EGF/EGFR axis contributes to the progression of cholangiocarcinoma through the induction of an epithelial-mesenchymal transition

Clapéron, Audrey; Mergey, Martine; Ho-Bouldoires, Thanh Huong Nguyen; Vignjević, Danijela; Wendum, Dominique; Chrétien, Yves; Merabtene, Fatiha; Frazao, Alexandra; Paradis, Valérie; Housset, Chantal; Guedj, Nathalie; Fouassier, Laura

doi:10.1016/j.jhep.2014.03.033

Cited by 108 publications

(119 citation statements)

References 36 publications

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“…We recently showed that ectopic cytoplasmic localization of E-cadherin is correlated with EGFR overexpression in human iCCA and pCCA [29]. Interestingly, E-cadherin also displayed a cytoplasmic pattern in xenografted tumors, whereas the mice treatment with gefitinib restored the membranous expression of E-cadherin.…”

Section: Receptor Tyrosine Kinases (Figure 2b)mentioning

confidence: 97%

“…While E-cadherin is localized at the plasma membrane in healthy biliary epithelium, its down-regulation and/or ectopic localization, i.e. cytoplasmic internalization, have been reported in malignant cholangiocytes [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37]. Genetic mutations and epigenetic silencing through promoter hypermethylation of the E-cadherin gene (CDH1) are among the mechanisms that account for the down-regulation of E-cadherin [30,33,38].…”

Section: Disruption Of Intercellular Junctionsmentioning

confidence: 99%

“…Although, down-regulation of E-cadherin in iCCA has been correlated with poor tumor differentiation, tumor size, advanced pTNM stage, intrahepatic metastasis and lymph node metastasis [25,26,29,31,32,36], its prognostic value is still controversial. Ryu et al, did not find any impact of E-cadherin expression on overall survival (OS) or disease free survival (DFS) [24] whereas other groups demonstrated that E-cadherin loss was significantly associated with these parameters and was an independent prognostic factor [25,32,36].…”

Section: Disruption Of Intercellular Junctionsmentioning

confidence: 99%

“…Interestingly, E-cadherin also displayed a cytoplasmic pattern in xenografted tumors, whereas the mice treatment with gefitinib restored the membranous expression of E-cadherin. In vitro, EGF and HB-EGF, two EGFR ligands, induced scattering of CCA cells that resulted from the disruption of adherens junctions [29,68]. In EGFstimulated CCA cells, EMT-TFs (SLUG and ZEB1) and mesenchymal markers (N-cadherin and α-SMA) were induced, favoring cell invasiveness through cytoskeleton remodeling [29,89].…”

Section: Receptor Tyrosine Kinases (Figure 2b)mentioning

confidence: 99%

“…In vitro, EGF and HB-EGF, two EGFR ligands, induced scattering of CCA cells that resulted from the disruption of adherens junctions [29,68]. In EGFstimulated CCA cells, EMT-TFs (SLUG and ZEB1) and mesenchymal markers (N-cadherin and α-SMA) were induced, favoring cell invasiveness through cytoskeleton remodeling [29,89]. We obtained similar results after down-regulating the PDZ scaffold protein EBP50 which led to the implementation of an EMT program through EGFR activation with the subsequent 13 acquisition of invasive and migratory properties by CCA cells [86].…”

Section: Receptor Tyrosine Kinases (Figure 2b)mentioning

confidence: 99%

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Epithelial-mesenchymal transition in cholangiocarcinoma: From clinical evidence to regulatory networks

Vaquero

Guedj

Clapéron

et al. 2017

Journal of Hepatology

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Cholangiocarcinoma (CCA) is an aggressive tumor with a poor prognosis due to its late clinical presentation and the lack of effective non-surgical therapies. Unfortunately, most of the patients are not eligible for curative surgery owing to the presence of metastases at the time of diagnosis. Therefore, it is important to understand the steps leading to cell dissemination in patients with CCA. To metastasize from the primary site, cancer cells must acquire migratory and invasive properties by a cell plasticity-promoting phenomenon known as epithelial-mesenchymal transition (EMT). EMT is a reversible dynamic process by which epithelial cells gradually adopt structural and functional characteristics of mesenchymal cells, and has lately become a center of attention in the field of metastatic dissemination. In the present review, we aim to provide an extensive overview of the current clinical data and the prognostic value of different EMT markers that have been analyzed in CCA. We summarize all the regulatory networks implicated in EMT from the membrane receptors to the main EMT-inducing transcription factors (SNAIL, TWIST and ZEB). Furthermore, since a tumor is a complex structure not exclusively formed by tumor cells, we also address the prominent role of the main cell types of the desmoplastic stroma that characterizes CCA in the regulation of EMT. Finally, we discuss the therapeutic considerations and difficulties faced to develop an effective anti-EMT treatment due to the redundancies and bypasses among the pathways regulating EMT. 4Key Point Box -EMT is an early event of metastasis that endows tumor cells with invasive properties enabling them to spread toward other territories.-EMT contributes to CCA progression and chemoresistance.-The three families of transcription factors that regulate epithelial and mesenchymal marker expression during EMT (SNAIL, TWIST and ZEB) contribute to CCA progression.-Cells of CCA microenvironment, and not only cancer cells, lead to the activation of EMT.

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Section: Receptor Tyrosine Kinases (Figure 2b)mentioning

confidence: 97%

Section: Disruption Of Intercellular Junctionsmentioning

confidence: 99%

Section: Disruption Of Intercellular Junctionsmentioning

confidence: 99%

Section: Receptor Tyrosine Kinases (Figure 2b)mentioning

confidence: 99%

Section: Receptor Tyrosine Kinases (Figure 2b)mentioning

confidence: 99%

See 3 more Smart Citations

Epithelial-mesenchymal transition in cholangiocarcinoma: From clinical evidence to regulatory networks

Vaquero

Guedj

Clapéron

et al. 2017

Journal of Hepatology

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125

122

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OTUD6B promotes cholangiocarcinoma growth by regulating STAT3 phosphorylation through deubiquitination of PTK2

Xing,

Chen,

Guo

et al. 2024

Cell Biology International

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Cholangiocarcinoma (CCA) is a hepatobiliary carcinoma with uncontrolled cell proliferation, poor prognosis, and high mortality. The ovarian tumor structural domain (OTU) containing protein 6B (OTUD6B) belongs to the OTU deubiquitin family and is vital in tumor development. However, its expression and biological function in CCA remain unknown. The expression of OTUD6B in CCA was analyzed using TIMER2.0, UALCAN, and GEO databases. MTT, clonal formation assay, immunofluorescence staining, immunohistochemistry staining, and flow cytometry examined the regulation of OTUD6B on cell proliferation, cycle, and apoptosis. The effects of OTUD6B on tumor volume and weight were assessed using the xenograft tumor model. The activities of PTK2 and STAT3 were detected by western blot and CO‐IP. The biological database identified that OTUD6B was upregulated in CCA. In CCA cells, OTUD6B knockdown reduced CCA cell proliferation and promoted apoptosis. Cell cycle analysis indicated that the cycle stopped at the G0/G1 phase after OTU6B downregulation. Furthermore, OTUD6B knockdown resulted in a decrease in tumor volume and weight in xenograft tumor models. Mechanistically, OTUD6B is involved in the deubiquitination of PTK2. PTK2 further affected the phosphorylation of STAT3 thereby regulating the CCA process. Our study demonstrates that OTUD6B knockdown participates in the ubiquitination of PTK2 and phosphorylation of STAT3 to alleviate the process of CCA. These results suggest that OTUD6B may be a potential new strategy for CCA treatment.

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Serum extracellular vesicles contain protein biomarkers for primary sclerosing cholangitis and cholangiocarcinoma

et al. 2017

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EGF/EGFR axis contributes to the progression of cholangiocarcinoma through the induction of an epithelial-mesenchymal transition

Cited by 108 publications

References 36 publications

Epithelial-mesenchymal transition in cholangiocarcinoma: From clinical evidence to regulatory networks

Epithelial-mesenchymal transition in cholangiocarcinoma: From clinical evidence to regulatory networks

OTUD6B promotes cholangiocarcinoma growth by regulating STAT3 phosphorylation through deubiquitination of PTK2

Serum extracellular vesicles contain protein biomarkers for primary sclerosing cholangitis and cholangiocarcinoma

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