The Role of Yes-Associated Protein (YAP) in Regulating Programmed Death-Ligand 1 (PD-L1) in Thoracic Cancer

Hsu, Ping‐Chih; Yang, Cheng‐Ta; Jablons, David M.; Li, You

doi:10.3390/biomedicines6040114

Cited by 29 publications

(22 citation statements)

References 76 publications

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“…It was recently shown that IL-13 producing cells, type 2 innate lymphoid cells (ILC2s), are destabilized in response to PD-1/PD-L1 pathway upon high-fat feeding resulting in impaired tissue metabolism [20]. Furthermore, PD-1 blockade showed a partial restore in type 2 innate axis and could serve as promising targets of immune-modulatory NASH therapy [21][22][23][24][25]. Importantly, PD-L1 was found to be responsible for HCC development in NASH via inducing the exhaustion of HCC-directed CD8 + T cells [26].…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms in Interleukin 13 Signaling and Interacting Genes Predict Advanced Fibrosis and Hepatocellular Carcinoma Development in Non-Alcoholic Steatohepatitis

El-Derany

2020

Biology

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Background: non-alcoholic steatohepatitis (NASH) recently headlined hepatocellular carcinoma (HCC) worldwide. This study aims to unveil the role of some unaddressed critical players that might aid in understanding, predicting, and targeting NASH and NASH-HCC. Methods: Serum interleukin 13 (IL-13) levels and single nucleotide polymorphisms (SNPs) within interleukin (IL)-13 rs20541, IL-13 receptors (IL-13R1) rs2248841, (IL-13R2) rs5946040, signal transducer activator of transcription 6 (STAT6) rs167769, yes-associated protein (YAP1) rs11225163, programmed death-ligand 1 (PD-L1) rs2282055, and programmed death-ligand 2 (PD-L2) rs7854413 genes were analyzed by qRT-PCR. Multiple stepwise regression analysis was performed on a cohort of 134 Egyptian male patients diagnosed with NASH and NASH-HCC. RESULTS: higher serum alpha-fetoprotein (AFP) and higher serum IL-13 levels were directly associated with HCC development in NASH (odds ratio (OR) 19.6 and 1.9 p < 0.01). Reversibly, the presence of the C/C genotype in STAT6 rs167769 and the C allele carrier YAP1 rs11225163 were inversely associated with HCC in NASH patients (OR 0.015 and 0.047 p < 0.01). A predictive model was formulated with 97.5% specificity, 90.9% sensitivity, and 94.8% accuracy. Moreover, higher serum IL-13 levels and the presence of PD-L2 rs7854413 C allele carriers were associated with advanced fibrosis progression in NASH patients (OR 1.432 and 3.797 p < 0.01). Serum levels of IL-13 and C/C genotype in STAT6 rs167769 significantly increased the predictive capacity of serum AFP to predict HCC in F1–F2 and in F3–F4 fibrosis grades NASH patients. Conclusion: association between serum IL-13 and PD-L2 rs7854413 polymorphism successfully predict advanced fibrosis in NASH. However, HCC development in NASH is associated with higher serum AFP, IL-13 levels, and STAT6 rs167769, YAP1 rs11225163 polymorphisms.

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Section: Introductionmentioning

confidence: 99%

Polymorphisms in Interleukin 13 Signaling and Interacting Genes Predict Advanced Fibrosis and Hepatocellular Carcinoma Development in Non-Alcoholic Steatohepatitis

El-Derany

2020

Biology

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“…Yap is a pro-survival signal for cells subjected to various stress environments. For example, Yap modulates the viability of thoracic cancer by affecting the activity of programmed death-ligand 1 (PD-L1) [65]. The inhibition of Yap expression can activate breast cancer cell apoptosis; and in cardiac reperfusion injury, the Yap-Hippo pathway is inhibited and contributes to the progression of cardiac dysfunction by augmenting cardiomyocytes [66].…”

Section: Discussionmentioning

confidence: 99%

Mitofusin-2 regulates inflammation-mediated mouse neuroblastoma N2a cells dysfunction and endoplasmic reticulum stress via the Yap-Hippo pathway

2019

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Endoplasmic reticulum (ER) stress is involved in inflammation-induced neurotoxicity. Mitofusin 2 (Mfn2), a member of the GTPase family of proteins, resides in the ER membrane and is known to regulate ER stress. However, the potential role and underlying mechanism of Mfn2 in inflammation-induced neuronal dysfunction is unknown. In our study, we explored the potential of Mfn2 to attenuate inflammation-mediated neuronal dysfunction by inhibiting ER stress. Our data show that Mfn2 overexpression significantly ameliorated tumor necrosis factor alpha (TNFα)-induced ER stress, as indicated by the downregulation of the ER stress proteins PERK, GRP78 and CHOP. Mfn2 overexpression also prevented the TNFα-mediated activation of caspase-3, caspase-12 and cleaved poly (ADP-ribose) polymerase (PARP). Cellular antioxidant dysfunction and reactive oxygen species overproduction were also improved by Mfn2 in the setting of TNFα in mouse neuroblastoma N2a cells in vitro. Similarly, disordered calcium homeostasis, indicated by disturbed levels of calcium-related proteins and calcium overloading, was corrected by Mfn2, as evidenced by the increased expression of store-operated calcium entry (SERCA), decreased levels of inositol trisphosphate receptor (IP3R), and normalized calcium content in TNFα-treated N2a cells. Mfn2 overexpression was found to elevate Yes-associated protein (Yap) expression; knockdown of Yap abolished the regulatory effects of Mfn2 on ER stress, oxidative stress, calcium balance, neural death and inflammatory injury. These results lead us to conclude that re-activation of the Mfn2-Yap signaling pathway alleviates TNFα-induced ER stress and dysfunction of mouse neuroblastoma N2a cells. Our findings provide a better understanding of the regulatory role of Mfn2-Yap-ER stress in neuroinflammation and indicate that the Mfn2-Yap axis may be a focus of research in terms of having therapeutic value for the treatment of neurodegenerative diseases.

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“…In the Hippo pathway, YAP is negatively regulated by MST1, MST2, LATS1 and LATS2 kinases through modulated phosphorylation events of kinase cascade in most situations. In addition, YAP activity or function is regulated by many factors that do not influence the LATS/MST kinase activity and have crosstalk with other pathways . CDK7 regulates transcription primarily by phosphorylating serine 5 at the C‐terminal domain of RNA polymerase II, as well as transcription factors such as oestrogen receptor‐α .…”

Section: Discussionmentioning

confidence: 99%

Inhibition of cyclin‐dependent kinase 7 down‐regulates yes‐associated protein expression in mesothelioma cells

Miao

Kyoyama

Liu

et al. 2019

J Cellular Molecular Medi

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Cyclin‐dependent kinase 7 (CDK7) is a protein kinase that plays a major role in transcription initiation. Yes‐associated protein (YAP) is a main effector of the Hippo/YAP signalling pathway. Here, we investigated the role of CDK7 on YAP regulation in human malignant pleural mesothelioma (MPM). We found that in microarray samples of human MPM tissue, immunohistochemistry staining showed correlation between the expression level of CDK7 and YAP (n = 70, r = .513). In MPM cells, CDK7 expression level was significantly correlated with GTIIC reporter activity (r = .886, P = .019). Inhibition of CDK7 by siRNA decreased the YAP protein level and the GTIIC reporter activity in the MPM cell lines 211H, H290 and H2052. Degradation of the YAP protein was accelerated after CDK7 knockdown in 211H, H290 and H2052 cells. Inhibition of CDK7 reduced tumour cell migration and invasion, as well as tumorsphere formation ability. Restoration of the CDK7 gene rescued the YAP protein level and GTIIC reporter activity after siRNA knockdown in 211H and H2052 cells. Finally, we performed a co‐immunoprecipitation analysis using an anti‐YAP antibody and captured the CDK7 protein in 211H cells. Our results suggest that CDK7 inhibition reduces the YAP protein level by promoting its degradation and suppresses the migration and invasion of MPM cells. Cyclin‐dependent kinase 7 may be a promising therapeutic target for MPM.

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The Role of Yes-Associated Protein (YAP) in Regulating Programmed Death-Ligand 1 (PD-L1) in Thoracic Cancer

Cited by 29 publications

References 76 publications

Polymorphisms in Interleukin 13 Signaling and Interacting Genes Predict Advanced Fibrosis and Hepatocellular Carcinoma Development in Non-Alcoholic Steatohepatitis

Polymorphisms in Interleukin 13 Signaling and Interacting Genes Predict Advanced Fibrosis and Hepatocellular Carcinoma Development in Non-Alcoholic Steatohepatitis

Mitofusin-2 regulates inflammation-mediated mouse neuroblastoma N2a cells dysfunction and endoplasmic reticulum stress via the Yap-Hippo pathway

Inhibition of cyclin‐dependent kinase 7 down‐regulates yes‐associated protein expression in mesothelioma cells

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