The Experts below are selected from a list of 1137 Experts worldwide ranked by ideXlab platform
Yunzhao Chen - One of the best experts on this subject based on the ideXlab platform.
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Hypomethylation-Linked Activation of PLCE1 Impedes Autophagy and Promotes Tumorigenesis through MDM2-Mediated Ubiquitination and Destabilization of p53.
Cancer research, 2020Co-Authors: Yunzhao Chen, Hao Peng, Xi Chen, Xueping Han, Huahua Xin, Qi Shi, Tian Yanxia, Yi ZhengAbstract:Esophageal squamous cell carcinoma (ESCC) is one of the deadliest malignant diseases. Multiple studies with large clinic-based cohorts have revealed that variations of phospholipase C epsilon 1 (PLCE1) correlate with esophageal cancer susceptibility. However, the causative role of PLCE1 in ESCC has remained elusive. Here, we observed that hypomethylation-mediated upregulation of PLCE1 expression was implicated in esophageal carcinogenesis and poor prognosis in ESCC cohorts. PLCE1 inhibited cell autophagy and suppressed the protein expression of p53 and various p53-targeted genes in ESCC. Moreover, PLCE1 decreased the half-life of p53 and promoted p53 ubiquitination, whereas it increased the half-life of mouse double minute 2 homolog (MDM2) and inhibited its ubiquitination, leading to MDM2 stabilization. Mechanistically, the function of PLCE1 correlated with its direct binding to both p53 and MDM2, which promoted MDM2-dependent ubiquitination of p53 and subsequent degradation in vitro. Consequently, knockdown of PLCE1 combined with transfection of a recombinant adenoviral vector encoding wild-type p53 resulted in significantly increased levels of autophagy and apoptosis of esophageal cancer in vivo. Clinically, the upregulation of PLCE1 and mutant p53 protein predicted poor overall survival of patients with ESCC, and PLCE1 was positively correlated with p53 in ESCC cohorts. Collectively, this work identified an essential role for PLCE1- and MDM2-mediated ubiquitination and degradation of p53 in inhibiting ESCC autophagy and indicates that targeting the PLCE1-MDM2-p53 axis may provide a novel therapeutic approach for ESCC. SIGNIFICANCE: These findings identify hypomethylation-mediated activation of PLCE1 as a potential oncogene that blocks cellular autophagy of esophageal carcinoma by facilitating the MDM2-dependent ubiquitination of p53 and subsequent degradation. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/11/2175/F1.large.jpg.
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Epigenetically upregulated oncoprotein PLCE1 drives esophageal carcinoma angiogenesis and proliferation via activating the PI-PLCε-NF-κB signaling pathway and VEGF-C/ Bcl-2 expression
Molecular cancer, 2019Co-Authors: Yunzhao Chen, Dandan Wang, Hao Peng, Xi Chen, Xueping Han, Wenjie Wang, Lirong Liang, Zheng Liu, Yi ZhengAbstract:Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies. Neovascularization during tumorigenesis supplies oxygen and nutrients to proliferative tumor cells, and serves as a conduit for migration. Targeting oncogenes involved in angiogenesis is needed to treat organ-confined and locally advanced ESCC. Although the phospholipase C epsilon-1 (PLCE1) gene was originally identified as a susceptibility gene for ESCC, how PLCE1 is involved in ESCC is unclear. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry were used to measure the methylation status of the PLCE1 promoter region. To validate the underlying mechanism for PLCE1 in constitutive activation of the NF-κB signaling pathway, we performed studies using in vitro and in vivo assays and samples from 368 formalin-fixed esophageal cancer tissues and 215 normal tissues with IHC using tissue microarrays and the Cancer Genome Atlas dataset. We report that hypomethylation-associated up-regulation of PLCE1 expression was correlated with tumor angiogenesis and poor prognosis in ESCC cohorts. PLCE1 can activate NF-κB through phosphoinositide-phospholipase C-e (PI-PLCe) signaling pathway. Furthermore, PLCE1 can bind p65 and IκBα proteins, promoting IκBα-S32 and p65-S536 phosphorylation. Consequently, phosphorylated IκBα promotes nuclear translocation of p50/p65 and p65, as a transcription factor, can bind vascular endothelial growth factor-C and bcl-2 promoters, enhancing angiogenesis and inhibiting apoptosis in vitro. Moreover, xenograft tumors in nude mice proved that PLCE1 can induce angiogenesis, inhibit apoptosis, and increase tumor aggressiveness via the NF-κB signaling pathway in vivo. Our findings not only provide evidence that hypomethylation-induced PLCE1 confers angiogenesis and proliferation in ESCC by activating PI-PLCe-NF-κB signaling pathway and VEGF-C/Bcl-2 expression, but also suggest that modulation of PLCE1 by epigenetic modification or a selective inhibitor may be a promising therapeutic approach for the treatment of ESCC.
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Epigenetically upregulated oncoprotein PLCE1 drives esophageal carcinoma angiogenesis and proliferation via activating the PI-PLCε-NF-κB signaling pathway and VEGF-C/ Bcl-2 expression
BMC, 2019Co-Authors: Yunzhao Chen, Dandan Wang, Hao Peng, Xi Chen, Xueping Han, Wenjie Wang, Lirong Liang, Zheng Liu, Yi ZhengAbstract:Abstract Background Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies. Neovascularization during tumorigenesis supplies oxygen and nutrients to proliferative tumor cells, and serves as a conduit for migration. Targeting oncogenes involved in angiogenesis is needed to treat organ-confined and locally advanced ESCC. Although the phospholipase C epsilon-1 (PLCE1) gene was originally identified as a susceptibility gene for ESCC, how PLCE1 is involved in ESCC is unclear. Methods Matrix-assisted laser desorption ionization time-of-flight mass spectrometry were used to measure the methylation status of the PLCE1 promoter region. To validate the underlying mechanism for PLCE1 in constitutive activation of the NF-κB signaling pathway, we performed studies using in vitro and in vivo assays and samples from 368 formalin-fixed esophageal cancer tissues and 215 normal tissues with IHC using tissue microarrays and the Cancer Genome Atlas dataset. Results We report that hypomethylation-associated up-regulation of PLCE1 expression was correlated with tumor angiogenesis and poor prognosis in ESCC cohorts. PLCE1 can activate NF-κB through phosphoinositide-phospholipase C-ε (PI-PLCε) signaling pathway. Furthermore, PLCE1 can bind p65 and IκBα proteins, promoting IκBα-S32 and p65-S536 phosphorylation. Consequently, phosphorylated IκBα promotes nuclear translocation of p50/p65 and p65, as a transcription factor, can bind vascular endothelial growth factor-C and bcl-2 promoters, enhancing angiogenesis and inhibiting apoptosis in vitro. Moreover, xenograft tumors in nude mice proved that PLCE1 can induce angiogenesis, inhibit apoptosis, and increase tumor aggressiveness via the NF-κB signaling pathway in vivo. Conclusions Our findings not only provide evidence that hypomethylation-induced PLCE1 confers angiogenesis and proliferation in ESCC by activating PI-PLCε-NF-κB signaling pathway and VEGF-C/Bcl-2 expression, but also suggest that modulation of PLCE1 by epigenetic modification or a selective inhibitor may be a promising therapeutic approach for the treatment of ESCC
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Additional file 1: of Epigenetically upregulated oncoprotein PLCE1 drives esophageal carcinoma angiogenesis and proliferation via activating the PI-PLCÎľ-NF-ÎşB signaling pathway and VEGF-C/ Bcl-2 expression
2019Co-Authors: Yunzhao Chen, Dandan Wang, Hao Peng, Xi Chen, Xueping Han, Wenjie Wang, Lirong Liang, Zheng Liu, Yi ZhengAbstract:Table S1. Correlation between DNA methylation and PLCE1 expression in ESCC tissues; Table S2. Correlation between the expression and promoter methylation of PLCE1 in ESCC tissues; Table S3. Compare the CpG sites methylation of PLCE1 between ESCC and NCAT tissues; Table S4. Sequences of PCR primers used in this study. (DOCX 26 kb
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Additional file 4: of Epigenetically upregulated oncoprotein PLCE1 drives esophageal carcinoma angiogenesis and proliferation via activating the PI-PLCÎľ-NF-ÎşB signaling pathway and VEGF-C/ Bcl-2 expression
2019Co-Authors: Yunzhao Chen, Dandan Wang, Hao Peng, Xi Chen, Xueping Han, Wenjie Wang, Lirong Liang, Zheng Liu, Yi ZhengAbstract:Figure S3. PLCE1 ablation reduces the IP3-dependent intracellular calcium release. a Laser scanning confocal microscopy was used to measure intracellular calcium fluorescence pixel values of ESCC cells after treatment with PLCE1 shRNA, TPA, and BIM. (PDF 95 kb
Hao Peng - One of the best experts on this subject based on the ideXlab platform.
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Identification of a PLCE1‑regulated competing endogenous RNA regulatory network for esophageal squamous cell carcinoma
Oncology reports, 2021Co-Authors: Zhihao Yang, Hao Peng, Yi Hui, Hongpan Zhang, Lingxie Song, Xiaobin CuiAbstract:Phospholipase C epsilon 1 (PLCE1) and the competing endogenous RNA (ceRNA) network are crucial for tumorigenesis and the progression of esophageal squamous cell carcinoma (ESCC). However, whether PLCE1 can regulate the ceRNA network in ESCC has not been clarified. In the present study, we aimed to identify the PLCE1‑regulated ceRNA network and further elucidate the regulatory mechanisms by which ESCC is promoted. Microarray analysis was used to identify differentially expressed lncRNAs (DELs) and differentially expressed genes (DEGs) from three pairs of samples of PLCE‑silenced Eca109 and control Eca109 cells. Next, the ceRNA regulatory network was established and visualized in Cytoscape, and functional enrichment analysis was performed to analyze DEGs from ceRNAs. Protein‑protein interaction (PPI) networks among the DEGs were established by the STRING database to screen hub genes. Kaplan‑Meier survival analysis was used to validate hub genes. Finally, PLCE1‑related hub gene/lncRNA/miRNA axes were also constructed based on the ceRNA network. A total of 105 DELs and 346 DEGs were found to be dysregulated in the microarray data (|log2FC| >1.5, adjusted P
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identification of a PLCE1 regulated competing endogenous rna regulatory network for esophageal squamous cell carcinoma
Oncology Reports, 2021Co-Authors: Zhihao Yang, Hao Peng, Yi Hui, Hongpan Zhang, Lingxie Song, Xiaobin CuiAbstract:Phospholipase C epsilon 1 (PLCE1) and the competing endogenous RNA (ceRNA) network are crucial for tumorigenesis and the progression of esophageal squamous cell carcinoma (ESCC). However, whether PLCE1 can regulate the ceRNA network in ESCC has not been clarified. In the present study, we aimed to identify the PLCE1‑regulated ceRNA network and further elucidate the regulatory mechanisms by which ESCC is promoted. Microarray analysis was used to identify differentially expressed lncRNAs (DELs) and differentially expressed genes (DEGs) from three pairs of samples of PLCE‑silenced Eca109 and control Eca109 cells. Next, the ceRNA regulatory network was established and visualized in Cytoscape, and functional enrichment analysis was performed to analyze DEGs from ceRNAs. Protein‑protein interaction (PPI) networks among the DEGs were established by the STRING database to screen hub genes. Kaplan‑Meier survival analysis was used to validate hub genes. Finally, PLCE1‑related hub gene/lncRNA/miRNA axes were also constructed based on the ceRNA network. A total of 105 DELs and 346 DEGs were found to be dysregulated in the microarray data (|log2FC| >1.5, adjusted P<0.05). We constructed a PLCE1‑regulated ceRNA network that incorporated 12 lncRNAs, 43 miRNAs, and 169 mRNAs. Functional enrichment analysis indicated that the DEGs might be associated with ESCC onset and development. A PPI network was established, and 9 hub genes [WD and tetratricopeptide repeats 1 (WDTC1), heat shock protein family A (Hsp70) member 5 (HSPA5), N‑ethylmaleimide sensitive factor, vesicle fusing ATPase (NSF), fibroblast growth factor 2 (FGF2), cyclin dependent kinase inhibitor 1A (CDKN1A or P21), bone morphogenetic protein 2 (BMP2), complement C3 (C3), GM2 ganglioside activator (GM2A) and discs large MAGUK scaffold protein 4 (DLG4)] were determined from the network. Kaplan‑Meier survival analysis validated four hub genes (BMP2, CDKN1A, GM2A, and DLG4) that were treated as prognostic factors. Ultimately, hub gene/lncRNA/miRNA subnetworks were obtained based on the 4 hub genes, 13 DEmiRNAs, and 10 DELs. In conclusion, the PLCE1‑regulated ceRNA contributes to the onset and progression of ESCC and the underlying molecular mechanisms may provide insights into personalized prognosis and new therapies for ESCC patients.
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Hypomethylation-Linked Activation of PLCE1 Impedes Autophagy and Promotes Tumorigenesis through MDM2-Mediated Ubiquitination and Destabilization of p53.
Cancer research, 2020Co-Authors: Yunzhao Chen, Hao Peng, Xi Chen, Xueping Han, Huahua Xin, Qi Shi, Tian Yanxia, Yi ZhengAbstract:Esophageal squamous cell carcinoma (ESCC) is one of the deadliest malignant diseases. Multiple studies with large clinic-based cohorts have revealed that variations of phospholipase C epsilon 1 (PLCE1) correlate with esophageal cancer susceptibility. However, the causative role of PLCE1 in ESCC has remained elusive. Here, we observed that hypomethylation-mediated upregulation of PLCE1 expression was implicated in esophageal carcinogenesis and poor prognosis in ESCC cohorts. PLCE1 inhibited cell autophagy and suppressed the protein expression of p53 and various p53-targeted genes in ESCC. Moreover, PLCE1 decreased the half-life of p53 and promoted p53 ubiquitination, whereas it increased the half-life of mouse double minute 2 homolog (MDM2) and inhibited its ubiquitination, leading to MDM2 stabilization. Mechanistically, the function of PLCE1 correlated with its direct binding to both p53 and MDM2, which promoted MDM2-dependent ubiquitination of p53 and subsequent degradation in vitro. Consequently, knockdown of PLCE1 combined with transfection of a recombinant adenoviral vector encoding wild-type p53 resulted in significantly increased levels of autophagy and apoptosis of esophageal cancer in vivo. Clinically, the upregulation of PLCE1 and mutant p53 protein predicted poor overall survival of patients with ESCC, and PLCE1 was positively correlated with p53 in ESCC cohorts. Collectively, this work identified an essential role for PLCE1- and MDM2-mediated ubiquitination and degradation of p53 in inhibiting ESCC autophagy and indicates that targeting the PLCE1-MDM2-p53 axis may provide a novel therapeutic approach for ESCC. SIGNIFICANCE: These findings identify hypomethylation-mediated activation of PLCE1 as a potential oncogene that blocks cellular autophagy of esophageal carcinoma by facilitating the MDM2-dependent ubiquitination of p53 and subsequent degradation. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/11/2175/F1.large.jpg.
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Epigenetically upregulated oncoprotein PLCE1 drives esophageal carcinoma angiogenesis and proliferation via activating the PI-PLCε-NF-κB signaling pathway and VEGF-C/ Bcl-2 expression
Molecular cancer, 2019Co-Authors: Yunzhao Chen, Dandan Wang, Hao Peng, Xi Chen, Xueping Han, Wenjie Wang, Lirong Liang, Zheng Liu, Yi ZhengAbstract:Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies. Neovascularization during tumorigenesis supplies oxygen and nutrients to proliferative tumor cells, and serves as a conduit for migration. Targeting oncogenes involved in angiogenesis is needed to treat organ-confined and locally advanced ESCC. Although the phospholipase C epsilon-1 (PLCE1) gene was originally identified as a susceptibility gene for ESCC, how PLCE1 is involved in ESCC is unclear. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry were used to measure the methylation status of the PLCE1 promoter region. To validate the underlying mechanism for PLCE1 in constitutive activation of the NF-κB signaling pathway, we performed studies using in vitro and in vivo assays and samples from 368 formalin-fixed esophageal cancer tissues and 215 normal tissues with IHC using tissue microarrays and the Cancer Genome Atlas dataset. We report that hypomethylation-associated up-regulation of PLCE1 expression was correlated with tumor angiogenesis and poor prognosis in ESCC cohorts. PLCE1 can activate NF-κB through phosphoinositide-phospholipase C-e (PI-PLCe) signaling pathway. Furthermore, PLCE1 can bind p65 and IκBα proteins, promoting IκBα-S32 and p65-S536 phosphorylation. Consequently, phosphorylated IκBα promotes nuclear translocation of p50/p65 and p65, as a transcription factor, can bind vascular endothelial growth factor-C and bcl-2 promoters, enhancing angiogenesis and inhibiting apoptosis in vitro. Moreover, xenograft tumors in nude mice proved that PLCE1 can induce angiogenesis, inhibit apoptosis, and increase tumor aggressiveness via the NF-κB signaling pathway in vivo. Our findings not only provide evidence that hypomethylation-induced PLCE1 confers angiogenesis and proliferation in ESCC by activating PI-PLCe-NF-κB signaling pathway and VEGF-C/Bcl-2 expression, but also suggest that modulation of PLCE1 by epigenetic modification or a selective inhibitor may be a promising therapeutic approach for the treatment of ESCC.
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Epigenetically upregulated oncoprotein PLCE1 drives esophageal carcinoma angiogenesis and proliferation via activating the PI-PLCε-NF-κB signaling pathway and VEGF-C/ Bcl-2 expression
BMC, 2019Co-Authors: Yunzhao Chen, Dandan Wang, Hao Peng, Xi Chen, Xueping Han, Wenjie Wang, Lirong Liang, Zheng Liu, Yi ZhengAbstract:Abstract Background Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies. Neovascularization during tumorigenesis supplies oxygen and nutrients to proliferative tumor cells, and serves as a conduit for migration. Targeting oncogenes involved in angiogenesis is needed to treat organ-confined and locally advanced ESCC. Although the phospholipase C epsilon-1 (PLCE1) gene was originally identified as a susceptibility gene for ESCC, how PLCE1 is involved in ESCC is unclear. Methods Matrix-assisted laser desorption ionization time-of-flight mass spectrometry were used to measure the methylation status of the PLCE1 promoter region. To validate the underlying mechanism for PLCE1 in constitutive activation of the NF-κB signaling pathway, we performed studies using in vitro and in vivo assays and samples from 368 formalin-fixed esophageal cancer tissues and 215 normal tissues with IHC using tissue microarrays and the Cancer Genome Atlas dataset. Results We report that hypomethylation-associated up-regulation of PLCE1 expression was correlated with tumor angiogenesis and poor prognosis in ESCC cohorts. PLCE1 can activate NF-κB through phosphoinositide-phospholipase C-ε (PI-PLCε) signaling pathway. Furthermore, PLCE1 can bind p65 and IκBα proteins, promoting IκBα-S32 and p65-S536 phosphorylation. Consequently, phosphorylated IκBα promotes nuclear translocation of p50/p65 and p65, as a transcription factor, can bind vascular endothelial growth factor-C and bcl-2 promoters, enhancing angiogenesis and inhibiting apoptosis in vitro. Moreover, xenograft tumors in nude mice proved that PLCE1 can induce angiogenesis, inhibit apoptosis, and increase tumor aggressiveness via the NF-κB signaling pathway in vivo. Conclusions Our findings not only provide evidence that hypomethylation-induced PLCE1 confers angiogenesis and proliferation in ESCC by activating PI-PLCε-NF-κB signaling pathway and VEGF-C/Bcl-2 expression, but also suggest that modulation of PLCE1 by epigenetic modification or a selective inhibitor may be a promising therapeutic approach for the treatment of ESCC
Adam Mor - One of the best experts on this subject based on the ideXlab platform.
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PLCε1 suppresses tumor growth by regulating murine T cell mobilization.
Clinical and experimental immunology, 2020Co-Authors: Marianne Strazza, Alan V. Smrcka, Kieran Adam, Shalom Lerrer, Adam MorAbstract:Phospholipase C epsilon 1 (PLCE1) is a unique member of the phospholipase family, in that it also functions as a guanine nucleotide exchange factor (GEF) for the small GTPase Rap1. It is this function as a Rap1 GEF that gives PLCE1 an essential role in chemokine-mediated T cell adhesion. We have utilized a syngeneic tumor model, MC38 cells in C57BL/6 mice, and observed that tumors grow larger and more quickly in the absence of PLCE1. Single-cell analysis revealed an increased CD4+ /CD8+ ratio in the spleens, lymph nodes and tumors of PLCE1 knock-out tumor-bearing mice. T cells isolated from PLCE1 knock-out mice were less activated by multiple phenotypical parameters than those from wild-type mice. We additionally noted a decrease in expression of the chemokine receptors C-X-C chemokine receptor type 4 (CXCR4) and C-C motif chemokine receptor 4 (CCR4) on CD4+ T cells from the spleens, lymph nodes and tumors of PLCE1 knock-out mice compared to wild-type mice, and diminished migration of PLCE1-depleted CD3+ T cells towards stromal cell-derived factor (SDF)-1α. Based on these results, we conclude that PLCE1 is a potential regulator of tumor-infiltrating lymphocytes, functioning, at least in part, at the level of T cell trafficking and recruitment.
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PLCE1 suppresses tumor growth by regulating murine t cell mobilization
Clinical and Experimental Immunology, 2020Co-Authors: Marianne Strazza, Alan V. Smrcka, Kieran Adam, Shalom Lerrer, Adam MorAbstract:Phospholipase C epsilon 1 (PLCE1) is a unique member of the phospholipase family, in that it also functions as a guanine nucleotide exchange factor (GEF) for the small GTPase Rap1. It is this function as a Rap1 GEF that gives PLCE1 an essential role in chemokine-mediated T cell adhesion. We have utilized a syngeneic tumor model, MC38 cells in C57BL/6 mice, and observed that tumors grow larger and more quickly in the absence of PLCE1. Single-cell analysis revealed an increased CD4+ /CD8+ ratio in the spleens, lymph nodes and tumors of PLCE1 knock-out tumor-bearing mice. T cells isolated from PLCE1 knock-out mice were less activated by multiple phenotypical parameters than those from wild-type mice. We additionally noted a decrease in expression of the chemokine receptors C-X-C chemokine receptor type 4 (CXCR4) and C-C motif chemokine receptor 4 (CCR4) on CD4+ T cells from the spleens, lymph nodes and tumors of PLCE1 knock-out mice compared to wild-type mice, and diminished migration of PLCE1-depleted CD3+ T cells towards stromal cell-derived factor (SDF)-1α. Based on these results, we conclude that PLCE1 is a potential regulator of tumor-infiltrating lymphocytes, functioning, at least in part, at the level of T cell trafficking and recruitment.
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PLCE1 regulates sdf 1α induced lymphocyte adhesion and migration to sites of inflammation
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Marianne Strazza, Alan V. Smrcka, Inbar Azoulayalfaguter, Michael Peled, Edward Y Skolnik, Shekhar Srivastava, Adam MorAbstract:Regulation of integrins is critical for lymphocyte adhesion to endothelium and migration throughout the body. Inside-out signaling to integrins is mediated by the small GTPase Ras-proximate-1 (Rap1). Using an RNA-mediated interference screen, we identified phospholipase Ce 1 (PLCE1) as a crucial regulator of stromal cell-derived factor 1 alpha (SDF-1α)-induced Rap1 activation. We have shown that SDF-1α-induced activation of Rap1 is transient in comparison with the sustained level following cross-linking of the antigen receptor. We identified that PLCE1 was necessary for SDF-1α-induced adhesion using shear stress, cell morphology alterations, and crawling on intercellular adhesion molecule 1 (ICAM-1)-expressing cells. Structure-function experiments to separate the dual-enzymatic function of PLCE1 uncover necessary contributions of the CDC25, Pleckstrin homology, and Ras-associating domains, but not phospholipase activity, to this pathway. In the mouse model of delayed type hypersensitivity, we have shown an essential role for PLCE1 in T-cell migration to inflamed skin, but not for cytokine secretion and proliferation in regional lymph nodes. Our results reveal a signaling pathway where SDF-1α induces T-cell adhesion through activation of PLCE1, suggesting that PLCE1 is a specific potential target in treating conditions involving migration of T cells to inflamed organs.
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PLCε1 regulates SDF-1α–induced lymphocyte adhesion and migration to sites of inflammation
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Marianne Strazza, Alan V. Smrcka, Michael Peled, Edward Y Skolnik, Shekhar Srivastava, Inbar Azoulay-alfaguter, Adam MorAbstract:Regulation of integrins is critical for lymphocyte adhesion to endothelium and migration throughout the body. Inside-out signaling to integrins is mediated by the small GTPase Ras-proximate-1 (Rap1). Using an RNA-mediated interference screen, we identified phospholipase Ce 1 (PLCE1) as a crucial regulator of stromal cell-derived factor 1 alpha (SDF-1α)-induced Rap1 activation. We have shown that SDF-1α-induced activation of Rap1 is transient in comparison with the sustained level following cross-linking of the antigen receptor. We identified that PLCE1 was necessary for SDF-1α-induced adhesion using shear stress, cell morphology alterations, and crawling on intercellular adhesion molecule 1 (ICAM-1)-expressing cells. Structure-function experiments to separate the dual-enzymatic function of PLCE1 uncover necessary contributions of the CDC25, Pleckstrin homology, and Ras-associating domains, but not phospholipase activity, to this pathway. In the mouse model of delayed type hypersensitivity, we have shown an essential role for PLCE1 in T-cell migration to inflamed skin, but not for cytokine secretion and proliferation in regional lymph nodes. Our results reveal a signaling pathway where SDF-1α induces T-cell adhesion through activation of PLCE1, suggesting that PLCE1 is a specific potential target in treating conditions involving migration of T cells to inflamed organs.
Xiaobin Cui - One of the best experts on this subject based on the ideXlab platform.
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Identification of a PLCE1‑regulated competing endogenous RNA regulatory network for esophageal squamous cell carcinoma
Oncology reports, 2021Co-Authors: Zhihao Yang, Hao Peng, Yi Hui, Hongpan Zhang, Lingxie Song, Xiaobin CuiAbstract:Phospholipase C epsilon 1 (PLCE1) and the competing endogenous RNA (ceRNA) network are crucial for tumorigenesis and the progression of esophageal squamous cell carcinoma (ESCC). However, whether PLCE1 can regulate the ceRNA network in ESCC has not been clarified. In the present study, we aimed to identify the PLCE1‑regulated ceRNA network and further elucidate the regulatory mechanisms by which ESCC is promoted. Microarray analysis was used to identify differentially expressed lncRNAs (DELs) and differentially expressed genes (DEGs) from three pairs of samples of PLCE‑silenced Eca109 and control Eca109 cells. Next, the ceRNA regulatory network was established and visualized in Cytoscape, and functional enrichment analysis was performed to analyze DEGs from ceRNAs. Protein‑protein interaction (PPI) networks among the DEGs were established by the STRING database to screen hub genes. Kaplan‑Meier survival analysis was used to validate hub genes. Finally, PLCE1‑related hub gene/lncRNA/miRNA axes were also constructed based on the ceRNA network. A total of 105 DELs and 346 DEGs were found to be dysregulated in the microarray data (|log2FC| >1.5, adjusted P
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identification of a PLCE1 regulated competing endogenous rna regulatory network for esophageal squamous cell carcinoma
Oncology Reports, 2021Co-Authors: Zhihao Yang, Hao Peng, Yi Hui, Hongpan Zhang, Lingxie Song, Xiaobin CuiAbstract:Phospholipase C epsilon 1 (PLCE1) and the competing endogenous RNA (ceRNA) network are crucial for tumorigenesis and the progression of esophageal squamous cell carcinoma (ESCC). However, whether PLCE1 can regulate the ceRNA network in ESCC has not been clarified. In the present study, we aimed to identify the PLCE1‑regulated ceRNA network and further elucidate the regulatory mechanisms by which ESCC is promoted. Microarray analysis was used to identify differentially expressed lncRNAs (DELs) and differentially expressed genes (DEGs) from three pairs of samples of PLCE‑silenced Eca109 and control Eca109 cells. Next, the ceRNA regulatory network was established and visualized in Cytoscape, and functional enrichment analysis was performed to analyze DEGs from ceRNAs. Protein‑protein interaction (PPI) networks among the DEGs were established by the STRING database to screen hub genes. Kaplan‑Meier survival analysis was used to validate hub genes. Finally, PLCE1‑related hub gene/lncRNA/miRNA axes were also constructed based on the ceRNA network. A total of 105 DELs and 346 DEGs were found to be dysregulated in the microarray data (|log2FC| >1.5, adjusted P<0.05). We constructed a PLCE1‑regulated ceRNA network that incorporated 12 lncRNAs, 43 miRNAs, and 169 mRNAs. Functional enrichment analysis indicated that the DEGs might be associated with ESCC onset and development. A PPI network was established, and 9 hub genes [WD and tetratricopeptide repeats 1 (WDTC1), heat shock protein family A (Hsp70) member 5 (HSPA5), N‑ethylmaleimide sensitive factor, vesicle fusing ATPase (NSF), fibroblast growth factor 2 (FGF2), cyclin dependent kinase inhibitor 1A (CDKN1A or P21), bone morphogenetic protein 2 (BMP2), complement C3 (C3), GM2 ganglioside activator (GM2A) and discs large MAGUK scaffold protein 4 (DLG4)] were determined from the network. Kaplan‑Meier survival analysis validated four hub genes (BMP2, CDKN1A, GM2A, and DLG4) that were treated as prognostic factors. Ultimately, hub gene/lncRNA/miRNA subnetworks were obtained based on the 4 hub genes, 13 DEmiRNAs, and 10 DELs. In conclusion, the PLCE1‑regulated ceRNA contributes to the onset and progression of ESCC and the underlying molecular mechanisms may provide insights into personalized prognosis and new therapies for ESCC patients.
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MicroRNA-34a functions as a tumor suppressor by directly targeting oncogenic PLCE1 in Kazakh esophageal squamous cell carcinoma
Oncotarget, 2017Co-Authors: Xiaobin Cui, Hao Peng, Chunxia Liu, Lan Yang, Yutao WeiAbstract:Esophageal squamous cell carcinoma (ESCC) is one of the frequent malignant tumors with poor prognosis worldwide. Identifying the prognostic biomarkers and potential mechanisms of such tumors has attracted increasing interest in esophageal cancer biology. Our previous study showed that phospholipase C elipson 1 (PLCE1) expression is up-regulated and associated with disease progression in esophageal carcinoma. MicroRNAs (miRNAs) play vital roles in regulating its target gene expression. However, studies on miRNA-regulated PLCE1 expression and its cellular function are still very few. We found that miR-34a is significantly expressed lower in ESCC tissues. We further showed that PLCE1 is a direct functional target gene of miR-34a, and the functional roles of miR-34a in ESCC cell lines in vitro were also determined through gain- and loss-of-function analyses. Results revealed that miR-34a functions as a tumor suppressor by inhibiting the proliferation, migration, and EMT phenotype, as well as promoting apoptosis of ESCC cell lines. Moreover, PLCE1 is overexpressed in ESCC tumors and promotes tumorigenicity in vivo and vitro. PLCE1 expression is negatively correlated with miR-34a profiles in ESCC tissues. Our data suggest that miR-34a exerts its anti-cancer function by suppressing PLCE1. The newly identified miR-34a/PLCE1 axis partially illustrates the molecular mechanism of ESCC metastasis and represents a new candidate therapeutic target for ESCC treatment.
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Comprehensive bioinformatics analysis of the mRNA profile of PLCE1 knockdown in esophageal squamous cell carcinoma
Molecular medicine reports, 2017Co-Authors: Xiaobin Cui, Hao Peng, Huahua Xin, Yunzhao ChenAbstract:The authors previously reported that Phospholipase C epsilon 1 (PLCE1) exacerbated esophageal squamous cell carcinoma (ESCC), however, the underlying mechanism remains to be fully elucidated. The present study aimed to identify key differentially expressed genes (DEGs) and signaling pathways regulated by PLCE1 in ESCC. EC9706 and Eca109 cell lines were transfected with the specific small interfering (si) RNA of PLCE1, reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blotting were performed to detect the expression levels of PLCE1, and subsequently, mRNA array and multiple bioinformatics analysis were conducted. RT‑qPCR was used to verify gene expression array results. The findings of the present study indicated that PLCE1 mRNA and protein expression were significantly suppressed (P 2‑fold alterations were screened between the PLCE1 siRNA‑treated cells, including 168 upregulated and 53 downregulated DEGs. In particular, inflammation or immune‑associated molecules, including Toll‑like receptor (TLR)‑4 interleukin‑6, ‑8 and chemokine C‑X‑C motif ligand 2 were significantly increased following PLCE1 knockdown. Furthermore, Gene Ontology enrichment revealed terms associated with cell proliferation, differentiation, apoptosis, signal transduction, invasion and metastasis, which may potentially be associated with PLCE1 function. Kyoto Encyclopedia of Genes and Genomes pathway analysis demonstrated 46 pathways were disturbed by DEGs, including focal adhesion, mitogen activated protein kinase, TLR, p53 and janus kinase/signal transducer and activator of transcription signaling pathways. The RT‑qPCR results for validation of the selected DEGs were consistent with that of the microarray data. Overall, the results of the multiple bioinformatic analysis contributes to a systematic understanding of the roles of PLCE1 in ESCC.
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Targeting oncogenic PLCE1 by miR-145 impairs tumor proliferation and metastasis of esophageal squamous cell carcinoma.
Oncotarget, 2015Co-Authors: Xiaobin Cui, Hao Peng, Ting-ting Jin, Shu-mao Zhang, Chunxia Liu, Lan Yang, Yao-yuan ShenAbstract:Phospholipase C epsilon 1 (PLCE1) is a susceptibility gene in esophageal squamous cell carcinoma (ESCC). Nevertheless, the role of PLCE1 in ESCC tumorigenesis has not been elucidated. In this study, we determined the function of PLCE1 and its regulatory microRNA (miRNA) in ESCC. PLCE1 protein was excessively expressed in ESCC and precancerous lesions compared with that in normal tissues. High PLCE1 expression levels in ESCC were significantly linked with poor overall survival. Knockdown of PLCE1 promoted the apoptosis, cytokine-induced apoptosis, and sensitivity of cancer cells to chemotherapeutic drugs but abrogated the proliferation and EMT phenotype of ESCC in vitro. Notably, miR-145 was newly identified as a potent repressor of PLCE1 expression by directly targeting the 3'UTR of PLCE1. MiR-145 also inhibited cell proliferation, migration, and metastasis, as well as controlled the cytoskeleton dynamics of esophageal cancer. Moreover, miR-145 was expressed at low levels in a large cohort of patients with ESCC and was inversely correlated with PLCE1 protein expression in cancer cells and tissues. These findings demonstrate that PLCE1 functions as tumor promoter in ESCC and can be suppressed by miR-145 through inhibition of PLCE1 translation. Hence, delivery of PLCE1-targeting miR-145 is a potential therapeutic approach for esophageal cancer.
Michelle Hall - One of the best experts on this subject based on the ideXlab platform.
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Mutational analysis of the PLCE1 gene in steroid resistant nephrotic syndrome.
Journal of Medical Genetics, 2010Co-Authors: Olivia Boyer, Genevieve Benoit, Fabien Nevo, Olivier Gribouval, Audrey Pawtowski, Ilmay Bilge, Zelal Bircan, Georges Deschênes, Lisa Guay-woodford, Michelle HallAbstract:BACKGROUND: Mutations in the PLCE1 gene encoding phospholipase C epsilon 1 (PLCepsilon1) have been recently described in patients with early onset nephrotic syndrome (NS) and diffuse mesangial sclerosis (DMS). In addition, two cases of PLCE1 mutations associated with focal segmental glomerulosclerosis (FSGS) and later NS onset have been reported. METHOD: In order to better assess the spectrum of phenotypes associated with PLCE1 mutations, mutational analysis was performed in a worldwide cohort of 139 patients (95 familial cases belonging to 68 families and 44 sporadic cases) with steroid resistant NS presenting at a median age of 23.0 months (range 0-373). RESULTS: Homozygous or compound heterozygous mutations were identified in 33% (8/24) of DMS cases. PLCE1 mutations were found in 8% (6/78) of FSGS cases without NPHS2 mutations. Nine were novel mutations. No clear genotype-phenotype correlation was observed, with either truncating or missense mutations detected in both DMS and FSGS, and leading to a similar renal evolution. Surprisingly, three unaffected and unrelated individuals were also found to carry the homozygous mutations identified in their respective families. CONCLUSION: PLCE1 is a major gene of DMS and is mutated in a non-negligible proportion of FSGS cases without NPHS2 mutations. Although additional variants in 19 candidate genes (16 other PLC genes, BRAF,IQGAP1 and NPHS1) were not identified, it is speculated that other modifier genes or environmental factors may play a role in the renal phenotype variability observed in individuals bearing PLCE1 mutations. This observation needs to be considered in the genetic counselling offered to patients.
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Mutational analysis of the PLCE1 gene in steroid-resistant nephrotic syndrome
Journal of Medical Genetics, 2010Co-Authors: Olivia Boyer, Genevieve Benoit, Fabien Nevo, Olivier Gribouval, Audrey Pawtowski, Ilmay Bilge, Zelal Bircan, Georges Deschênes, Lisa Guay-woodford, Michelle HallAbstract:Background: Mutations in the PLCE1 gene encoding phospholipase C epsilon 1 (PLCε1) have been recently described in patients with early-onset nephrotic syndrome (NS) and diffuse mesangial sclerosis (DMS). In addition, two cases of PLCE1 mutations associated with focal segmental glomerulosclerosis (FSGS) and later NS onset have been reported. Methods: In order to better assess the spectrum of phenotypes associated with PLCE1 mutations, we performed mutational analysis in a worldwide cohort of 139 patients (95 familial cases belonging to 68 families and 44 sporadic cases) with steroid-resistant NS presenting at a median age of 23.0 months (range 0-373). Results: We identified homozygous or compound heterozygous mutations in 33% (8/24) of DMS cases. PLCE1 mutations were found in 8% (6/78) of FSGS cases without NPHS2 mutations. Nine were novel mutations. No clear genotype-phenotype correlation was observed, with either truncating or missense mutations detected in both DMS and FSGS, and leading to a similar renal evolution. Surprisingly, 3 unaffected and unrelated individuals were also found to carry the homozygous mutations identified in their respective families. Conclusion: PLCE1 is a major gene of DMS and is mutated in a non-negligible proportion of FSGS cases without NPHS2 mutations. Although we did not identify additional variants in 19 candidate genes (16 other PLC genes, BRAF, IQGAP1 and NPHS1), we speculate that other modifier genes or environmental factors may play a role in the renal phenotype variability observed in individuals bearing PLCE1 mutations. This observation needs to be considered in the genetic counselling offered to patients.