Journal
MOLECULAR CANCER
Volume 18, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s12943-018-0930-x
Keywords
Esophageal carcinoma; PLCE1; NF-B; Angiogenesis; Proliferation
Categories
Funding
- National Natural Science Foundation of China [81460362, 81773116, 81760436, 81560399, 81860518, 81360358]
- medical and health science and technology project of Suzhou high tech Zone [2017Z006]
- international science and technology cooperation project of Shihezi University [GJHZ201702]
- Applied Basic Research Projects of Xinjiang Production and Construction Corps [2016AG020]
- Youth Science and Technology Innovation Leading Talents Project of Corps [2017CB004]
- Major science and technology projects of Shihezi University [gxjs2014-zdgg06]
- high-level talent project of Shihezi University [RCZX201533]
- Foundation for Distinguished Young Scholars of Shihezi University [2015ZRKXJQ02]
Ask authors/readers for more resources
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-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.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-B through phosphoinositide-phospholipase C-epsilon (PI-PLC epsilon) signaling pathway. Furthermore, PLCE1 can bind p65 and IB proteins, promoting IB-S32 and p65-S536 phosphorylation. Consequently, phosphorylated IB 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.ConclusionsOur findings not only provide evidence that hypomethylation-induced PLCE1 confers angiogenesis and proliferation in ESCC by activating PI-PLC epsilon-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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available