ZEB1 expression is associated with prognosis of intrahepatic cholangiocarcinoma

Terashita, Katsumi; Chuma, Makoto; Hatanaka, Yutaka; Hatanaka, Kanako C.; Mitsuhashi, Tomoko; Yokoo, Hideki; Ohmura, Takumi; Ishizu, Hideki; Muraoka, Shunji; Nagasaka, Atsushi; Tsuji, Takeshi; Yamamoto, Yoshiya; Kurauchi, Nobuaki; Shimoyama, Norihiko; Toyoda, Hidenori; Kumada, Takashi; Kikuchi, Yuji; Maeda, Atsuyuki; Ogawa, Koji; Natsuizaka, Mitsuteru; Kamachi, Hirofumi; Kakisaka, Tatsuhiko; Kamiyama, Toshiya; Taketomi, Akinobu; Matsuno, Yoshihiro; Sakamoto, Naoya

doi:10.1136/jclinpath-2015-203115

Cited by 18 publications

(22 citation statements)

References 28 publications

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“…In addition, vimentin was mostly detected in poorly differentiated tumor foci and a multivariate analysis demonstrated that aberrant vimentin expression is an independent adverse prognostic factor in iCCA [50]. As expected, vimentin expression was negatively correlated with the expression of CK19 and Ecadherin in iCCA [24,25,35]. Consistently, in eCCA cases (both pCCA and dCCA) expressing SNAIL, CK19 expression was lower and vimentin prevailed [48].…”

Section: Intermediate Filamentsmentioning

confidence: 62%

“…Several studies confirmed an aberrant staining of vimentin in CCA tumor cells while there was no staining in benign cholangiocytes [24,25,32,35,40,[48][49][50]. Vimentin expression was associated with lymph node metastasis, portal vein invasion, tumor size, pTNM stage and poorer OS and DFS [25,31,32,35,50]. In addition, vimentin was mostly detected in poorly differentiated tumor foci and a multivariate analysis demonstrated that aberrant vimentin expression is an independent adverse prognostic factor in iCCA [50].…”

Section: Intermediate Filamentsmentioning

confidence: 96%

“…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%

“…CK19 down-regulation has been observed in tumor cells of CCA, and this down-regulation was significantly associated with neural invasion, intrahepatic metastasis, undifferentiated tumor grade and shortened DFS and OS [24]. Several studies confirmed an aberrant staining of vimentin in CCA tumor cells while there was no staining in benign cholangiocytes [24,25,32,35,40,[48][49][50]. Vimentin expression was associated with lymph node metastasis, portal vein invasion, tumor size, pTNM stage and poorer OS and DFS [25,31,32,35,50].…”

Section: Intermediate Filamentsmentioning

confidence: 99%

“…Nuclear ZEB1 was highly expressed in malignant iCCA cells compared to normal non-neoplastic epithelial cells and was associated with aggressive parameters and poorer OS [35,59]. High expression of ZEB2 was found in 51% of CCA and correlated with metastasis and poor prognosis [60].…”

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confidence: 97%

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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: Intermediate Filamentsmentioning

confidence: 62%

Section: Intermediate Filamentsmentioning

confidence: 96%

Section: Disruption Of Intercellular Junctionsmentioning

confidence: 99%

Section: Intermediate Filamentsmentioning

confidence: 99%

mentioning

confidence: 97%

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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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Zinc Finger E‐Box Binding Homeobox 1 Promotes Cholangiocarcinoma Progression Through Tumor Dedifferentiation and Tumor–Stroma Paracrine Signaling

et al. 2021

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BaCKgRoUND aND aIMS:Zinc finger E-box binding homeobox 1 (ZEB1) is a transcription factor that promotes metastatic and stem cell features, which has been associated with poor prognosis in cholangiocarcinoma (CCA), a desmoplastic cancer enriched in cancer-associated fibroblasts (CAFs). We aimed to define ZEB1 regulatory functions in malignant and stromal compartments of CCA.appRoaCH aND ReSUltS: Bioinformatic and immunohistochemical analyses were performed to determine correlations between ZEB1 and markers of progressiveness in human intrahepatic CCA (iCCA). Gain-of-function and loss-of-function models were generated in CCA cells and liver myofibroblasts as a model of CAFs. Conditioned media (CM) was used to unravel tumor-stroma interplay. In vivo experiments were performed using a xenograft CCA model. ZEB1 expression in tumor cells of human iCCA was associated with undifferentiated tumor and vascular invasion. In vitro, ZEB1 promoted epithelial-mesenchymal transition and stemness in tumor cells, leading to cell migration and spheroid formation. In vivo, ZEB1-overexpressing CCA cells formed larger tumors with more abundant stroma. Expression of cellular communication network factor 2 (CCN2, encoding connective tissue growth factor [CTGF]) was increased in tumor cells from ZEB1overexpressing xenografts and correlated with ZEB1 expression in human tumors. In vitro, CM from ZEB1-overexpressing tumor cells or recombinant CTGF induced myofibroblast proliferation. ZEB1 was also expressed by CAFs in human CCA, and its expression correlated with CCN2 in myofibroblasts and CCA stroma. In mice, cotransplantation of CCA cells with ZEB1-depleted myofibroblasts reduced CCA progressiveness compared to CCA cells/ZEB1-expressing myofibroblasts. Furthermore, ZEB1 controls the expression of paracrine signals (i.e., HGF and IL6) in tumor cells and myofibroblasts.CoNClUSIoNS: ZEB1 plays a key role in CCA progression by regulating tumor cell-CAF crosstalk, leading to tumor dedifferentiation and CAF activation. (Hepatology 2021;74:3194-3212). C holangiocarcinoma (CCA) includes a heterogeneous group of malignancies that develop from the epithelial layer of the biliary tract. (1,2) CCA is the second most common primary liver tumor after hepatocellular carcinoma,

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A TP73‐AS1/miR‐200a/ZEB1 regulating loop promotes breast cancer cell invasion and migration

Zou

Zhou

et al. 2017

J of Cellular Biochemistry

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Breast cancer (BC) is one of the leading causes of cancer deaths worldwide and the most common cancer among women. In our previous study, we revealed that lncRNA TP73-AS1 promotes breast cancer cell proliferation through directly binding to miR-200a. Herein, we evaluated the effect of TP73-AS1 in breast cancer cell invasion and migration, and further demonstrated the direct binding between TP73-AS1 and miR-200a, between miR-200a and 3'UTR of ZEB1, an essential metastasis-related transcription factor. TP73-AS1 promoted ZEB1 expression via competing with ZEB1 3'UTR for miR-200a binding. Moreover, ZEB1 could bind to the promoter region of TP73-AS1 to activate its expression. TP73-AS1 and ZEB1 expression was up-regulated, whereas miR-200a expression was down-regulated in breast cancer tissues. Taken together, we demonstrated a TP73-AS1/miR-200a/ZEB1 regulating loop in breast cancer cells, which promote cancer cell invasion and migration through regulating E-cadherin and Twist expression. Suppressing TP73-AS1 expression to rescue miR-200a expression, thus to inhibit ZEB1 and Twist expression and up-regulate E-cadherin might improve breast cancer cell invasion and migration.

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ZEB1 expression is associated with prognosis of intrahepatic cholangiocarcinoma

Cited by 18 publications

References 28 publications

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

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

Zinc Finger E‐Box Binding Homeobox 1 Promotes Cholangiocarcinoma Progression Through Tumor Dedifferentiation and Tumor–Stroma Paracrine Signaling

A TP73‐AS1/miR‐200a/ZEB1 regulating loop promotes breast cancer cell invasion and migration

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