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

Abstract

BackgroundEsophageal 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.MethodsMatrix-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.ResultsWe 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0930-x) contains supplementary material, which is available to authorized users.

BACH family members regulate angiogenesis and lymphangiogenesis by modulating VEGFC expression

“…In various human cancers, enhanced expression of VEGFC and higher levels of VEGFC in serum are commonly associated with tumor aggressiveness and lymph-node metastasis (Su et al, 2007;Lohela et al, 2009). In esophageal carcinoma, for instance, angiogenesis is driven via the phosphoinositide-phospholipase C-ε (PI-PLCε)/NF-κB signaling pathway by direct promotion of VEGFC transcription (Chen et al, 2019). In xenograft or transgenic tumor models, stimulation of lymphangiogenesis by VEGFC promotes malignant cell dissemination (Stacker et al, 2014).…”

lncRNA-PLACT1 sustains activation of NF-κB pathway through a positive feedback loop with IκBα/E2F1 axis in pancreatic cancer

“…Sustained activation of NF-κB signaling pathway is a common event in various cancers, including PDAC, and considered to be essential to cancer development. Chen et al showed that PLCE1 constitutively activated the NF-κB signaling pathway to drive esophageal carcinoma angiogenesis and proliferation [41]. Jeong et al reported that miR-196b/Meis2/PPP3CC axis sustained the activation of NF-κB signaling pathway to induce prostate cancer castration resistance [42].…”

miR-148a-3p inhibits DNMT1-mediated methylation of VEGF and promotes proliferation and invasion in glioma cells via the PI3K/Akt/eNOS signaling pathway

“…The high lethality rate of gliomas highlights the urgent need for e cient treatment. The pathogenesis of glioma is complex and can be induced by a variety of mechanisms, as shown by abnormal activation of glioma stem cells [28], tumor angiogenesis [29] and isocitrate dehydrogenase mutation [30]. VEGF acts as a regulator of angiogenesis has been widely recognized as a critical contributor to the development and progression of glioma [12,14].…”