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

• DOI: 10.1186/s12943-018-0930-x
• Publication Date: 2019-01-04T13:15:54Z
• Authors: Yunzhao Chen; Dandan Wang; Hao Peng; Xi Chen; Xueping Han; Jie Yu; Wenjie Wang; Lirong Liang; Zheng Liu; Yi Zheng; Jianming Hu; Lan Yang; Jun Li; Hong Zhou; Xiaobin Cui; Feng Li
• Keywords: Male; Esophageal Neoplasms; Proliferation; Mice, Nude; Apoptosis; NF-κB; Cell Line; Epigenesis, Genetic; Mice; 03 medical and health sciences; Phosphoinositide Phospholipase C; PLCE1; Cell Line, Tumor; Human Umbilical Vein Endothelial Cells; Animals; Humans; RC254-282; Cell Proliferation; 0303 health sciences; Neovascularization, Pathologic; Research; NF-kappa B; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Middle Aged; 3. Good health; Proto-Oncogene Proteins c-bcl-2; Esophageal carcinoma; Female; Angiogenesis; Esophageal Squamous Cell Carcinoma; Signal Transduction

Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies. Neovascularization during tumorigenesis supplies oxygen and nutrients to proliferative tumor cells, serves as a conduit for migration. Targeting oncogenes involved in angiogenesis needed treat organ-confined locally advanced ESCC. Although phospholipase C epsilon-1 (PLCE1) gene was originally identified susceptibility ESCC, how PLCE1 ESCC unclear. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry were used measure methylation status promoter region. To validate underlying mechanism constitutive activation NF-κB signaling pathway, we performed studies using vitro vivo assays samples from 368 formalin-fixed esophageal cancer tissues 215 normal with IHC tissue microarrays Cancer Genome Atlas dataset. We report that hypomethylation-associated up-regulation expression correlated poor prognosis cohorts. can activate through phosphoinositide-phospholipase C-ε (PI-PLCε) pathway. Furthermore, bind p65 IκBα proteins, promoting IκBα-S32 p65-S536 phosphorylation. Consequently, phosphorylated promotes nuclear translocation p50/p65 p65, transcription factor, vascular endothelial growth factor-C bcl-2 promoters, enhancing inhibiting apoptosis vitro. Moreover, xenograft tumors nude mice proved induce angiogenesis, inhibit apoptosis, increase aggressiveness via pathway vivo. Our findings not only provide evidence hypomethylation-induced confers proliferation by activating PI-PLCε-NF-κB VEGF-C/Bcl-2 expression, but also suggest modulation epigenetic modification or selective inhibitor may be promising therapeutic approach treatment