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Impact of deregulation of the gene expression of hedgehog signaling pathway in resectable pancreatic cancer
Abstracts / Pancreatology 13 (2013) S2–S98
pattern were different. Lesser stroma was seen in the xenografts. A subset of genes with different expression in patient tumour and xenograft was identified. Those were mainly stroma and blood cell related genes. There was no significant change in expression profiles between xenograft passages. Conclusion: Xenografts maintain histological characteristics of primary tumours. They have less stromal tissue, probably due to the fact, that the stromal tissue is provided by the host (mouse). RNA expression analysis also shows the loss of human stromal tissue but shows no further changes between xenograft passages.
PII-20 Abstract id: 119. Impact of deregulation of the gene expression of hedgehog signaling pathway in resectable pancreatic cancer Beatrice Mohelnikova-Duchonova 1, Veronika Brynychova 1, Martin Oliverius 2, Jan Hlavsa 3, Eva Honsova 4, Jan Mazanec 5, Zdenek Kala 3, Pavel Soucek 1. 1 Department of Toxicogenomics, NIPH in Prague; Biomedical Centre, Faculty of Medicine in Plzen, Charles University, Czech Republic 2 Department of Transplantation Surgery, Institute of Clinical and Experimental Medicine in Prague, Czech Republic 3 Department of Surgery, Masaryk University Hospital and Faculty of Medicine in Brno, Czech Republic 4 Department of Clinical and Transplantation Pathology, Institute of Clinical and Experimental Medicine in Prague, Czech Republic 5 Department of Pathology, Masaryk University Hospital and Faculty of Medicine in Brno, Czech Republic
S59
Aims: The goal of this multicenter study was to identify microRNAs (miRNAs) as potential prognostic biomarkers in patients affected by IPMNs of the pancreas. Patients & methods: The expression of three candidate miRNAs (miR21, miR-155 and miR-101) was quantified by quantitative RT-PCR in 86 laser-microdissected (LMD) formalin-fixed paraffin embedded (FFPE) specimens, including 65 invasive IPMNs, 16 non-invasive IPMNs and 5 normal pancreatic ductal tissues. Univariate and multivariate analyses compared miRNAs and clinical parameters with overall and disease-freesurvival (OS, DFS) using log-rank test and Cox’s proportional hazards model. Results: MiR-21 and miR-155 were significantly upregulated in invasive IPMN compared to non-invasive IPMN, as well as in non-invasive IPMN compared to normal ductal tissues. Conversely, miR-101 levels were significantly higher in non-invasive IPMN and normal tissues versus invasive IPMN. Kaplan-Meier survival analysis revealed that high levels of miR-21 expression were closely associated with worse OS (hazard ratio [HR] 2.47, P¼0.0047). Patients with high miR-21 expression also had a significantly shorter median DFS (10.9 vs. 29.9 months, log-rank P¼0.01). Multivariate analysis confirmed miR-21 as independently prognostic for both mortality and disease progression (death-risk, HR¼3.3, P¼0.02; progression-risk, HR¼2.3, P¼0.02), as well as positive lymph-node status (death-risk, HR¼2.6, P¼0.03; progression-risk, HR¼2.2, P¼0.04). Conclusion: The miRNAs evaluated in the present study showed significant differences in invasive versus non-invasive IPMN, and miR-21 expression emerged as an independent prognostic biomarker in patients affected by invasive IPMN, offering innovative tools for the optimal management of these tumors.
PII-22 Abstract id: 153. Introduction: The hedgehog signaling pathway (SHH) was reported to enhance proliferation and invasiveness and to block apoptosis in pancreatic tumor cells. Aims: The aim of the present study was to investigate prognostic significance of SHH in pancreatic cancer patients who underwent a radical resection in association with clinical and pathological characteristics. Patients & methods: Tumors and adjacent non-neoplastic pancreatic tissues were obtained from 45 patients with histologically verified ductal pancreatic adenocarcinoma (PDAC). The transcript profile of 34 hedgehog signaling pathway genes was assessed using quantitative real-time polymerase chain reaction with a relative standard curve. Results: Most of investigated SHH genes were deregulated in PDAC when compared with adjacent nonmalignant pancreatic tissue and 7 genes were associated with pathological characteristics with a borderline statistical significance. KIF3A was significantly up-regulated in moderately differentiated tumors when compared to high grade tumors (P¼0.009). High expression of PRKACA was associated with a shorter OS of resectable pancreatic cancer patients (P¼0.018) and high level of DHH was associated with a shorter OS in chemotherapy-treated subgroup of the patients (P¼0.038). Conclusion: Despite the fact that expression of majority of SHH genes was strongly deregulated in PDAC it seems to have no striking effect on the prognosis of patients with the resectable stage of the disease. Supported by Czech Science Foundation grant No. P301/12/1734 and project ED/2.1.00/03.0076 from European Regional Development Fund
PII-21 Abstract id: 192. Clinical impact of MiR-101, MiR-155 and MiR-21 in pancreatic intraductal papillary mucinous neoplasms (IPMNs) Niccola Funel 1, Sara Caponi 1, Adam E. Frampton 2, Luca E. Pollina 1, Vittorio Perrone 1, Enrico Vasile 1, Godefridus J. Peters 1, Nelide De Lio 3, Long R. Jiao 2, Ugo Boggi 1, Elisa Giovannetti 3. 1
University of Pisa, Italy Imperial College University, United Kingdom 3 VUmc University of Amsterdam, Netherlands 2
Introduction: The Intraductal Papillary Mucinos Neoplasm (IPMNs) show a wide spectrum of histological presentations ranging from adenoma to adenocarcinoma.
The role of the Eps8 binding partners Sos1 and Abi1 in pancreatic cancer Philip Kiely, Jo Tod, Veronika Jenei, Colin Johnson, Gareth Jarvis Thomas. Cancer Sciences, University of Southampton School of Medicine, Southampton, United Kingdom Introduction: Pancreatic cancer (PC) is characterised by marked local invasion, which requires actin cytoskeletal remodelling. EGF receptor pathway substrate 8 (Eps8) is an actin-binding protein with multiple binding partners including Abi1, Sos1, and certain b integrin subunits. avb6 integrin is overexpressed in w70% of PC and enhances invasion. Aims: To examine the role of Abi1 and Sos1 in avb6-dependent PC invasion. Materials & methods: We used immunohistochemistry to examine expression of Eps8, Abi1 and Sos1 in normal pancreas and PC in vivo. A retrospective patient database was generated of those treated surgically for PC (2000-2008) and used to identify 38 short (< 2 year) and 19 long (> 4 years) survivors. Resection tissue was then stained for Eps8/Abi1/Sos1/avb6. We identified three PC cell lines that showed avb6-dependent motility in vitro, and performed TranswellÒ assays to study the functional roles of Abi1 and Sos1. Results: Eps8, Sos1 and Abi1 were upregulated in PC compared with normal tissue. Expression of these proteins in long and short survivors is currently being examined. Eps8, Sos1, Abi1 and avb6 expression was confirmed in all three PC cell lines tested. Knock-down of Eps8, Sos1 or Abi1 significantly suppressed avb6-dependent migration and invasion. Conclusion: Eps8, Sos1 and Abi1 are upregulated in PC and appear to be critical to avb6-dependent PC motility. Interestingly, Sos1 expression was previously shown to fall in response to gemcitabine, the current gold standard chemotherapeutic agent for the treatment of PC. Sos1 therefore requires further investigation as a potential molecular target in the treatment of PC.
PII-23 Abstract id: 139. Associations of gene expression of major drug transporters with the prognosis of pancreatic cancer Pavel Soucek 1, Veronika Brynychova 1, Martin Oliverius 2, Jan Hlavsa 3, Eva Honsova 4, Jan Mazanec 5, Zdenek Kala 3, Beatrice MohelnikovaDuchonova 1.
pattern were different. Lesser stroma was seen in the xenografts. A subset of genes with different expression in patient tumour and xenograft was identified. Those were mainly stroma and blood cell related genes. There was no significant change in expression profiles between xenograft passages. Conclusion: Xenografts maintain histological characteristics of primary tumours. They have less stromal tissue, probably due to the fact, that the stromal tissue is provided by the host (mouse). RNA expression analysis also shows the loss of human stromal tissue but shows no further changes between xenograft passages.
PII-20 Abstract id: 119. Impact of deregulation of the gene expression of hedgehog signaling pathway in resectable pancreatic cancer Beatrice Mohelnikova-Duchonova 1, Veronika Brynychova 1, Martin Oliverius 2, Jan Hlavsa 3, Eva Honsova 4, Jan Mazanec 5, Zdenek Kala 3, Pavel Soucek 1. 1 Department of Toxicogenomics, NIPH in Prague; Biomedical Centre, Faculty of Medicine in Plzen, Charles University, Czech Republic 2 Department of Transplantation Surgery, Institute of Clinical and Experimental Medicine in Prague, Czech Republic 3 Department of Surgery, Masaryk University Hospital and Faculty of Medicine in Brno, Czech Republic 4 Department of Clinical and Transplantation Pathology, Institute of Clinical and Experimental Medicine in Prague, Czech Republic 5 Department of Pathology, Masaryk University Hospital and Faculty of Medicine in Brno, Czech Republic
S59
Aims: The goal of this multicenter study was to identify microRNAs (miRNAs) as potential prognostic biomarkers in patients affected by IPMNs of the pancreas. Patients & methods: The expression of three candidate miRNAs (miR21, miR-155 and miR-101) was quantified by quantitative RT-PCR in 86 laser-microdissected (LMD) formalin-fixed paraffin embedded (FFPE) specimens, including 65 invasive IPMNs, 16 non-invasive IPMNs and 5 normal pancreatic ductal tissues. Univariate and multivariate analyses compared miRNAs and clinical parameters with overall and disease-freesurvival (OS, DFS) using log-rank test and Cox’s proportional hazards model. Results: MiR-21 and miR-155 were significantly upregulated in invasive IPMN compared to non-invasive IPMN, as well as in non-invasive IPMN compared to normal ductal tissues. Conversely, miR-101 levels were significantly higher in non-invasive IPMN and normal tissues versus invasive IPMN. Kaplan-Meier survival analysis revealed that high levels of miR-21 expression were closely associated with worse OS (hazard ratio [HR] 2.47, P¼0.0047). Patients with high miR-21 expression also had a significantly shorter median DFS (10.9 vs. 29.9 months, log-rank P¼0.01). Multivariate analysis confirmed miR-21 as independently prognostic for both mortality and disease progression (death-risk, HR¼3.3, P¼0.02; progression-risk, HR¼2.3, P¼0.02), as well as positive lymph-node status (death-risk, HR¼2.6, P¼0.03; progression-risk, HR¼2.2, P¼0.04). Conclusion: The miRNAs evaluated in the present study showed significant differences in invasive versus non-invasive IPMN, and miR-21 expression emerged as an independent prognostic biomarker in patients affected by invasive IPMN, offering innovative tools for the optimal management of these tumors.
PII-22 Abstract id: 153. Introduction: The hedgehog signaling pathway (SHH) was reported to enhance proliferation and invasiveness and to block apoptosis in pancreatic tumor cells. Aims: The aim of the present study was to investigate prognostic significance of SHH in pancreatic cancer patients who underwent a radical resection in association with clinical and pathological characteristics. Patients & methods: Tumors and adjacent non-neoplastic pancreatic tissues were obtained from 45 patients with histologically verified ductal pancreatic adenocarcinoma (PDAC). The transcript profile of 34 hedgehog signaling pathway genes was assessed using quantitative real-time polymerase chain reaction with a relative standard curve. Results: Most of investigated SHH genes were deregulated in PDAC when compared with adjacent nonmalignant pancreatic tissue and 7 genes were associated with pathological characteristics with a borderline statistical significance. KIF3A was significantly up-regulated in moderately differentiated tumors when compared to high grade tumors (P¼0.009). High expression of PRKACA was associated with a shorter OS of resectable pancreatic cancer patients (P¼0.018) and high level of DHH was associated with a shorter OS in chemotherapy-treated subgroup of the patients (P¼0.038). Conclusion: Despite the fact that expression of majority of SHH genes was strongly deregulated in PDAC it seems to have no striking effect on the prognosis of patients with the resectable stage of the disease. Supported by Czech Science Foundation grant No. P301/12/1734 and project ED/2.1.00/03.0076 from European Regional Development Fund
PII-21 Abstract id: 192. Clinical impact of MiR-101, MiR-155 and MiR-21 in pancreatic intraductal papillary mucinous neoplasms (IPMNs) Niccola Funel 1, Sara Caponi 1, Adam E. Frampton 2, Luca E. Pollina 1, Vittorio Perrone 1, Enrico Vasile 1, Godefridus J. Peters 1, Nelide De Lio 3, Long R. Jiao 2, Ugo Boggi 1, Elisa Giovannetti 3. 1
University of Pisa, Italy Imperial College University, United Kingdom 3 VUmc University of Amsterdam, Netherlands 2
Introduction: The Intraductal Papillary Mucinos Neoplasm (IPMNs) show a wide spectrum of histological presentations ranging from adenoma to adenocarcinoma.
The role of the Eps8 binding partners Sos1 and Abi1 in pancreatic cancer Philip Kiely, Jo Tod, Veronika Jenei, Colin Johnson, Gareth Jarvis Thomas. Cancer Sciences, University of Southampton School of Medicine, Southampton, United Kingdom Introduction: Pancreatic cancer (PC) is characterised by marked local invasion, which requires actin cytoskeletal remodelling. EGF receptor pathway substrate 8 (Eps8) is an actin-binding protein with multiple binding partners including Abi1, Sos1, and certain b integrin subunits. avb6 integrin is overexpressed in w70% of PC and enhances invasion. Aims: To examine the role of Abi1 and Sos1 in avb6-dependent PC invasion. Materials & methods: We used immunohistochemistry to examine expression of Eps8, Abi1 and Sos1 in normal pancreas and PC in vivo. A retrospective patient database was generated of those treated surgically for PC (2000-2008) and used to identify 38 short (< 2 year) and 19 long (> 4 years) survivors. Resection tissue was then stained for Eps8/Abi1/Sos1/avb6. We identified three PC cell lines that showed avb6-dependent motility in vitro, and performed TranswellÒ assays to study the functional roles of Abi1 and Sos1. Results: Eps8, Sos1 and Abi1 were upregulated in PC compared with normal tissue. Expression of these proteins in long and short survivors is currently being examined. Eps8, Sos1, Abi1 and avb6 expression was confirmed in all three PC cell lines tested. Knock-down of Eps8, Sos1 or Abi1 significantly suppressed avb6-dependent migration and invasion. Conclusion: Eps8, Sos1 and Abi1 are upregulated in PC and appear to be critical to avb6-dependent PC motility. Interestingly, Sos1 expression was previously shown to fall in response to gemcitabine, the current gold standard chemotherapeutic agent for the treatment of PC. Sos1 therefore requires further investigation as a potential molecular target in the treatment of PC.
PII-23 Abstract id: 139. Associations of gene expression of major drug transporters with the prognosis of pancreatic cancer Pavel Soucek 1, Veronika Brynychova 1, Martin Oliverius 2, Jan Hlavsa 3, Eva Honsova 4, Jan Mazanec 5, Zdenek Kala 3, Beatrice MohelnikovaDuchonova 1.