96. Jahrestagung der Deutschen Gesellschaft für Pathologie e. V ...

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HCV-positive formalin-fixed and paraffin-embedded biopsies, sections were prepared and HCC were macrodissected. Subsequently, miR-125b was analyzed by real-time PCR. Putative miR-125b binding sites were fused to the luciferase reporter and reporter assays were carried out with miR-125b treated hepatoma cells. Results. During development of mouse HCC, the expression of miR-125b progressively decreased. In agreement miR-125b was reduced in human hepatoma cells in comparison to normal liver. Furthermore, miR-125b decrease depending on the progression of hepatocarcinogenesis was confirmed in human samples, showing significant lower levels in HCC high grades than in dysplastic foci or cirrhosis. Overexpression of miR- 125b in Hep3B and Pop10 cells resulted in a pronounced reduction of cell growth. Screening of putative miR-125b target transcripts by various algorithm calculations identified various pathways involved in proliferation and apoptosis. Reporter assays of 3’-UTR-regions of the putative targets identified miR-125b binding sites in lin-28 mRNA. Since lin28 is known to effect synthesis of the mitogen IGF-II, the miR-125b/lin28 axis is suggested to be involved in HCC pathogenesis by IGF-II mediated regulation of cell growth. Conclusions. Expression of miR-125b is down-regulated during progression of hepatocarcinogenesis leading to up-regulation of lin-28 that in turn triggers enhanced cell growth and proliferation. DO-005 The PI3K-AKT-mTOR axis contributes to the functional inactivation of p53 through stabilization of MDM4 in human hepatocellular carcinoma R . Pellegrino1 , O . Neumann1 , P . Schirmacher1 , T . Longerich1 1University Hospital Heidelberg/Institute of Pathology, Heidelberg Aims. Mutational inactivation of p53 gene is rare in Western hepatocellular carcinoma (HCC). MDM4, one of the main p53-regulating factors, is frequently upregulated in human HCC. This overexpression can be in part explained by chromosomal gains at 1q34.1. Here we investigated the role of the PI3K-AKT axis in the stabilization of the MDM4 protein. Methods. All experiments were performed in human HCC cell lines with different p53 gene status. PI3K and mTOR were specifically inhibited using chemical compounds in vitro; specific siRNAs were transiently transfected to target AKT1 and ATK2 and to validate the results from drug treatment. Realtime RT-PCR analysis was used to check for restored p53 transcriptional activity. In addition, combined cycloheximide and siRNAs treatment was performed to study the protein stability of MDM4 under these experimental conditions. Results. Using a specific PI3K inhibitor or siRNAs targeting AKT1/2 in HCC cell lines, we observed a strong decrease of MDM4 protein levels, which resulted in the activation of p53 target genes (e.g. PUMA, BAX and p21) indicating restored p53 gene function in these lines. Cycloheximide treatment combined with siRNA-mediated AKT inhibition indicated that MDM4 is phosphorylated by AKT2 and that this phosphorylation is responsible for the stabilization of the protein via the protection from proteasomal degradation. This effect was independent from both MDM2 and p53 gene status. Furthermore, we showed that the Eukaryotic translational Elongation Factor 1 alpha 2 (EEF1A2), which we reported upregulated in human HCC, is involved in the activation of the PI3K-AKT axis. Specific siRNA inhibition of EEF1A2 resulted in decreased pAKT and MDM4 protein levels in HCC cell lines. Moreover, treatment with the mTOR inhibitors, Rapamycin and PI-103, decreased MDM4 protein levels indicating that the PI3K-AKT-mTOR axis is involved in the MDM4 regulation in vitro. Conclusions. Our data demonstrate that the EEF1A2-PI3K-AKT-mTOR axis is involved in maintaining protumorigenic MDM4 levels in human HCC cell lines, which in turn promotes functional inactivation of p53. Moreover, we showed that the AKT-mediated phosphorylation of MDM4 is the crucial mechanism to prevent its proteasomal degradation. DO-006 HSF1 is a downstream effector of Ras and AKT protooncogenes and contributes to hepatocellular carcinoma development and progression D .F . Calvisi1 , S . Mattu1 , S . Delogu1 , V . De Murtas1 , G . Gasparetti1 , G . Destefanis1 , X . Chen2 , F . Dombrowski1 , M . Evert1 1University Medicine Greifswald, Institute for Pathology, Greifswald, 2University of San Francisco, Liver Center, San Francisco, United States Aims. Recent evidence suggests an oncogenic role of heat shock transcription factor 1 (HSF1) in cancer, but its functional relevance in hepatocellular carcinoma (HCC) remains poorly delineated. Methods. We have investigated HSF1 function both via in vitro and in vivo approaches as well as in a collection of human HCC. Results. In human liver specimens, we found that HSF1 was progressively induced from non-tumorous surrounding livers to HCC, reaching the highest levels in tumors with a poorer outcome (as defined by the length of patient’s survival). In HCC cell lines, overexpression of HSF1 resulted in increased activity of MAPK and AKT/mTOR pathways and suppression of JNK cascade, leading to augmented proliferation and angiogenesis and reduced apoptosis in vitro. Conversely, suppression of HSF1 in HCC cell lines decreased MAPK and AKT/mTOR activity, and induced JNK-dependent apoptosis. Forced overexpression of either Ras or AKT protooncogenes triggered upregulation of HSF1 in HCC cell lines via the small RalA GTPase. Of note, HSF1-overexpressing cells were specifically sensitive to growth inhibition and induction of apoptosis following the treatment with either AMPK activators or hexokinase inhibitors. Finally, overexpression of a HSF1 dominant negative form by hydrodynamic gene delivery strongly reduced the oncogenic potential of activated Ras and AKT in a mouse model of aggressive liver cancer. Conclusions. Altogether, the present data indicate that activation of HSF1 plays a major role in hepatocarcinogenesis by enhancing the activity of Ras and AKT, and might represent a valuable candidate for innovative targeted therapies against human HCC. DO-007 Perturbation of hepatocytes metabolism by AKT contributes to growth in insulin-induced hepatocarcinogenesis and is reverted by the PI3K/mTOR dual inhibitor NVP-BEZ235 M . Evert1 , D .F . Calvisi1 , K . Evert1 , V . De Murtas1 , G . Gasparetti1 , S . Mattu1 , G . Destefanis1 , S . Thiel1 , A . Thiele1 , S . Ribback1 , F . Dombrowski1 1University Medicine Greifswald, Institute for Pathology, Greifswald Aims. Mounting evidence supports a role of insulin signaling deregulation and diabetes mellitus in human hepatocarcinogenesis. To study the oncogenic effect of chronically elevated secretion of insulin on hepatocytes in the presence of mild hyperglycemia, we developed a model of pancreatic islet transplantation into the liver. Methods. In this model, islets of a donor rat are transplanted into the liver of a recipient diabetic rat, with resulting local hyperinsulinism that leads to the development of preneoplastic lesions and hepatocellular carcinoma (HCC). Here, we investigated the metabolic and growth properties of the AKT pathway in this model of insulin-induced hepatocarcinogenesis. These findings were recapitulated in HCC cell lines in vitro. Results. We found that activation of insulin signaling triggers a strong induction of the AKT cascade that is paralleled by increased synthesis of fatty acids, cholesterol, and triglycerides, induction of glycolysis and decrease of fatty acid oxidation and gluconeogenesis in rat preneoplastic and neoplastic liver lesions when compared with normal liver. AKT-dependent metabolic effects of insulin on hepatocytes were recapitulated in vitro using human HCC cell lines. In these cells, suppression of lipogenesis, glycolysis, and the pentose phosphate pathway triggered a strong growth restraint despite insulin administration. Of note, metabolic abnormalities and proliferation driven by insulin were effectively reverted Der Pathologe · Supplement 1 · 2012 | 17
Abstracts using the dual PI3K/mTOR inhibitor, NVP-BEZ235, both in vitro and in vivo. Conclusions. Thus, AKT activation by unconstrained insulin signaling induces a defined module of metabolic alterations in hepatocytes contributing to aberrant cell growth. The inhibition of AKT and related metabolic changes might represent a novel preventive and therapeutic approach to effectively inhibit insulin-induced hepatocarcinogenesis. AG Gastroenteropathologie IV – Oberer GI-Trakt DO-015 STAT3 activation and Mcl-1 and MMP9 target gene expression is preferentially seen in esophageal squamous cell carcinomas, but not Barrett‘s adenocarcinomas S . Timme1 , K . Atanasov1 , C .D . Fichter 1 , A . Schoepflin1 , L . Bogatyreva2 , D . Hauschke2 , L . Tang 3 , H . Geddert4 , G . Faller 4 , D . Klimstra 3 , O . Opitz5 , M . Werner1 , S . Lassmann1 1 2 Institute of Pathology, University Medical Center, Freiburg, Institute of Medical Biometry and Medical Informatics, University Medical Center, Freiburg, 3Dept . of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States, 4Institute of Pathology, St-Vincentius-Kliniken, Karlsruhe, 5Tumorzentrum Ludwig Heilmeyer – CCCF, Freiburg Aims. Active (phosphorylated) signal transducer and activator of transcription 3 (P-STAT3) is translocated to the nucleus. By this, (P-)STAT3 suppresses apoptosis or induces cell migration via Mcl-1, Bcl-xl and Survivin or matrix metalloproteinases (e.g. MMP9) expression, respectively. This STAT3 activity can be triggered by an active EGFR. To complement our data on P-STAT3 expression in esophageal squamous cell carcinomas (ESCC) and Barrett’s adenocarcinomas (BAC), we investigated EGF-mediated STAT3 activity in ESCC and BAC cell lines as well as inactive STAT3 expression in ESCCs and BACs. Methods. Serial sections of 105 esophageal carcinomas (n=60 BAC; n=45 ESCC) were evaluated for STAT3 expression by semi-quantitative immunohistochemistry. Data of nuclear P-STAT3 expression was already available. Statistical analysis was performed using Mann-Whitney-U tests at p
Page 2 and 3: Inhalt Der Pathologe · Supplement
Page 4 and 5: Inhalt Der Pathologe · Supplement
Page 6 and 7: Editorial Liebe Kolleginnen und Kol
Page 8 and 9: Kolorektales Karzinom 2 VO-005 Tran
Page 10 and 11: Keynote Lecture VO-014 Genetic dete
Page 12 and 13: (AMACR, FASN, GOLM1, GSP-pi, ERG) t
Page 14 and 15: to assess the correct rate of R1 re
Page 16 and 17: DNA damage, and cytotoxic drugs. Au
Page 20 and 21: well as MET activation were examine
Page 22 and 23: or BRAF mutation, c-MYC and SIRT1 e
Page 24 and 25: AG Pneumopathologie III DO-032 Remo
Page 26 and 27: immature granulopoiesis showed a st
Page 28 and 29: ned, if well-defined mantle zones,
Page 30 and 31: phomas). Most prominent gains or am
Page 32 and 33: DO-062 Tumor-associated macrophages
Page 34 and 35: DO-080 DOG1: an immunohistochemical
Page 36 and 37: AG Oralpathologie DO-087 Detection
Page 38 and 39: DO-094 Do activated fibroblasts inf
Page 40 and 41: DO-101 Histopathological analysis o
Page 42 and 43: DO-108 Identification of potential
Page 44 and 45: Conclusions. In conclusion, 454 par
Page 46 and 47: subgroup of patients with B-Raf mut
Page 48 and 49: DO-002b Impact of terminologies in
Page 50 and 51: Methods. We performed MCPyV-FISH of
Page 52 and 53: FR-013 HPV-genotype distribution in
Page 54 and 55: Methods. Three different techniques
Page 56 and 57: (i.e. investment in equipment and e
Page 58 and 59: FR-032 COLD-PCR: a powerful tool in
Page 60 and 61: dissection (MBLND) technique to imp
Page 62 and 63: SO-005 Prevalence of mutations in s
Page 64 and 65: SO-011 Methylation profiling and in
Page 66 and 67: more effective than SAHA alone and
Page 68 and 69:
SO-022 Specialized pathology review
Page 70 and 71:
SO-027 Ki-67 in mitotic score group
Page 72 and 73:
nificantly associated with advanced
Page 74 and 75:
liver did not correlate with the mu
Page 76 and 77:
AG Paidopathologie II SO-046 Overex
Page 78 and 79:
Results. Histomorphology of the ova
Page 80 and 81:
p42 and p27 have not yet been inves
Page 82 and 83:
SO-068 Recent advances in understan
Page 84 and 85:
SO-075 A novel, dual role of CCN3 i
Page 86 and 87:
Pancreatic Adenocarcinoma SG-137 Se
Page 88 and 89:
sease and 30 colon cancer serum sam
Page 90 and 91:
Conclusions. Although CRC is charac
Page 92 and 93:
differentiated and TNM stage III or
Page 94 and 95:
pressed moderate levels of the prot
Page 96 and 97:
FR-P-037 MALDI imaging reveals COX7
Page 98 and 99:
in the context of therapy response
Page 100 and 101:
on primary cells of wild-type and c
Page 102 and 103:
chemotherapy was recommended and co
Page 104 and 105:
aims are twofold: 1) to verify the
Page 106 and 107:
Results. Her2/neu status in TMAs an
Page 108 and 109:
prognostic impact was found in rect
Page 110 and 111:
provided information on survival ti
Page 112 and 113:
Methods. Biopsy specimens from 430
Page 114 and 115:
the OS rate was 53% for patients wi
Page 116 and 117:
FR-P-098 Immunohistological stainin
Page 118 and 119:
FR-P-104 Histopathological evaluati
Page 120 and 121:
within the earliest morphologic det
Page 122 and 123:
Conclusions. In primary imaging a g
Page 124 and 125:
fibrotic neointma development as we
Page 126 and 127:
FR-P-129 Alpha-1-antitrypsin-PiZ-an
Page 128 and 129:
FR-P-136 The expression of central
Page 130 and 131:
cosa and in the periarterial tissue
Page 132 and 133:
FR-P-149 Combination of Castleman d
Page 134 and 135:
or without different concentrations
Page 136 and 137:
Results. In 18 cases (79%) the caus
Page 138 and 139:
FR-P-168 Autopsy findings in a 2-ye
Page 140 and 141:
FR-P-174 MPGN-like glomerulonephrit
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Poster: Gynäkopathologie und Mamma
Page 144 and 145:
SA-P-011 Genetic aberrations of pre
Page 146 and 147:
Mechanismen, die eine Progression d
Page 148 and 149:
internet server. A network of inter
Page 150 and 151:
Methods. HE-gefärbte Schnittpräpa
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Conclusions. The newly released 450
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and desmoplastic reaction are diffe
Page 156 and 157:
one patient revealed more than 9 mi
Page 158 and 159:
situation, the V600E mutation in th
Page 160 and 161:
SA-P-064 Evolution of molecular pat
Page 162 and 163:
nic markers such as myf4 and MyoD1
Page 164 and 165:
Conclusions. To our knowledge, this
Page 166 and 167:
SA-P-085 Expression of the eukaryot
Page 168 and 169:
Results. The papillary RCC type II
Page 170 and 171:
SA-P-098 Male infertility: assessme
Page 172 and 173:
SA-P-104 Process oriented scientifi
Page 174 and 175:
Conclusions. The IBDW offers a uniq
Page 176 and 177:
L Lasitschka F. DO-046 Lehmann A. F
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96. Jahrestagung der Deutschen Gesellschaft für Pathologie e. V ...

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