Comparative protein expression profiles of hilar and peripheral hepatic cholangiocarcinomas

Guedj, Nathalie; Zhan, Qian; Périgny, Martine; Rautou, Pierre‐Emmanuel; Degos, Françoise; Belghiti, Jacques; Farges, Olivier; Bédossa, Pierre; Paradis, Valérie

doi:10.1016/j.jhep.2009.03.017

Cited by 82 publications

(68 citation statements)

References 30 publications

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“…Our results give a rationale to previous observations in lung cancer and peripheral cholangiocarcinoma whereby FLNA expression correlates with VEGF-A expression (29,30).…”

Section: Discussionsupporting

confidence: 85%

Hypoxia-induced and calpain-dependent cleavage of filamin A regulates the hypoxic response

Zheng¹,

Zhou

Rouhi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The cellular response to hypoxia is regulated by hypoxia-inducible factor-1α and -2α (HIF-1α and -2α). We have discovered that filamin A (FLNA), a large cytoskeletal actin-binding protein, physically interacts with HIF-1α and promotes tumor growth and angiogenesis. Hypoxia induces a calpain-dependent cleavage of FLNA to generate a naturally occurring C-terminal fragment that accumulates in the cell nucleus. This fragment interacts with the N-terminal portion of HIF-1α spanning amino acid residues 1-390 but not with HIF-2α. In hypoxia this fragment facilitates the nuclear localization of HIF-1α, is recruited to HIF-1α target gene promoters, and enhances HIF-1α function, resulting in up-regulation of HIF-1α target gene expression in a hypoxia-dependent fashion. These results unravel an important mechanism that selectively regulates the nuclear accumulation and function of HIF-1α and potentiates angiogenesis and tumor progression.cancer | subcellular localization | signal transduction

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“…Our results give a rationale to previous observations in lung cancer and peripheral cholangiocarcinoma whereby FLNA expression correlates with VEGF-A expression (29,30).…”

Section: Discussionsupporting

confidence: 85%

Hypoxia-induced and calpain-dependent cleavage of filamin A regulates the hypoxic response

Zheng¹,

Zhou

Rouhi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…interesting observation is that peripheral-type ICCs show MUC5AC expression less commonly than hilar cholangiocarcinomas. In the study by Guedj et al [29], 32 (62%) of 52 hilar cholangiocarcinomas showed positive MUC5AC immunostaining in contrast to 13 (22%) of 59 peripheral ICCs. Similarly, Aishima et al [28] reported positive MUC5AC staining in 69% to 72% of hilar tumors but in only 25% to 27% of peripheral ICCs (2 different anti-MUC5AC antibodies were used in this study).…”

Section: Discussionmentioning

confidence: 89%

“…Overexpression of MUC5AC in PDA has been reported in 70% to 100% of the cases in several studies [13,14,25]. Similarly, a high frequency of MUC5AC expression has been reported in cholangiocarcinoma [11,13,14,[26][27][28][29] and gallbladder adenocarcinoma [11,15]. In the studies where ICC and extrahepatic cholangiocarcinoma (ECC) were separately evaluated, it was apparent that ECCs more frequently expressed MUC5AC than ICCs.…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical distinction between intrahepatic cholangiocarcinoma and pancreatic ductal adenocarcinoma

et al. 2014

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Summary Distinction between primary intrahepatic cholangiocarcinoma (ICC) and metastatic pancreatic ductal adenocarcinoma (PDA) on a liver biopsy is essentially impossible histologically but has important clinical implications. In this study, 41 ICCs and 60 PDAs were immunohistochemically evaluated for the expression of S100P, pVHL, IMP3, maspin, MUC5AC, and CK17 proteins. The results showed pVHL expression in 29 (71%) ICCs but in only 3 (5%) PDAs. S100P, MUC5AC, and CK17 were frequently expressed in PDAs, seen in 57 (95%), 40 (67%), and 36 (60%) cases, respectively. In contrast, only 11 (27%), 5 (12%), and 5 (12%) ICC cases expressed these proteins. IMP3 was expressed in 37 (90%) ICC and 54 (90%) PDA cases with equal frequency. All 60 (100%) PDA and 30 (73%) ICC cases showed positive maspin immunoreactivity. A S100P−/pVHL+/MUC5A C−/CK17− staining pattern was essentially indicative of ICC, whereas the S100P+/pVHL−/MUC5AC+/ CK17+ and S100P+/pVHL−/MUC5AC−/CK17+ staining patterns were suggestive of PDA. These observations demonstrate that S100P, pVHL, MUC5AC, and CK17 are a useful immunohistochemical panel that may help distinguish primary ICC from metastatic PDA.

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“…We retrospectively retrieved, from the files of surgical and pathology departments, the cases of 106 patients who underwent liver resection for intrahepatic cholangiocarcinoma, between 1995 and 2006 at Beaujon Hospital, Clichy, France. The clinicopathological characteristics of these patients have been reported previously (Guedj et al, 2009). In all, 54 patients were men and 52 were women, with a mean age of 59.5 ± 11 years.…”

Section: Immunohistochemical Analysis Of Human Cholangiocarcinomasmentioning

confidence: 96%

“…We found no significant association between EBP50 status and the other clinicopathological features. One possible explanation is that the human cholangiocarcinoma specimens included in our study were from patients who underwent surgical resection and, therefore, had better clinical outcome than is often the case (Guedj et al, 2009). …”

Section: Loss Of Ebp50-egfr Interplay In Biliary Carcinomamentioning

confidence: 98%

Loss of EBP50 stimulates EGFR activity to induce EMT phenotypic features in biliary cancer cells

et al. 2011

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Scaffold proteins form multiprotein complexes that are central to the regulation of intracellular signaling. The scaffold protein ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) is highly expressed at the plasma membrane of normal biliary epithelial cells and binds epidermal growth factor receptor (EGFR), a tyrosine kinase receptor with oncogenic properties. This study investigated EBP50-EGFR interplay in biliary cancer. We report that in a collection of 106 cholangiocarcinomas, EBP50 was delocalized to the cytoplasm of tumor cells in 66% of the cases. Ectopic expression of EBP50 was correlated with the presence of satellite nodules and with the expression of EGFR, which was at the plasma membrane, implying a loss of interaction with EBP50 in these cases. In vitro, loss of interaction between EBP50 and EGFR was mimicked by EBP50 depletion using a small interfering RNA approach in human biliary carcinoma cells co-expressing the two proteins at their plasma membrane, and in which interaction between EBP50 and EGFR was validated. EBP50 depletion caused an increase in EGFR expression at their surface, and a sustained activation of the receptor and of its downstream effectors (extracellular signal-regulated kinase 1/2, signal transducer and activator of transcription 3) in both basal and EGF-stimulated conditions. Cells lacking EBP50 showed epithelial-to-mesenchymal transition-associated features, including reduction in E-cadherin and cytokeratin-19 expression, induction of S100A4 and of the E-cadherin transcriptional repressor, Slug, and loss of cell polarity. Accordingly, depletion of EBP50 induced the disruption of adherens junctional complexes, the development of lamellipodia structures and the subsequent acquisition of motility properties. All these phenotypic changes were prevented upon inhibition of EGFR tyrosine kinase by gefitinib. These findings indicate that loss of EBP50 at the plasma membrane in tumor cells may contribute to biliary carcinogenesis through EGFR activation.

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Comparative protein expression profiles of hilar and peripheral hepatic cholangiocarcinomas

Cited by 82 publications

References 30 publications

Hypoxia-induced and calpain-dependent cleavage of filamin A regulates the hypoxic response

Hypoxia-induced and calpain-dependent cleavage of filamin A regulates the hypoxic response

Immunohistochemical distinction between intrahepatic cholangiocarcinoma and pancreatic ductal adenocarcinoma

Loss of EBP50 stimulates EGFR activity to induce EMT phenotypic features in biliary cancer cells

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