YAP forms autocrine loops with the ERBB pathway to regulate ovarian cancer initiation and progression

He, Chunbo; Lv, Xiaozhen; Hua, Guohua; Lele, Subodh M.; Remmenga, Steven W.; Dong, Jixin; Davis, John S.; Wang, Cheng

doi:10.1038/onc.2015.52

Cited by 95 publications

(108 citation statements)

References 45 publications

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“…This raised the possibility of the existence of a feedforward loop between these two pathways. Indeed, an autocrine loop between the Hippo signaling pathway and a receptor tyrosine kinase pathway (ERRB) has been described recently in ovarian cancer cells (43). We confirmed the presence of an autocrine, feed-forward pathway between the oncogenic Hippo signaling pathway and FGFR pathway by adding FGF5 to a CCA cell line with virtually no basal YAP immunoreactivity and observed a marked increase in YAP expression.…”

Section: Discussionsupporting

confidence: 71%

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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Section: Discussionsupporting

confidence: 71%

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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“…A research group found that YAP plays an important role in regulating ovarian adult granulosa cell tumor cell proliferation, migration, and steroidogenesis 25. They also found that YAP interacts with epidermal growth factor receptor signaling pathway to regulate growth of ovarian surface epithelial cells and OC cells 26. Most recently, the same group came to a conclusion that YAP may be involved in the initiation and progression of fallopian tube epithelia-derived cancer 27.…”

Section: Discussionmentioning

confidence: 99%

Verteporfin, a suppressor of YAP–TEAD complex, presents promising antitumor properties on ovarian cancer

Feng¹,

Gou²,

Jia³

et al. 2016

OTT

114

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Yes-associated protein (YAP) is a key transcriptional coactivator of Hippo pathway and has been shown to be an oncoprotein in ovarian cancer (OC). Verteporfin (VP), clinically used in photodynamic therapy for neovascular macular degeneration, has been recently proven to be a suppressor of YAP–TEAD complex and has shown potential in anticancer treatment. In this study, we aimed to explore the potential effect of VP in the treatment of OC. Our results showed that VP led to inhibition of proliferation in a time- and dose-dependent manner and to the suppression of migratory and invasive capacities of OC cells. Western blot and real-time polymerase chain reaction demonstrated that VP induced YAP cytoplasmic retention and deregulated inducible YAP and CCNs in OC cells. In vivo, VP exerted a significant effect on tumor growth in OVCAR8 xenograft mice, resulting in tumor nodules with lower average weight and reduced volume of gross ascites. In addition, VP treatment remarkably upregulated cytoplasmic YAP and phosphorylation YAP and downregulated CCN1 and CCN2, but exerted little effect on YAP-upstream components in Hippo pathway. In conclusion, our results suggested that VP may be a promising agent for OC, acting by suppressing YAP–TEAD complex.

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“…Such relationship between YAP1 and the EGFR pathway was found to be important in the progression of oesophageal cancer in patients treated with EGFR inhibitors [61]. Recently published results of knockdown of YAP1 and knockdown of ERBB3 study suggested presence of an autocrine loop between YAP1 and EGFR which may control ovarian cell tumourigenesis and cancer progression [63].…”

Section: Hippo Upregulates Egfr/kras Pathwaymentioning

confidence: 99%

“…Recent reports [50,[61][62][63] revealed that the Hippo pathway effector, YAP1 protein, is involved in the regulation of EGFR/KRAS signalling ( Figure 3). During homeostasis, degradation of YAP1 is triggered by ubiquitin ligase complex substrate recognition factors SOCS5/6.…”

Section: Hippo Upregulates Egfr/kras Pathwaymentioning

confidence: 99%

The Hippo pathway in colorectal cancer

Wierzbicki

Rybarczyk

2015

Folia Histochem Cytobiol.

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Colorectal cancer (CRC) is one the most frequently diagnosed neoplastic diseases worldwide. Currently, aside from traditional chemotherapy, advanced CRCs are treated with modern drugs targeting cellular components such as epithelial growth factor receptor (EGFR). Since up to 70% of metastasized CRCs are drug resistant, the description of recent progress in cellular homeostasis regulation may shed new light on the development of new molecular targets in cancer treatment. The Hippo pathway has recently become subject of intense investigations since it plays a crucial role in cell proliferation, differentiation, apoptosis and tumourigenesis. Components of the Hippo pathway are deregulated in various human malignancies, and expression levels of its major signal transducers were proposed as prognostic factors in colorectal cancer. In this review we focused on recent data regarding Hippo pathway, its up-stream signals and down-stream effectors. Hippo negatively regulates its major effectors, YAP1 and TAZ kinases, which act as transcriptional co-activators inducing expression of genes involved not only in tissue repair and proliferation but are also oncoproteins involved in tumour development and progression. The deregulation of Hippo pathway components was found in many malignancies. The interactions between Hippo and Wnt/b-catenin signalling, crucial in the maintenance of cell homeostasis, have been described in relation to the control of intestinal stem cell proliferation and CRC development. The recently discovered positive feedback loop between activated YAP1 and increased EGFR/KRAS signalling found in oesophageal, ovarian and hepatocellular cancer has been related to the CRC progression and resistance to EGFR inhibitors during CRC therapy.

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YAP forms autocrine loops with the ERBB pathway to regulate ovarian cancer initiation and progression

Cited by 95 publications

References 45 publications

A Hippo and Fibroblast Growth Factor Receptor Autocrine Pathway in Cholangiocarcinoma

A Hippo and Fibroblast Growth Factor Receptor Autocrine Pathway in Cholangiocarcinoma

Verteporfin, a suppressor of YAP–TEAD complex, presents promising antitumor properties on ovarian cancer

The Hippo pathway in colorectal cancer

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YAP forms autocrine loops with the ERBB pathway to regulate ovarian cancer initiation and progression

Cited by 95 publications

References 45 publications

A Hippo and Fibroblast Growth Factor Receptor Autocrine Pathway in Cholangiocarcinoma

A Hippo and Fibroblast Growth Factor Receptor Autocrine Pathway in Cholangiocarcinoma

Verteporfin, a suppressor of YAP&ndash;TEAD complex, presents promising antitumor properties on ovarian cancer

The Hippo pathway in colorectal cancer

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Verteporfin, a suppressor of YAP–TEAD complex, presents promising antitumor properties on ovarian cancer