ANXA8 Down-regulation by EGF-FOXO4 Signaling Is Involved in Cell Scattering and Tumor Metastasis of Cholangiocarcinoma

Lee, Mi–Jin; Yu, Gyung–Ran; Yoo, Hee-Jung; Kim, Jong Hyun; Yoon, Byung–Il; Choi, Yang‐Kyu; Kim, Dae‐Ghon

doi:10.1053/j.gastro.2009.04.015

Cited by 60 publications

(65 citation statements)

References 43 publications

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“…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%

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

Vaquero

Guedj

Clapéron

et al. 2017

Journal of Hepatology

125

122

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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: 99%

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

Vaquero

Guedj

Clapéron

et al. 2017

Journal of Hepatology

125

122

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“…Recently, it has been shown that cholangiocarcinoma acquired EMT/sarcomatoid phenotypes by epidermal growth factor (EGF)-EGF receptor signaling pathway, thereby promoting tumor progression and metastasis. 19 To date, however, the occurrence of EMT mediated by TGF-␤1/Snail activation has not been studied in cholangiocarcinoma. Our previous in vitro studies demonstrated that nonneoplastic cholangiocytes underwent EMT-like phenotypic changes following TGF-␤1 stimulation, 20,21 indicating that TGF-␤1 may also be able to induce EMT in cholangiocarcinoma.…”

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confidence: 99%

Epithelial-Mesenchymal Transition Induced by Transforming Growth Factor-β1/Snail Activation Aggravates Invasive Growth of Cholangiocarcinoma

Sato

Harada

Itatsu

et al. 2010

The American Journal of Pathology

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Epithelial-mesenchymal transition is an important mechanism behind initiation of cancer invasion and metastasis. This study was performed to clarify the involvement of epithelial-mesenchymal transition in the progression of cholangiocarcinoma. Cholangiocarcinoma cell lines, CCKS-1 and TFK-1, were treated with transforming growth factor-␤1 (TGF-␤1), and the phenotypic changes and invasive activity were examined. Immunohistochemical analysis was performed using tissue sections of cholangiocarcinoma. In vitro, TGF-␤1 induced mesenchymal features in CCKS-1 and TFK-1 characterized by the reduction of E-cadherin and cytokeratin 19 expression and the induction of mesenchymal markers , such as vimentin and S100A4. TGF-␤1 also induced the nuclear expression of Snail , and the invasive activity was significantly increased in both cell lines. Studies using a mouse xenograft model showed that TGF-␤1 worsened the peritoneal dissemination of CCKS-1. All these changes by TGF-␤1 were inhibited by the simultaneous administration of soluble TGF-␤ type II receptor. In vivo, six (16%) of 37 cholangiocarcinoma cases showed marked immunoreactivity of Snail in their nuclei. In these six cases, the immuno-expression of cytokeratin 19 was significantly reduced , and the expression of vimentin was significantly increased. The Snail expression significantly correlated with the lymph node metastasis and a poor survival rate of the patients. These results suggest that epithelial-mesenchymal transition induced by TGF-␤1/Snail activation is closely associated with the aggressive growth of cholangiocarcinoma, resulting in a poor

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“…In our study, E-cadherin and Vimentin both correlated with survival in NSCLC in our multivariate analysis. Recently, Lee et al suggested FoxO4 might play an important role in inhibiting the process of EMT in cholangiocarcinoma (Lee et al, 2009). But there is no report to state the relationship between FoxO4 and EMT in NSCLC.…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that EGF and resultant EGFR activation could promote EMT in HCC cell lines by altered the expression and morphology of EMT-associated markers (E-cadherin/β-catenin complex) (Fan et al, 2014). Recently, Lee et al suggested that in cholangiocarcinoma cells, EGF-mediated phosphorylated FoxO4 could negatively regulate the transcription of ANXA8, leading to the morphologic changes similar to epithelial-mesenchymal transition (EMT) (Lee et al, 2009). Based on current knowledge, growth factor or insulin inhibits the transcription activity of FoxO4 by phosphorylated via phosphatidylinositol-3-kinase (PI3K)/ AKT signaling (Kops et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Low Expression of the FoxO4 Gene may Contribute to the Phenomenon of EMT in Non-small Cell Lung Cancer

Mao²,

Liu³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Because of its importance in tumor invasion and metastasis, the epithelial-mesenchymal transition (EMT) has become a research focus in the field of cancer. Recently, evidence has been presented that FoxO4 might be involved in EMT. Our study aimed to detect the expression of FoxO4, E-cadherin and vimentin in non-small cell lung cancers (NSCLCs). We also investigated clinical features and their correlations with the markers. In our study, FoxO4, E-cadherin and vimentin were assessed by immunohistochemistry in a tissue microarray (TMA) containing 150 cases of NSCLC. In addition, the expression level of FoxO4 protein was determined by Western blotting. The percentages of FoxO4, E-cadherin and vimentin positive expression in NSCLCs were 42.7%, 38.7% and 55.3%, respectively. Immunoreactivity of FoxO4 was low in NSCLC when compared with paired normal lung tissues. There were significant correlations between FoxO4 and TNM stage (P<0.001), histological differentiation (P=0.004) and lymph node metastasis (P<0.001), but no significant links with age (P=0.323), gender (P=0.410), tumor size (P=0.084), smoking status (P=0.721) and histological type (P=0.281). Our study showed that low expression of FoxO4 correlated with decreased expression of E-cadherin and elevated expression of vimentin. Cox regression analysis indicated FoxO4 to be an independent prognostic factor in NSCLC (P=0.046). These data suggested that FoxO4 might inhibit the process of EMT in NSCLC, and might therefore be a target for therapy. Particularly, the activation of EMT pathway often precedes cancer metastasis for tumors of the epithelial origin (Wells et al., 2008). Epithelial cells lead to loosen and even loss of cell-cell adhesion throughout EMT. Besides, at the molecular level, EMT is characterized by loss or downregulation of E-cadherin and cytokeratins, with the exception of mesenchymal proteins like Vimentin, fibronectin and N-cadherin, whose expression are often upregulated (Wells et al., 2008;Ivaska 2011; SatelliLi 2011;Vaid et al., 2011). It has been shown that EGF and resultant EGFR activation could promote EMT in HCC cell lines by altered the expression and morphology of EMT-associated markers (E-cadherin/β-catenin complex) (Fan et al., 2014 (Silhan et al., 2009). DBD is characterized by three α helices, three stranded β sheet and two wing-like loops, and is thought to play important roles interacting with other proteins (Boura et al., 2007). The interaction with 14-3-3 proteins affected FoxO4 binding to the target DNA and prevented FoxO4 from entering the nucleus by interfering with the function of nuclear localization sequence (NLS) (Obsilova et al., 2005;Boura et al., 2007). Human FoxO4 gene is located on chromosome Xq13.1 and encodes a protein of 65KD. FoxO4 participates in many cellular processes, including regulation of cell cycle, proliferation, differentiation, apoptosis, ageing, metabolism, response to stress and tumorigenesis (Tran et al., 2002). Another Fox family member-FoxK1, promoted cell proliferation by inhibiting the ...

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ANXA8 Down-regulation by EGF-FOXO4 Signaling Is Involved in Cell Scattering and Tumor Metastasis of Cholangiocarcinoma

Cited by 60 publications

References 43 publications

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

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

Epithelial-Mesenchymal Transition Induced by Transforming Growth Factor-β1/Snail Activation Aggravates Invasive Growth of Cholangiocarcinoma

Low Expression of the FoxO4 Gene may Contribute to the Phenomenon of EMT in Non-small Cell Lung Cancer

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