Epigenetically upregulated oncoprotein PLCE1 drives esophageal carcinoma angiogenesis and proliferation via activating the PI-PLCε-NF-B signaling pathway and VEGF-C/ Bcl-2 expression
Epigenetically upregulated oncoprotein PLCE1 drives esophageal carcinoma angiogenesis and proliferation via activating the PI-PLCε-NF-B signaling pathway and VEGF-C/ Bcl-2 expression
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表观遗传上调的癌蛋白 PLCE1 通过激活 PI-PLC epsilon-NF-B 信号通路和 VEGF-C/Bcl-2 表达来驱动食管癌血管生成和增殖
DOI：
10.1186/s12943-018-0930-x
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发表时间：
2019-01-04
期刊：
影响因子：
37.3
通讯作者：
Li, Feng
中科院分区：
文献类型：
--
作者：
Chen, Yunzhao;Wang, Dandan;Li, Feng
研究背景食管鳞癌(ESCC)是一种致死率最高的恶性肿瘤。肿瘤发生过程中的新生血管为增殖的肿瘤细胞提供氧气和营养物质，并作为迁移的管道。靶向参与血管生成的癌基因是治疗器官受限和局部晚期ESCC所必需的。虽然磷脂酶C epsilon-1(PLCE1)基因最初被认为是ESCC的易感基因，但PLCE1在ESCC中的作用尚不清楚。方法采用基质辅助激光解吸电离飞行时间质谱仪检测PLCE1启动子区甲基化状态。为了验证PLCE1在NF-κB信号通路结构性激活中的作用机制，我们利用组织芯片和肿瘤基因组图谱，对36 8例福尔马林固定的食道癌组织和2 15例正常食管鳞癌组织进行了体内外检测和样本分析。PLCE1可通过磷脂酰肌醇-磷脂酶C-κ(PI-PLCε，PI-PLCε)信号通路激活NF-PLC B。此外，PLCE1还能结合p65和IκBα蛋白，促进IκBα-S32和p65-S536的磷酸化。因此，磷酸化的IκBα可以促进p50/p65的核转位，而p65作为一种转录因子，可以与血管内皮生长因子C和bcl2启动子结合，在体外促进血管生成和抑制细胞凋亡。结论低甲基化诱导的PLCE1通过激活PI-κ-ε-NF-κB信号通路和VEGFC/Bcl2的表达，促进食管癌的血管生成和增殖，并通过表观遗传修饰或选择性抑制物来调节PLCE1的表达，为食管癌的治疗提供了证据。
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.