Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 3 de 3
Filter
1.
BMC Cancer ; 19(1): 1191, 2019 Dec 05.
Article in English | MEDLINE | ID: mdl-31805897

ABSTRACT

BACKGROUND: Cholangiocarcinoma is a rapidly fatal cancer entity with a median survival of less than one year. In contrast to many other malignancies, no substantial therapeutic breakthrough has been made in the past few decades, thereby limiting the treatment to cytotoxic chemotherapy with little beneficial effect for most patients. Targeted therapy tailored to the individual has shown substantial success in the recent past as a promising avenue for cancer therapy. METHODS: In this study, we determined the frequency of amplification of the HER2 gene in a comprehensive and well-characterized European cholangiocarcinoma cohort encompassing 436 patients including intrahepatic (n = 155), proximal (n = 155) and distal (n = 126) cholangiocarcinoma by strict application of a combined immunohistochemical and in situ hybridization algorithm following the current guidelines for HER2 assessment in gastric cancer. RESULTS: We identified a proportion of 1.4% (n = 6) patients that demonstrated HER2 gene amplification, with the highest rate among the distal cholangiocarcinoma patients (2.4%). None of the patients with equivocal (2+) immunohistochemical staining results exhibited gene amplification molecularly. In four of the five patients with HER2 positivity, gene amplification was already present in concomitantly tested high-grade biliary intraepithelial neoplasia (80%). HER2 gene amplification was not significantly associated with other clinical parameters, including survival. CONCLUSIONS: This study identifies HER2 gene amplification as a rare event in cholangiocarcinoma of the Western population, occurring already in high-grade BilIN in a subset of patients. Furthermore, we provide a robust testing algorithm that may be used prior to therapy administration in future clinical trials evaluating the role of HER2 as a predictive marker in cholangiocarcinoma.


Subject(s)
Bile Duct Neoplasms/genetics , Cholangiocarcinoma/genetics , Gene Amplification , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , Adult , Aged , Aged, 80 and over , Bile Duct Neoplasms/metabolism , Bile Duct Neoplasms/mortality , Cholangiocarcinoma/metabolism , Cholangiocarcinoma/mortality , Cohort Studies , Europe , Female , Humans , In Situ Hybridization, Fluorescence , Male , Middle Aged , Precision Medicine , Survival Analysis
2.
Gastroenterology ; 152(8): 2037-2051.e22, 2017 06.
Article in English | MEDLINE | ID: mdl-28249813

ABSTRACT

BACKGROUND & AIMS: Many different types of cancer cells have chromosome instability. The hippo pathway leads to phosphorylation of the transcriptional activator yes-associated protein 1 (YAP1, YAP), which regulates proliferation and has been associated with the development of liver cancer. We investigated the effects of hippo signaling via YAP on chromosome stability and hepatocarcinogenesis in humans and mice. METHODS: We analyzed transcriptome data from 242 patients with hepatocellular carcinoma (HCC) to search for gene signatures associated with chromosomal instability (CIN); we investigated associations with overall survival time and cancer recurrence using Kaplan-Meier curves. We analyzed changes in expression of these signature genes, at mRNA and protein levels, after small interfering RNA-mediated silencing of YAP in Sk-Hep1, SNU182, HepG2, or pancreatic cancer cells, as well as incubation with thiostrepton (an inhibitor of forkhead box M1 [FOXM1]) or verteporfin (inhibitor of the interaction between YAP and TEA domain transcription factor 4 [TEAD4]). We performed co-immunoprecipitation and chromatin immunoprecipitation experiments. We collected liver tissues from mice that express a constitutively active form of YAP (YAPS127A) and analyzed gene expression signatures and histomorphologic parameters associated with chromosomal instability. Mice were given injections of thiostrepton and livers were collected and analyzed by immunoblotting, immunohistochemistry, histology, and real-time polymerase chain reaction. We performed immunohistochemical analyses on tissue microarrays of 105 HCCs and 7 nontumor liver tissues. RESULTS: Gene expression patterns associated with chromosome instability, called CIN25 and CIN70, were detected in HCCs from patients with shorter survival time or early cancer recurrence. TEAD4 and YAP were required for CIN25 and CIN70 signature expression via induction and binding of FOXM1. Disrupting the interaction between YAP and TEAD4 with verteporfin, or inhibiting FOXM1 with thiostrepton, reduced the chromosome instability gene expression patterns. Hyperplastic livers and tumors from YAPS127A mice had increased CIN25 and CIN70 gene expression patterns, aneuploidy, and defects in mitosis. Injection of YAPS127A mice with thiostrepton reduced liver overgrowth and signs of chromosomal instability. In human HCC tissues, high levels of nuclear YAP correlated with increased chromosome instability gene expression patterns and aneuploidy. CONCLUSIONS: By analyzing cell lines, genetically modified mice, and HCC tissues, we found that YAP cooperates with FOXM1 to contribute to chromosome instability. Agents that disrupt this pathway might be developed as treatments for liver cancer. Transcriptome data are available in the Gene Expression Omnibus public database (accession numbers: GSE32597 and GSE73396).


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Carcinoma, Hepatocellular/genetics , Chromosomal Instability , Forkhead Box Protein M1/genetics , Liver Neoplasms/genetics , Phosphoproteins/genetics , Adaptor Proteins, Signal Transducing/antagonists & inhibitors , Adaptor Proteins, Signal Transducing/metabolism , Animals , Antineoplastic Agents/pharmacology , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , DNA-Binding Proteins/metabolism , Disease Models, Animal , Forkhead Box Protein M1/antagonists & inhibitors , Forkhead Box Protein M1/metabolism , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Genetic Predisposition to Disease , Hep G2 Cells , Humans , Kaplan-Meier Estimate , Liver Neoplasms/drug therapy , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Mice, Inbred C57BL , Mice, Transgenic , Muscle Proteins/metabolism , Phenotype , Phosphoproteins/antagonists & inhibitors , Phosphoproteins/metabolism , Porphyrins/pharmacology , Prognosis , RNA Interference , Signal Transduction , TEA Domain Transcription Factors , Thiostrepton/pharmacology , Time Factors , Tissue Array Analysis , Transcription Factors/metabolism , Transcriptome , Transfection , Verteporfin , YAP-Signaling Proteins
3.
Hepatology ; 62(3): 816-28, 2015 Sep.
Article in English | MEDLINE | ID: mdl-25951810

ABSTRACT

UNLABELLED: Apoptosis is critical for maintaining tissue homeostasis, and apoptosis evasion is considered as a hallmark of cancer. However, increasing evidence also suggests that proapoptotic molecules can contribute to the development of cancer, including liver cancer. The aim of this study was to further clarify the role of the proapoptotic B-cell lymphoma 2 homology domain 3 (BH3)-only protein BH3 interacting-domain death agonist (BID) for chronic liver injury (CLI) and hepatocarcinogenesis (HCG). Loss of BID significantly delayed tumor development in two mouse models of Fah-mediated and HBsTg-driven HCG, suggesting a tumor-promoting effect of BID. Liver injury as well as basal and mitogen-stimulated hepatocyte proliferation were not modulated by BID. Moreover, there was no in vivo or in vitro evidence that BID was involved in DNA damage response in hepatocytes and hepatoma cells. Our data revealed that CLI was associated with strong activation of oxidative stress (OS) response and that BID impaired full activation of p38 after OS. CONCLUSION: We provide evidence that the tumor-promoting function of BID in CLI is not related to enhanced proliferation or an impaired DNA damage response. In contrast, BID suppresses p38 activity and facilitates malignant transformation of hepatocytes.


Subject(s)
BH3 Interacting Domain Death Agonist Protein/genetics , Carcinogenesis/genetics , Cell Transformation, Neoplastic/genetics , Hepatocytes/metabolism , MAP Kinase Signaling System/genetics , Analysis of Variance , Animals , Apoptosis/genetics , Cell Line, Tumor , Cell Proliferation/genetics , Cell Survival/genetics , Disease Models, Animal , Gene Expression Regulation , Hepatic Insufficiency/pathology , Hepatic Insufficiency/physiopathology , Hepatocytes/cytology , Liver Neoplasms, Experimental/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Random Allocation , Reference Values
SELECTION OF CITATIONS
SEARCH DETAIL
...