU inhibits proliferation, migration, invasion, and 3D spheroid growth and epithelial-to-mesenchymal transition in pancreatic cancer cells. Furthermore, CLU enhanced sensitivity of pancreatic cancer cells, representing the aggressive patient subset, to the chemotherapeutic drug gemcitabine. Taken together, targeting HNF1B/CLU axis may attenuate disease progression with potential therapeutic implication in a subset of pancreatic cancer. Citation Format: Shouhui Yang, Wei Tang, Peijun He, Limin Wang, Jochen Gaedcke, B. Michael Ghadim, Philipp Ströbel, Azadeh Azizian, Matthias M. Gaida, Frank Bergmann, H. Richard Alexander, Nader Hanna, S. Perwez Hussain. Dysregulation of HNF1B/Clusterin axis enhances disease progression in a highly aggressive subset of pancreatic cancer [abstract] . In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C61.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.PANCA19-C61
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 5
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    Abstract 4789: A novel MIF signaling pathway drives the malignant character of pancreatic cancer by targeting NR3C2
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 4789-4789
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 4789-4789
    Abstract: Pancreatic cancers with aberrant expression of macrophage migration inhibitory factor (MIF) are particularly aggressive. To identify key signaling pathways that drive disease aggressiveness in tumors with high MIF expression, we analyzed the expression of coding and noncoding genes in high and low MIF-expressing tumors in multiple cohorts of pancreatic ductal adenocarcinoma (PDAC) patients. The key genes and pathways identified were linked to patient survival and were mechanistically, functionally, and clinically characterized using cell lines, a genetically engineered mouse model, and PDAC patient cohorts. Here, we report evidence of a novel MIF-driven signaling pathway that inhibits the orphan nuclear receptor NR3C2, a previously undescribed tumor suppressor that impacts aggressiveness and survival in PDAC. Mechanistically, MIF upregulated miR-301b that targeted NR3C2 and suppressed its expression. PDAC tumors expressing high levels of MIF displayed elevated levels of miR-301b and reduced levels of NR3C2. In addition, reduced levels of NR3C2 expression correlated with poorer survival in multiple independent cohorts of PDAC patients. Functional analysis showed that NR3C2 inhibited epithelial-to-mesenchymal transition and enhanced sensitivity to the gemcitabine, a chemotherapeutic drug used in PDAC standard of care. Furthermore, genetic deletion of MIF disrupted a MIF-mir-301b-NR3C2 signaling axis, reducing metastasis and prolonging survival in a genetically engineered mouse model of PDAC. Taken together, our results offer a preclinical proof of principle for candidate therapies to target a newly described MIF-miR-301b-NR3C2 signaling axis for PDAC management. Citation Format: Shouhui Yang, Peijun He, Liming Wang, Jian Wang, Aaron Schetter, Wei Tang, Naotake Funamizu, Katsuhiko Yanaga, Tadashi Uwagawa, Abhay R. Satoskar, Jochen Gaedcke, Markus Bernhardt, B. Michael Ghadimi, Matthias M Gaida, Frank Bergmann, Jens Werner, Thomas Ried, Nader Hanna, H. Richard Alexander, S. Perwez Hussain. A novel MIF signaling pathway drives the malignant character of pancreatic cancer by targeting NR3C2 [abstract] . In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4789. doi:10.1158/1538-7445.AM2017-4789
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-4789
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
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  • 6
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    Abstract 4363: Macrophage migration inhibitory factor (MIF) and miR-301b interactively enhance disease aggressiveness by targeting NR3C2 in human pancreatic cancer
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 4363-4363
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 4363-4363
    Abstract: MIF is a pleiotropic cytokine, which plays a role in inflammatory and immune responses and is implicated in tumorigenesis. Our previous study showed that MIF enhances tumor aggressiveness and predicts outcome in patients with pancreatic ductal adenocarcinoma (PDAC). Aberrant microRNA (miRNA) expression is a common feature in cancer and cytokine responsive miRNAs are recently described as critical effectors in tumor progression. We have investigated MIF-associated miRNAs and their interactive roles in the progression of human pancreatic cancer. Global analysis of miRNA expression revealed 38 differentially expressed miRNAs in MIF-high as compared with MIF-low cases of PDAC based on the median value. Kaplan-Meier survival analysis showed that a higher expression of miR-301b in tumors was associated with poorer survival (p=0.008, N=37), which was further validated in an independent cohort of PDAC patients (p=0.021, N=42). Additionally, MIF expression positively correlated with miR-301b and mediated its expression in several human pancreatic cancer cells. Mechanistic analysis revealed that miR-301b promotes pancreatic cancer cell migration and invasion. Furthermore, nuclear receptor subfamily group c member 2 (NR3C2) was identified as a functional target of miR-301b. NR3C2 inhibited tumor migration and invasion and a higher expression of NR3C2 predicted better survival in pancreatic cancer patients. Further in vivo studies showed a significant decrease in NR3C2 in MIF-overexpressing orthotopic xenograft as compared to control. Taken together, our results demonstrate that MIF and miR-301b interactively contribute to pancreatic cancer progression by targeting NR3C2. This novel MIF-miR-301b-NR3C2 axis may provide potential targets for improving disease outcome in pancreatic cancer. Citation Format: Shouhui Yang, Peijun He, Jian Wang, Aaron Schetter, Naotake Funamizu, Katsuhiko Yanaga, Jochen Gaedcke, B. Michael Ghadimi, Matthias M. Gaida, Thomas Ried, Nader Hanna, H. Richard Alexander, S. Perwez Hussain. Macrophage migration inhibitory factor (MIF) and miR-301b interactively enhance disease aggressiveness by targeting NR3C2 in human pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4363. doi:10.1158/1538-7445.AM2014-4363
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-4363
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2036785-5
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  • 7
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    Abstract B34: A Novel MIF-driven Signaling Drives Disease Aggressiveness by Targeting NR3C2 in Pancreatic Cancer
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 24_Supplement ( 2016-12-15), p. B34-B34
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 24_Supplement ( 2016-12-15), p. B34-B34
    Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Pancreatic tumors with aberrant expression of macrophage migration inhibitory factor (MIF) are highly aggressive, and an increased MIF predicts poorer patient survival. We analyzed the expression of coding and non-coding genes in high and low MIF-expressing tumors in multiple cohorts of PDAC patients to identify key signaling pathways that drive disease aggressiveness in tumors with high MIF expression. The identified key genes and pathways were linked to patients’ survival and were mechanistically, functionally and clinically characterized using cell lines, genetically engineered mouse model and PDAC patient cohorts. Here, we report mechanistic, functional and clinical evidence of a novel MIF-driven signaling pathway that inhibits a previously undescribed tumor suppressor, nuclear-receptor-subfamily-3, group-C, member-2 (NR3C2), leading to enhanced disease aggressiveness and poorer survival in PDAC. MIF upregulated miR-301b, which then targeted and suppressed NR3C2 expression. Tumors with high MIF expression showed an elevated miR-301b and a reduced NR3C2 expression. Additionally, patients with a lower NR3C2 expression in tumors showed poorer survival in multiple independent cohorts of PDAC patients. NR3C2 inhibited epithelial-to-mesenchymal transition and enhanced sensitivity to chemotherapeutic drug gemcitabine. Furthermore, genetic deletion of MIF disrupted MIF-mir-301b-NR3C2 axis, which resulted in reduced metastasis and prolonged survival in genetically engineered mouse model of PDAC. These findings provide proof-of-principle that therapies targeting MIF-miR-301b-NR3C2 axis may improve disease outcome in PDAC Citation Format: Shouhui Yang, Peijun He, Jian Wang, Aaron Schetter, Wei Tang, Naotake Funamizu, Katsuhiko Yanaga, Tadashi Uwagawa, Abhay R. Satoskar, Jochen Gaedcke, Markus Bernhardt, B. Michael Ghadimi, Matthias M. Gaida, Frank Bergmann, Jens Werner, Thomas Ried, Nader Hanna, H. Richard Alexander, S. Perwez Hussain.{Authors}. A Novel MIF-driven Signaling Drives Disease Aggressiveness by Targeting NR3C2 in Pancreatic Cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B34.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.PANCA16-B34
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 8
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    A Novel MIF Signaling Pathway Drives the Malignant Character of Pancreatic Cancer by Targeting NR3C2
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 13 ( 2016-07-01), p. 3838-3850
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 13 ( 2016-07-01), p. 3838-3850
    Abstract: Pancreatic cancers with aberrant expression of macrophage migration inhibitory factor (MIF) are particularly aggressive. To identify key signaling pathways that drive disease aggressiveness in tumors with high MIF expression, we analyzed the expression of coding and noncoding genes in high and low MIF-expressing tumors in multiple cohorts of pancreatic ductal adenocarcinoma (PDAC) patients. The key genes and pathways identified were linked to patient survival and were mechanistically, functionally, and clinically characterized using cell lines, a genetically engineered mouse model, and PDAC patient cohorts. Here, we report evidence of a novel MIF-driven signaling pathway that inhibits the orphan nuclear receptor NR3C2, a previously undescribed tumor suppressor that impacts aggressiveness and survival in PDAC. Mechanistically, MIF upregulated miR-301b that targeted NR3C2 and suppressed its expression. PDAC tumors expressing high levels of MIF displayed elevated levels of miR-301b and reduced levels of NR3C2. In addition, reduced levels of NR3C2 expression correlated with poorer survival in multiple independent cohorts of PDAC patients. Functional analysis showed that NR3C2 inhibited epithelial-to-mesenchymal transition and enhanced sensitivity to the gemcitabine, a chemotherapeutic drug used in PDAC standard of care. Furthermore, genetic deletion of MIF disrupted a MIF–mir-301b–NR3C2 signaling axis, reducing metastasis and prolonging survival in a genetically engineered mouse model of PDAC. Taken together, our results offer a preclinical proof of principle for candidate therapies to target a newly described MIF–miR-301b–NR3C2 signaling axis for PDAC management. Cancer Res; 76(13); 3838–50. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-15-2841
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 9
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    Abstract 926: Nitric oxide enhances tumor progression and disease aggressiveness in pancreatic cancer
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 926-926
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 926-926
    Abstract: Pancreatic Ductal Adenocarcinoma (PDAC) is among the most malignant cancer, with 5-year survival of a mere 6%. Chronic inflammation is associated with an increased risk of PDAC. Nitric oxide (NO•) is an important mediator of immune and inflammatory responses and plays a role in tumorigenesis. The principal source of an increased and sustained level of NO• is inducible nitric oxide synthase (NOS2). In this study, we have tested the hypothesis that NO• enhances tumor progression in pancreatic cancer. We found that a higher NOS2 expression in tumors was associated with poor survival in resected PDAC patients (p=0.011). We then used a genetic strategy to investigate the role of NO• in the development and progression of PDAC by deleting NOS2 gene in a genetically engineered mouse model of pancreatic cancer (KPC mice) with pancreas specific activation of mutant KRAS and P53, which faithfully recapitulates the development and progression of human pancreatic cancer. NOS2-deficient KPC mice showed a longer survival as compared to the KPC littermates with wild type NOS2 (p & lt;0.01). Tumors from KPC/NOS2-/- mice showed reduced tumor cell proliferation and increased apoptosis as indicated by a lower expression of Ki67 and a higher level of activated caspase-3, as compared with KPC mice. Furthermore, tumors from KPC/NOS2-/- mice were less vascularized as compared with KPC mice, as indicated by CD31 expression. Additionally, NOS2-deficiency led to a decreased inflammatory response by attenuation of macrophage recruitment in pancreatic tumors as indicated by a significantly lower expression of F4/80. However, in contrast FOXP3+ regulatory T-cells were increased in tumors from KPC/NOS2-/- mice. Further mechanistic analysis revealed a higher expression of ph-FOXO3 and nuclear ph-ERK in tumors from KPC mice as compared with KPC/NOS2-/- mice. Analysis of human PDAC samples showed a positive correlation between NOS2 and ph-FOXO3 expression (P=0.004). In summary, NOS2 gene expression in tumors is a candidate prognostic marker in resected pancreatic cancer patients, and NOS2/NO• signaling may contribute to the pancreatic tumor progression by inactivating FOXO3 in KPC mice. In this ongoing study, we are further investigating the mechanistic role of NO• in disease progression. Citation Format: Jian Wang, Peijun He, Matthias M. Gaida, Shouhui Yang, Aaron Schetter, Jochen Gaedcke, Michael Ghadimi, Thomas Ried, Harris G. Yfantis, Dong H. Lee, Jonathan M. Weiss, Jim Stauffer, Nader Hanna, H. Richard Alexander, S. Perwez Hussain. Nitric oxide enhances tumor progression and disease aggressiveness in pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 926. doi:10.1158/1538-7445.AM2014-926
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-926
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 10
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    Abstract 922: Macrophage migration inhibitory factor (MIF) and miR-301b interactively enhance disease aggressiveness by targeting NR3C2 (nuclear receptor subfamily group c member 2) in human pancreatic cancer
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 922-922
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 922-922
    Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal malignancy. Aberrant macrophage migration inhibitory factor (MIF) expression is associated with disease aggressiveness and increased MIF in PDAC predicts poor patient survival. Here we show that MIF-induced disease aggressiveness and poor survival in PDAC involves the inhibition of the nuclear receptor subfamily group c member 2 (NR3C2). Tumors with aberrant high levels of MIF (MIF-high) showed an increased expression of mir-301b and a decrease in NR3C2 expression as compared to the tumors with a lower level of MIF (MIF-low) in PDAC cases and a negative correlation existed between MIF and NR3C2 expressions in these tumors. Furthermore, patients with an increase in mir-301b or decrease in NR3C2 expression had a significantly shorter survival than other patients. MIF overexpression and knockdown confirmed that MIF up-regulates miR-301b, which then binds to the 3′UTR of NR3C2 and markedly decreases its expression. Moreover, MIF-overexpressing orthotopic tumor xenografts showed an increase in mir-301b and a decrease in NR3C2 expressions. MIF-induced regulation of mir-301b and NR3C2 functionally involved the PI3Kinase/Akt pathway. Examination of the tumor suppressor mechanism of NR3C2 revealed that it inhibits proliferation, colony formation, migration and invasion, and enhances sensitivity to chemotherapeutic drug gemcitabine in pancreatic cancer cells. Furthermore, NR3C2 knock down enhanced epithelial-to-mesenchymal transition. These data identify a novel MIF-induced signaling pathway targeting NR3C2, leading to increased disease aggressiveness and poor outcome in PDAC. We identified a MIF-driven signaling pathway that inhibits a previously undescribed tumor suppressor of PDAC, NR3C2, involving miR-301b. The inhibition of NR3C2 enhanced disease aggressiveness and predicted to poor survival, as shown by our survival analysis. Therapies that target the MIF-miR-301b-NR3C2 axis may improve disease outcome in pancreatic cancer. Citation Format: Shouhui Yang, Peijun He, Jian Wang, Aaron Schetter, Wei Tang, Naotake Funamizu, Jochen Gaedcke, Michael Ghadimi, Matthias Gaida, Thomas Ried, Nader Hannah, H. Richard Alexander, S. Perwez Hussain. Macrophage migration inhibitory factor (MIF) and miR-301b interactively enhance disease aggressiveness by targeting NR3C2 (nuclear receptor subfamily group c member 2) in human pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 922. doi:10.1158/1538-7445.AM2015-922
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-922
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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