YAP Mediates Tumorigenesis in Neurofibromatosis Type 2 by Promoting Cell Survival and Proliferation through a COX-2–EGFR Signaling Axis

Guerrant, William; Kota, Smitha; Troutman, Scott; Mandati, Vinay; Fallahi, Mohammad; Stemmer‐Rachamimov, Anat; Kissil, Joseph L.

doi:10.1158/0008-5472.can-15-1144

Cited by 51 publications

(57 citation statements)

References 51 publications

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“…Hippo signaling pathway maintained tissue growth balance by cell proliferation inhibition and promoting apoptosis. [42][43][44] Dysregulation of Hippo signaling were identified during malignancy formation, 32,45 including HCC. 33 YAP is a crucial effector in Hippo signaling.…”

Section: Discussionmentioning

confidence: 99%

<p>Melatonin Regulates Cisplatin Resistance and Glucose Metabolism Through Hippo Signaling in Hepatocellular Carcinoma Cells</p>

Mi¹,

Kuang²

2020

CMAR

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Introduction and Aim: Hepatocellular carcinoma (HCC) is a primary malignancy that occurs in the liver. Clinical cases have been recorded worldwide, particularly in the Saharan area and Asia. In the present work, we aimed to probe the characteristics of melatonin involved in human HCC development, especially in cisplatin resistance and glucose metabolism. Methods: Two HCC cells, HepG2 and Hep3B cells, were treated with melatonin. Cell cycle test was then used to define the role of melatonin in cell progression while Western blotting and qPCR assay were applied to determine the associated proteins in the treatment. Annexin V/PI staining and MTT assay was used to probe the involvement of melatonin in cisplatininduced cell apoptosis process. Successively, we assessed glucose consumption in melatonin treated cells along with Western blotting for detection of GLUT-3 expression level. Yesassociated protein (YAP), a key regulator of Hippo signaling pathway, was further examined to characterize the function of melatonin on adjusting GLUT3 and Bcl-2 expression. Results: Melatonin enabled inhibition of HepG2 and Hep3B proliferation and cell cycle progression via affecting the cell cycle-associated proteins. Annexin V/PI staining and MTT assay results demonstrated that melatonin assisted cisplatin-induced apoptosis accompanied with upregulated caspase-3 and poly ADP-ribose polymerase (PARP) cleavage, as well as Bcl-2 expression. It revealed that melatonin inhibits glucose uptake and ATP production via downregulation of Glucose transporter 3 (GLUT3). In addition, YAP was downregulated by melatonin treatment. The YAP depletion in HepG2 and Hep3B cells suppressed mRNA and protein expression of Bcl-2 and GLUT3, whereas overexpression of YAP in melatonin treated cells partly reversed the melatonin-induced inhibition on proliferation, cisplatininduced apoptosis, and GLUT3 and Bcl-2 expression. Conclusion: Melatonin hindered HCC proliferation and aided cisplatin resistance via regulating the Hippo signaling pathway.

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Section: Discussionmentioning

confidence: 99%

<p>Melatonin Regulates Cisplatin Resistance and Glucose Metabolism Through Hippo Signaling in Hepatocellular Carcinoma Cells</p>

Mi¹,

Kuang²

2020

CMAR

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“…Nf2 deletion in the murine liver leads to the expansion of Sox9 + CK19 + liver progenitor cells (LPCs) and development of cholangiocarcinoma (CC) as well as hepatocellular carcinoma (HCC) in a Yap-dependent manner (Liu-Chittenden et al, 2012; Yimlamai et al, 2014; Zhang et al, 2010). The importance of Yap as a downstream effector of Merlin has been subsequently confirmed in NF2-relevant cell types (Guerrant et al, 2016; Lavado et al, 2013; Serinagaoglu et al, 2015), underscoring the value of the liver model in elucidating the molecular mechanisms of Nf2 tumorigenesis.…”

Section: Introductionmentioning

confidence: 91%

Rac1-Mediated DNA Damage and Inflammation Promote Nf2 Tumorigenesis but Also Limit Cell-Cycle Progression

et al. 2016

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SUMMARY Merlin encoded by the Nf2 gene is a bona fide tumor suppressor that has been implicated in regulation of both the Hippo-Yap and the Rac1-Pak1 pathways. Using genetically engineered murine liver models, we show that co-deletion of Rac1 with Nf2 blocks tumor initiation but paradoxically exacerbates hepatomegaly induced by Nf2 loss, which can be suppressed either by treatment with pro-oxidants or by co-deletion of Yap. Our results suggest that while Yap acts as the central driver of proliferation during Nf2 tumorigenesis, Rac1 primarily functions as an inflammation switch by inducing ROS that on one hand induces NFkB signaling and expression of inflammatory cytokines, and on the other activates p53 checkpoint and senescence programs dampening the cyclinD1-pRb-E2F1 pathway. Interestingly, senescence markers are associated with benign NF2 tumors but not with malignant NF2 mutant mesotheliomas, suggesting that senescence may underlie the benign nature of most NF2 tumors.

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“…The mammalian Hippo pathway has been a source of great interest in the development of NF2-deficient schwannomas. Guerrant and colleagues recently found that COX-2 is transcriptionally up regulated by YAP, a Hippo pathway effector that is transcriptionally activated in the setting of NF2- deficiency [ 6 ]. Further, that same group demonstrated that the COX-2 inhibitor celecoxib suppressed tumor expansion in an orthotopic model of tumorigenesis [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Chemopreventative celecoxib fails to prevent schwannoma formation or sensorineural hearing loss in genetically engineered murine model of neurofibromatosis type 2

Wahle

Hawley

et al. 2017

Oncotarget

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Mutations in the tumor suppressor gene NF2 lead to Neurofibromatosis type 2 (NF2), a tumor predisposition syndrome characterized by the development of schwannomas, including bilateral vestibular schwannomas with complete penetrance. Recent work has implicated the importance of COX-2 in schwannoma growth. Using a genetically engineered murine model of NF2, we demonstrate that selective inhibition of COX-2 with celecoxib fails to prevent the spontaneous development of schwannomas or sensorineural hearing loss in vivo, despite elevated expression levels of COX-2 in Nf2-deficient tumor tissue. These results suggest that COX-2 is nonessential to schwannomagenesis and that the proposed tumor suppressive effects of NSAIDs on schwannomas may occur through COX-2 independent mechanisms.

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YAP Mediates Tumorigenesis in Neurofibromatosis Type 2 by Promoting Cell Survival and Proliferation through a COX-2–EGFR Signaling Axis

Cited by 51 publications

References 51 publications

<p>Melatonin Regulates Cisplatin Resistance and Glucose Metabolism Through Hippo Signaling in Hepatocellular Carcinoma Cells</p>

<p>Melatonin Regulates Cisplatin Resistance and Glucose Metabolism Through Hippo Signaling in Hepatocellular Carcinoma Cells</p>

Rac1-Mediated DNA Damage and Inflammation Promote Nf2 Tumorigenesis but Also Limit Cell-Cycle Progression

Chemopreventative celecoxib fails to prevent schwannoma formation or sensorineural hearing loss in genetically engineered murine model of neurofibromatosis type 2

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