YAP is a critical oncogene in human cholangiocarcinoma

Pei, Tiemin; Li, Yuejin; Wang, Jiabei; Wang, Huanlai; Liang, Yingjian; Shi, Huawen; Sun, Bei; Yin, Dalong; Sun, Jing; Song, Ran; Pan, Shangha; Sun, Yutong; Jiang, Hongchi; Zheng, Tongsen; Liu, Lianxin

doi:10.18632/oncotarget.4043

Cited by 125 publications

(127 citation statements)

References 49 publications

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“…Consistent with immunohistochemical findings 151–153 , CCA cell lines display high levels of nuclear (i.e., transcriptionally active) YAP, whereas in non-malignant biliary epithelial cells, YAP is mainly sequestered in the cytoplasm 154 . Forced overexpression of YAP promoted the migratory and invasive capabilities of CCA cells, in vitro , and enhanced the metastatic dissemination of intraperitoneal CCA xenografts.…”

Section: Novel Signaling Mechanisms and Trascription Factors Promotinsupporting

confidence: 83%

“…In CCA samples, high nuclear expression of YAP by neoplastic bile ducts correlated with lymph node involvement and distant metastasis, as well as with high tumor stage and grade, and was even identified as an independent prognostic factor for overall survival 151 . Consistent with immunohistochemical findings 151–153 , CCA cell lines display high levels of nuclear (i.e., transcriptionally active) YAP, whereas in non-malignant biliary epithelial cells, YAP is mainly sequestered in the cytoplasm 154 .…”

Section: Novel Signaling Mechanisms and Trascription Factors Promotinmentioning

confidence: 94%

“…Forced overexpression of YAP promoted the migratory and invasive capabilities of CCA cells, in vitro , and enhanced the metastatic dissemination of intraperitoneal CCA xenografts. Conversely, YAP knockdown dramatically impaired CCA cell invasiveness, both in vitro and in vivo 151 . YAP may support the invasive functions of CCA cells either by promoting the expression of gankyrin (also known as PSMD10), an oncoprotein that positively regulates the IL-6/STAT-3 axis 151,155 , or by up-regulating a number of fibroblast growth factor receptor (FGFR) family members (i.e., FGFR1, FGFR2, FGFR4) 154 , overall providing CCA cells with pro-EMT inputs 151,156,157 .…”

Section: Novel Signaling Mechanisms and Trascription Factors Promotinmentioning

confidence: 95%

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Molecular Mechanisms Driving Cholangiocarcinoma Invasiveness: An Overview

et al. 2018

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The acquisition of invasive functions by tumor cells is a first and crucial step towards the development of metastasis, which nowadays represents the main cause of cancer-related death. Cholangiocarcinoma (CCA), a primary liver cancer originating from the biliary epithelium, typically develops intrahepatic or lymph node metastases at early stages, thus preventing the majority of patients from undergoing curative treatments, consistent with their very poor prognosis. As in most carcinomas, CCA cells gradually adopt a motile, mesenchymal-like phenotype, enabling them to cross the basement membrane, detach from the primary tumor, and invade the surrounding stroma. Unfortunately, little is known about the molecular mechanisms that synergistically orchestrate this pro-invasive phenotypic switch. Autocrine and paracrine signals (cyto/chemokines, growth factors, morphogens) permeating the tumor microenvironment undoubtedly play a prominent role in this context. Moreover, a number of recently identified signaling systems are currently drawing attention as putative mechanistic determinants of CCA cell invasion. They encompass transcription factors, protein kinases and phosphatases, ubiquitin ligases, adaptor proteins, and miRNAs, whose aberrant expression may result from either stochastic mutations or the abnormal activation of upstream pro-oncogenic pathways. Herein, we sought to summarize the most relevant molecules in this field, and to discuss their mechanism of action and potential prognostic relevance in CCA. Hopefully, a deeper knowledge of the molecular determinants of CCA invasiveness will help to identify clinically useful biomarkers and novel druggable targets, with the ultimate goal to develop innovative approaches to the management of this devastating malignancy.

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Section: Novel Signaling Mechanisms and Trascription Factors Promotinsupporting

confidence: 83%

Section: Novel Signaling Mechanisms and Trascription Factors Promotinmentioning

confidence: 94%

Section: Novel Signaling Mechanisms and Trascription Factors Promotinmentioning

confidence: 95%

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Molecular Mechanisms Driving Cholangiocarcinoma Invasiveness: An Overview

et al. 2018

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“…S10A). In contrast, Yes-associated protein (YAP) expression, which plays an important role in cholangiocarcinogenesis (27) and is reportedly activated by loss of E-cadherin (28), was significantly increased in ECC cells (Fig. S10B).…”

Section: Loss Of E-cadherin-mediated Yes-associated Protein Activationmentioning

confidence: 99%

Biliary epithelial injury-induced regenerative response by IL-33 promotes cholangiocarcinogenesis from peribiliary glands

Nakagawa

Suzuki

Hirata

et al. 2017

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

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The carcinogenic mechanism of extrahepatic cholangiocarcinoma (ECC) is unclear, due at least in part to the lack of an appropriate mouse model. Because human studies have reported frequent genetic alterations in the Ras-and TGFβ/SMAD-signaling pathways in ECC, mice with tamoxifen-inducible, duct-cell-specific Kras activation and a TGFβ receptor type 2 (TGFβR2) deletion were first generated by crossing LSL-Kras G12D , Tgfbr2 flox/flox , and K19 CreERT mice (KT-K19 CreERT ). However, KT-K19 CreERT mice showed only mild hyperplasia of biliary epithelial cells (BECs) in the extrahepatic bile duct (EHBD) and died within 7 wk, probably a result of lung adenocarcinomas. Next, to analyze the additional effect of E-cadherin loss, KT-K19 CreERT mice were crossed with CDH1 flox/flox mice (KTC-K19 CreERT ). Surprisingly, KTC-K19 CreERT mice exhibited a markedly thickened EHBD wall accompanied by a swollen gallbladder within 4 wk after tamoxifen administration. Histologically, invasive periductal infiltrating-type ECC with lymphatic metastasis was observed. Time-course analysis of EHBD revealed that recombined BECs lining the bile duct lumen detached due to E-cadherin loss, whereas recombined cells could survive in the peribiliary glands (PBGs), which are considered a BEC stem-cell niche. Detached dying BECs released high levels of IL-33, as determined by microarray analysis using biliary organoids, and stimulated inflammation and a regenerative response by PBGs, leading eventually to ECC development. Cell lineage tracing suggested PBGs as the cellular origin of ECC. IL-33 cooperated with Kras and TGFβR2 mutations in the development of ECC, and anti-IL-33 treatment suppressed ECC development significantly. Thus, this mouse model provided insight into the carcinogenic mechanisms, cellular origin, and potential therapeutic targets of ECC.extrahepatic cholangiocarcinoma | IL-33 | organoid | ILC2 | amphiregulin

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“…Hippo, a highly conserved growth control pathway, is deregulated in several human malignancies (5-7) including human CCA (8,9). Recently, we reported that direct transfection of the biliary tree with a constitutively active mediator of the Hippo pathway, YAPS127A, along with mouse myr-Akt as a permissive factor, induces CCA in mice (10).…”

mentioning

confidence: 99%

A Hippo and Fibroblast Growth Factor Receptor Autocrine Pathway in Cholangiocarcinoma

Rizvi

Yamada

Hirsova

et al. 2016

Journal of Biological Chemistry

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Cholangiocarcinomas are highly lethal hepatobiliary cancers with features of cholangiocyte differentiation (1). Although the incidence of CCA 4 is increasing in Western countries (2), therapeutic options for advanced disease not amenable to surgical extirpation remain limited, and overall survival rates are less than 10% (3). Treatment options for advanced CCA are limited, in part, because of the genetic heterogeneity of this malignancy and an incomplete understanding of CCA signaling pathways and biology. There is a critical need to elucidate the molecular mechanisms underlying CCA pathogenesis so that targeted, individualized therapies coupled with biomarkers may be developed (4). Hippo, a highly conserved growth control pathway, is deregulated in several human malignancies (5-7) including human CCA (8, 9). Recently, we reported that direct transfection of the biliary tree with a constitutively active mediator of the Hippo pathway, YAPS127A, along with mouse myr-Akt as a permissive factor, induces CCA in mice (10). This observation directly implicates oncogenic Hippo pathway signaling in CCA biology. The core machinery of the Hippo pathway consists of a kinase relay module and a transcriptional module (11). When the kinase module is "on" it inactivates the transcriptional module, and when it is "off" the transcriptional module becomes active (11). The core components of the kinase module consist of the serine/threonine kinases MST1 and MST2, large tumor suppressor 1 (LATS1), and LATS2 (6). The downstream kinases LATS1 and LATS2 directly phosphorylate the mediators of the transcriptional module, the co-transcriptional activators YAP, and its paralog TAZ, resulting in their inactivation (12). Indeed, the phosphorylation of YAP and TAZ results in their nuclear export, cytoplasmic retention, and/or degradation by the proteasome (6). Although YAP and TAZ have functional redundancy, they also have distinct functions, and accordingly YAP, but not TAZ, has been more strongly implicated in cancer biology to date. The Hippo pathway has been implicated in CCA biology based mainly on nuclear localization of YAP by immunohistochemistry (8), a finding suggesting disruption of the kinase module by yet undefined mechanisms. The Hippo pathway is unique in that it does not have an extracellular ligand or a dedicated plasma membrane receptor and therefore must be activated by cross-talk mechanisms.Fibroblast growth factor receptors (FGFR) are also deregulated in a myriad of malignancies (13). Recently, we and others have described FGFR2 gene fusions in solid organ malignancies including CCA (10 -15% prevalence in CCA) (4, 14 -17). * This work was supported by National Institutes of Health Grants DK59427(to G. J. G.), T32DK007198 (to S. R.), DK84567 (Optical Microscopy Core for the Mayo Center for Cell Signaling in Gastroenterology), and ES020715 (to E. T.) and by the Mayo Foundation. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the auth...

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YAP is a critical oncogene in human cholangiocarcinoma

Cited by 125 publications

References 49 publications

Molecular Mechanisms Driving Cholangiocarcinoma Invasiveness: An Overview

Molecular Mechanisms Driving Cholangiocarcinoma Invasiveness: An Overview

Biliary epithelial injury-induced regenerative response by IL-33 promotes cholangiocarcinogenesis from peribiliary glands

A Hippo and Fibroblast Growth Factor Receptor Autocrine Pathway in Cholangiocarcinoma

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