bcl-2 Expression in Cholangiocellular Carcinoma Is Inversely Correlated with Biologically Aggressive Phenotypes

Ito, Yasuhiro; Takeda, Tsutomu; Sasaki, Yo; Sakon, Masato; Monden, Morito; Yamada, Terumasa; Ishiguro, Shingo; Imaoka, Shingi; Tsujimoto, Masahiko; Matsuura, Nariaki

doi:10.1159/000012139

Cited by 30 publications

(14 citation statements)

References 27 publications

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“…Previous studies have examined the potential role of known genes involved in human carcinogenesis to elucidate the molecular pathways involved in cholangiocellular carcinoma, for example, members of the type Ⅰ family of growth factor receptors (EGF-R, c-erbB-2) [14][15][16] , (proto-) oncogenes (c-met, c-Ki-ras, Cyclin D) [17][18][19] , dysregulated tumor-suppressor genes (p53, pRB, p16INK4a, p21WAF1) [20,21] , and apoptosis-related genes (bcl2, FAS-L, BAX) [22,23] . Other studies have shown microsatellite instability and loss of heterogeneity (LOH) as contributing factors in the development of CCC [24,25] .…”

Section: Discussionmentioning

confidence: 99%

Identification of osteopontin as the most consistently over-expressed gene in intrahepatic cholangiocarcinoma: Detection by oligonucleotide microarray and real-time PCR analysis

Hass¹,

Nehls²,

Jobst³

et al. 2008

WJG

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AIM:To investigate the molecular pathways involved in human cholangiocarcinogenesis by gene expression profiling. METHODS:Oligonucleotide arrays (Affymetrix U133A) were used to establish a specific gene expression profile of intrahepatic CCC in comparison to corresponding nonmalignant liver tissue. To validate the expression values of the most overexpressed genes, RT-PCR experiments were performed. RESULTS:Five hundred and fifty-two statistically differentially expressed genes/ESTs (221 probes significantly up-regulated, 331 probes down-regulated; P < 0.05; fold change > 2; ≥ 70%) were identified.Using these data and two-dimensional cluster analysis, a specific gene expression profile was obtained allowing fast and reproducible differentiation of CCC, which was confirmed by supervised neuronal network modelling. The most consistently overexpressed gene (median fold change 33.5, significantly overexpressed in 100%) encoded osteopontin. Furthermore, an association of various genes with the histopathological grading could be demonstrated. CONCLUSION:A highly specific gene expression profile for intrahepatic CCC was identified, allowing for its fast and reproducible discrimination against nonmalignant liver tissue and other liver masses. The most overexpressed gene in intrahepatic CCC was the gene encoding osteopontin. These data may lead to a better understanding of human cholangiocarcinogenesis.

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Section: Discussionmentioning

confidence: 99%

Identification of osteopontin as the most consistently over-expressed gene in intrahepatic cholangiocarcinoma: Detection by oligonucleotide microarray and real-time PCR analysis

Hass¹,

Nehls²,

Jobst³

et al. 2008

WJG

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“…56 Other alterations that seem to occur early in cholangiocarcinogenesis include overexpression of the receptor tyrosine kinases (RTKs) ErbB-2 and Met 2,27,57-59 and the upregulation of COX-2. 2,26,27 Moreover, strong expression of ErbB-2, 2,27,57 Met, 27,58,59 COX-2, 2,27 Bcl-2, 60 and Fas ligand 61 have been detected more frequently in well-differentiated cholangiocarcinomas compared with moderate to poorly differentiated tumors, whereas downregulation of ␤-catenin and E-cadherin, 62,63 overexpression of aspartyl (asparaginyl) ␤-hydroxylase, 64 and decreased expression of such factors as Fas receptor 61 and p57 kip2 65 correlated with higher histological grades of tumor. No correlation was found between p27 kip1 expression and tumor grade, but low p27 kip1 expression was shown to be an independent predictor of survival for patients with either peripheral or hilar cholangiocarcinoma.…”

Section: Sirica Hepatology January 2005mentioning

confidence: 99%

Cholangiocarcinoma: Molecular targeting strategies for chemoprevention and therapy

2004

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Cholangiocarcinomas are devastating cancers that are increasing in both their worldwide incidence and mortality rates. The challenges posed by these often lethal biliary tract cancers are daunting, with conventional treatment options being limited and the only hope for long-term survival being that of complete surgical resection of the tumor. Unfortunately, the vast majority of patients with cholangiocarcinoma typically seek treatment with advanced disease, and often these patients are deemed poor candidates for curative surgery. Moreover, conventional chemotherapy and radiation therapy have not been shown to be effective in prolonging long-term survival, and although photodynamic therapy combined with stenting has been reported to be effective as a palliative treatment, it is not curative. Thus, there is a real need to develop novel chemopreventive and adjuvant therapeutic strategies for cholangiocarcinoma based on exploiting select molecular targets that would impact in a significant way on clinical outcome. This review focuses on potential preventive targets in cholangiocarcinogenesis, such as inducible nitric oxide synthase, cyclooxygenase-2, and altered bile acid signaling pathways. In addition, molecular alterations related to dysregulation of cholangiocarcinoma cell growth and survival, aberrant gene expression, invasion and metastasis, and tumor microenvironment are described in the context of various clinical and pathological presentations. Moreover, an emphasis is placed on the importance of critical signaling pathways and postulated interactions, including those of ErbB-2, hepatocyte growth factor/Met, interleukin-6/glycoprotein130, cyclooxygenase-2, vascular endothelial growth factor, transforming growth factor-␤, MUC1 and MUC4, ␤-catenin, telomerase, and Fas pathways as potential molecular therapeutic targets in cholangiocarcinoma. (HEPATOLOGY 2005;41:5-15.)

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“…Furthermore, these expression patterns may explain the controversial Bcl-2 data generated by previous studies. Most studies investigating Bcl-2 expression in ChCs have reported varying degrees of Bcl-2 protein expression [8, 16, 18, 23, 24]. A study by Charlotte et al [8] showed that the Bcl-2 protein is expressed by small bile duct epithelia in normal livers but not by hepatocytes or cells of the large duct.…”

Section: Discussionmentioning

confidence: 99%

Altered Expression of Cellular Bcl-2 in the Progression of Hamster Cholangiocarcinogenesis

Jeon

Yoon

2012

The Scientific World Journal

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Bcl-2 is an intracytoplasmic and membrane-associated apoptosis suppressor, and its overexpression is closely associated with survival of malignant tumors, in particular their aggressive behavior and poor prognosis. The role of Bcl-2 is, however, still controversial in cholangiocarcinogenesis because of the discrepancies in the expression of the protein. In the present study, alteration in the expression of Bcl-2 in cholangiocarcinogenesis was investigated by studying the immunoreactivities of this protein in normal, hyperplastic bile ducts with or without dysplastic changes, and neoplastic bile duct cells from a hamster cholangiocarcinoma (ChC) model. Cytoplasmic staining, which reflects high-Bcl-2 immunoreactivity, was negative to very weak in normal and hyperplastic bile ducts without dysplastic changes, while hyperplastic bile ducts with dysplasia indicated heterogeneously strong expression. On the other hand, most of the neoplastic cells of invasive cholangiocarcinomas were negative to weak as much as the level of normal bile ducts. The results suggest that the antiapoptotic factor Bcl-2 plays a limited role in the survival of highly proliferative, potentially dysplastic bile duct cells. However, the role of Bcl-2 in biliary cancer cells was not significant.

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bcl-2 Expression in Cholangiocellular Carcinoma Is Inversely Correlated with Biologically Aggressive Phenotypes

Cited by 30 publications

References 27 publications

Identification of osteopontin as the most consistently over-expressed gene in intrahepatic cholangiocarcinoma: Detection by oligonucleotide microarray and real-time PCR analysis

Identification of osteopontin as the most consistently over-expressed gene in intrahepatic cholangiocarcinoma: Detection by oligonucleotide microarray and real-time PCR analysis

Cholangiocarcinoma: Molecular targeting strategies for chemoprevention and therapy

Altered Expression of Cellular Bcl-2 in the Progression of Hamster Cholangiocarcinogenesis

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