YAP/TAZ Orchestrate VEGF Signaling during Developmental Angiogenesis

Wang, Xiaohong; Valls, Aïda; Schermann, Géza; Ying, Shao‐Yao; Moya, Iván M.; Castro, Laura C.; Urban, Severino; Solecki, Gergely; Winkler, Frank; Riedemann, Lars; Jain, Rakesh K.; Mazzone, Massimiliano; Schmidt, Thomas; Fischer, Tamás; Halder, Georg; Almodóvar, Carmen Ruiz de

doi:10.1016/j.devcel.2017.08.002

Cited by 286 publications

(323 citation statements)

References 63 publications

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“…Transcriptome and proteome data identified 7 overrepresented signaling pathways in normal diabetic mucosa that have been previously associated with tumor development: MAPK, Rap1, VEGF, Wnt, TGF‐β, Hippo, and Notch signaling pathways. These pathways regulate common downstream effectors that control downstream transcriptomic programs that promote carcinogenesis (Hiemer et al ., ; Hong et al ., ; Konsavage et al ., ; Slemmons et al ., ; X. Wang et al ., ).…”

Section: Resultsmentioning

confidence: 97%

“…In view of our results, we selected specific targets to confirm hyperglycemia influence. Many evidences suggested a role in cancer initiation of the protein complex YAP/TAZ‐TEAD (Zanconato et al ., ) including several signaling pathways that we found altered in normal diabetic mucosa: MAPK (Hong et al ., ), VEGF (X. Wang et al ., ), Wnt (Konsavage et al ., ), TGF‐β (Hiemer et al ., ), or the Notch pathway (Slemmons et al ., ). We observed activation of the YAP/TAZ‐TEAD axis under hyperglycemic conditions in the assay of cultured normal colon epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

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Molecular evidence of field cancerization initiated by diabetes in colon cancer patients

et al. 2019

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The potential involvement of type 2 diabetes mellitus (T2 DM ) as a risk factor for colon cancer ( CC ) has been previously reported. While several clinical studies show a higher incidence of CC and a lower survival rate in diabetics, others report no association. Our own experience indicates that diabetes does not seem to worsen the prognosis once the tumor is present. Despite this controversy, there are no wide‐spectrum molecular studies that delve into the impact of T2 DM ‐related mechanisms in colon carcinogenesis. Here, we present a transcriptomic and proteomic profiling of paired tumor and normal colon mucosa samples in a cohort of 42 CC patients, 23 of which have T2 DM . We used gene set enrichment and network approaches to extract relevant pathways in diabetics, referenced them to current knowledge, and tested them using in vitro techniques. Through our transcriptomics approach, we identified an unexpected overlap of pathways overrepresented in diabetics compared to nondiabetics, in both tumor and normal mucosa, including diabetes‐related metabolic and signaling processes. Proteomic approaches highlighted several cancer‐related signaling routes in diabetics found only in normal mucosa, not in tumors. An integration of the transcriptome and proteome analyses suggested the deregulation of key pathways related to colon carcinogenesis which converged on tumor initiation axis TEAD / YAP ‐ TAZ as a potential initiator of the process. In vitro studies confirmed upregulation of this pathway in nontumor colon cells under high‐glucose conditions. In conclusion, T2 DM associates with deregulation of cancer‐related processes in normal colon mucosa adjacent to tissue which has undergone a malignant transformation. These data support that in diabetic patients, the local microenvironment in normal colon mucosa may be a factor driving field cancerization promoting carcinogenesis. Our results set a new framework to study links between diabetes and colon cancer, including a new role of the TEAD / YAP ‐ TAZ complex as a potential driver.

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Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Molecular evidence of field cancerization initiated by diabetes in colon cancer patients

et al. 2019

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“…As a consequence, modulation of transcriptional factors that participate in controlling the expression of angiogenic factors has emerged as a promising strategy in antiangiogenic therapy. Recently, it has been revealed that transcriptional factor YAP acts as a potent mediator of angiogenesis in response to VEGF (Wang et al, ). In this study, we demonstrated that GA directly targeted YAP especially alleviated its nuclear expression and subsequently resulted in the inactivation of downstream STAT3, by which tumor angiogenesis was limited and tumor progression was prevented (Figure ).…”

Section: Discussionmentioning

confidence: 99%

Gambogic acid impairs tumor angiogenesis by targeting YAP/STAT3 signaling axis

Wan

Zhang

Wang

et al. 2019

Phytotherapy Research

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Angiogenesis is central to a wide range of physiological and pathological processes including wound healing, macular degeneration, and cancer. Excessive or inappropriate vascular supply of tumors is one of the main targets for cancer therapy. Recently, critical and selective transcriptional factors such as yes‐associated protein (YAP) that control the expression of angiogenesis factors have gained increasing attention in antiangiogenic therapy. In this study, we have identified and characterized a novel inhibitor of YAP, gambogic acid (GA), which exerted striking antiangiogenic effects both in vitro and in vivo. We demonstrated that GA remarkably inhibited a variety of vascular endothelial growth factor‐induced angiogenesis processes including proliferation, migration, sprouting, and tube formation of endothelial cells in vitro. In addition, GA resulted in decreased neo‐vessel formation in Matrigel plugs of mice and chick chorioallantoic membrane. More importantly, we showed that GA limited tumor growth via preventing tumor angiogenesis and vascular maturation. Further mechanistic studies illustrated that GA directly targeted YAP/STAT3 signaling axis, which is critical for the transcriptional regulation of a series of angiogenic factors. Taken together, these preclinical findings suggest that GA significantly repressed tumor angiogenesis and may serve as a promising drug candidate against cancer.

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“…On the other hand, recent studies have indicated that the Hippo-pathway facilitates mitochondrial function via Bcl-xL [24], demonstrating a possible relationship between Yap and cytoplasmic mitochondria. Furthermore, accumulating evidence has described the regulatory action of Yap on JNK [25, 26]. Thus, together with the confirmed role of JNK in initiating mitochondrial fission [27], these findings raise the possibility that Yap may govern mitochondrial fission via JNK.…”

Section: Introductionmentioning

confidence: 89%

YAP Inhibits the Apoptosis and Migration of Human Rectal Cancer Cells via Suppression of JNK-Drp1-Mitochondrial Fission-HtrA2/Omi Pathways

Zhao

et al. 2017

Cell Physiol Biochem

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Background/Aims: The Hippo-Yap pathway is associated with tumor development and progression. However, little evidence is available concerning its role in cancer cell apoptosis and migration via mitochondrial homeostasis. Here, we identify mitochondrial fission as a regulator of the Hippo–Yap pathway in human rectal cancer tumorigenesis and metastasis. Methods: In this study, we performed loss-of function assays concerning Yap in RCC via shRNA. Cellular viability and apoptosis were measured via MTT, the TUNEL assay and trypan blue staining. Mitochondrial function was assessed via JC1 staining, the mPTP opening assay, mitochondrial respiratory function analysis, electron microscopy and immunofluorescence analysis of HtrA2/Omi. Mitophagy and mitochondrial fission were assessed via western blots and immunofluorescence. Cell migration was evaluated via the Transwell assay, wound-healing assay and immunofluorescence analysis of F-actin. The interaction between JNK and Yap was detected via co-immunoprecipitation and Yap recombinant mutagenic plasmid transfection. Western blots were used to analyze signaling pathways in conjunction with JNK inhibitors or HtrA2/Omi siRNA. Results: Yap is upregulated in human rectal cancer cells, where its expression correlates positively with cell survival and migration. Functional studies established that silencing of Yap drove JNK phosphorylation, which induced Drp1 activation and translocation to the surface of mitochondria, initiating mitochondrial fission. Excessive mitochondrial fission mediated HtrA2/Omi leakage from the mitochondria into the cytoplasm, where HtrA2/Omi triggered cellular apoptosis via the mitochondrial apoptosis pathway. Moreover, released HtrA2/Omi also phosphorylated cofilin and inhibited cofilin-mediated F-actin polymerization. F-actin collapse perturbed lamellipodia formation and therefore impaired cellular migration and invasion. Conclusion: Collectively, our results demonstrate that Hippo-Yap can serve as a tumor promoter in human rectal cancer and acts by restricting JNK/Drp1/mitochondrial fission/ HtrA2/Omi, with potential implications for new approaches to human rectal cancer therapy.

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YAP/TAZ Orchestrate VEGF Signaling during Developmental Angiogenesis

Cited by 286 publications

References 63 publications

Molecular evidence of field cancerization initiated by diabetes in colon cancer patients

Molecular evidence of field cancerization initiated by diabetes in colon cancer patients

Gambogic acid impairs tumor angiogenesis by targeting YAP/STAT3 signaling axis

YAP Inhibits the Apoptosis and Migration of Human Rectal Cancer Cells via Suppression of JNK-Drp1-Mitochondrial Fission-HtrA2/Omi Pathways

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