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Epigenetically upregulated oncoprotein PLCE1 drives esophageal carcinoma angiogenesis and proliferation via activating the PI-PLC?-NF-?B signaling pathway and VEGF-C/ Bcl-2 expression.

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-?B 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-?B through phosphoinositide-phospholipase C-? (PI-PLC?) signaling pathway. Furthermore, PLCE1 can bind p65 and I?B? proteins, promoting I?B?-S32 and p65-S536 phosphorylation. Consequently, phosphorylated I?B? 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-?B signaling pathway in vivo. CONCLUSIONS:Our findings not only provide evidence that hypomethylation-induced PLCE1 confers angiogenesis and proliferation in ESCC by activating PI-PLC?-NF-?B 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.

SUBMITTER: Chen Y

PROVIDER: S-EPMC6320601 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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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.

Chen Yunzhao Y Wang Dandan D Peng Hao H Chen Xi X Han Xueping X Yu Jie J Wang Wenjie W Liang Lirong L Liu Zheng Z Zheng Yi Y Hu Jianming J Yang Lan L Li Jun J Zhou Hong H Cui Xiaobin X Li Feng F

Molecular cancer 20190104 1

<h4>Background</h4>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. ...[more]

PMID: 30609930

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Project description:Transient receptor potential classical (or canonical) (TRPC)3, TRPC6, and TRPC7 are a subfamily of TRPC channels activated by diacylglycerol (DAG) produced through the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) by phospholipase C (PLC). PI(4,5)P2 depletion by a heterologously expressed phosphatase inhibits TRPC3, TRPC6, and TRPC7 activity independently of DAG; however, the physiological role of PI(4,5)P2 reduction on channel activity remains unclear. We used Förster resonance energy transfer (FRET) to measure PI(4,5)P2 or DAG dynamics concurrently with TRPC6 or TRPC7 currents after agonist stimulation of receptors that couple to Gq and thereby activate PLC. Measurements made at different levels of receptor activation revealed a correlation between the kinetics of PI(4,5)P2 reduction and those of receptor-operated TRPC6 and TRPC7 current activation and inactivation. In contrast, DAG production correlated with channel activation but not inactivation; moreover, the time course of channel inactivation was unchanged in protein kinase C-insensitive mutants. These results suggest that inactivation of receptor-operated TRPC currents is primarily mediated by the dissociation of PI(4,5)P2. We determined the functional dissociation constant of PI(4,5)P2 to TRPC channels using FRET of the PLC? Pleckstrin homology domain (PHd), which binds PI(4,5)P2, and used this constant to fit our experimental data to a model in which channel gating is controlled by PI(4,5)P2 and DAG. This model predicted similar FRET dynamics of the PHd to measured FRET in either human embryonic kidney cells or smooth muscle cells, whereas a model lacking PI(4,5)P2 regulation failed to reproduce the experimental data, confirming the inhibitory role of PI(4,5)P2 depletion on TRPC currents. Our model also explains various PLC-dependent characteristics of channel activity, including limitation of maximum open probability, shortening of the peak time, and the bell-shaped response of total current. In conclusion, our studies demonstrate a fundamental role for PI(4,5)P2 in regulating TRPC6 and TRPC7 activity triggered by PLC-coupled receptor stimulation.

Project description: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<0.05) in the PLCE1 siRNA‑transfected cells. In addition, a total of 223 DEGs with >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.

Dataset Information

Epigenetically upregulated oncoprotein PLCE1 drives esophageal carcinoma angiogenesis and proliferation via activating the PI-PLC?-NF-?B signaling pathway and VEGF-C/ Bcl-2 expression.

Publications

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.

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