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.
Purpose: We aimed to evaluate the value of deep learning on positron emission tomography with computed tomography (PET/CT)-based radiomics for individual induction chemotherapy (IC) in advanced nasopharyngeal carcinoma (NPC). Experimental Design: We constructed radiomics signatures and nomogram for predicting disease-free survival (DFS) based on the extracted features from PET and CT images in a training set (n ¼ 470), and then validated it on a test set (n ¼ 237). Harrell's concordance indices (C-index) and time-independent receiver operating characteristic (ROC) analysis were applied to evaluate the discriminatory ability of radiomics nomogram, and compare radiomics signatures with plasma Epstein-Barr virus (EBV) DNA. Results: A total of 18 features were selected to construct CT-based and PET-based signatures, which were significantly associated with DFS (P < 0.001). Using these signatures , we proposed a radiomics nomogram with a C-index of 0.754 [95% confidence interval (95% CI), 0.709-0.800] in the training set and 0.722 (95% CI, 0.652-0.792) in the test set. Consequently, 206 (29.1%) patients were stratified as high-risk group and the other 501 (70.9%) as low-risk group by the radiomics nomogram, and the corresponding 5-year DFS rates were 50.1% and 87.6%, respectively (P < 0.0001). High-risk patients could benefit from IC while the low-risk could not. Moreover, radiomics nomogram performed significantly better than the EBV DNA-based model (C-index: 0.754 vs. 0.675 in the training set and 0.722 vs. 0.671 in the test set) in risk stratification and guiding IC. Conclusions: Deep learning PET/CT-based radiomics could serve as a reliable and powerful tool for prognosis prediction and may act as a potential indicator for individual IC in advanced NPC.
The prognostic value of plasma Epstein-Barr virus (EBV) DNA remains unknown in nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT). We retrospectively reviewed medical records of 584 newly diagnosed patients with nonmetastatic and biopsy-proven NPC treated using IMRT. Plasma EBV DNA concentration was measured before therapy (pre-DNA) and within 1 month of completing therapy (post-DNA) using real-time quantitative polymerase chain reaction. Receiver operating characteristic (ROC) curves were generated to identify pre-DNA and post-DNA cut-off values. Prognostic value was assessed using a multivariate Cox proportional hazards model .Three-year disease-free survival (DFS), overall survival (OS), loco-regional relapse-free survival (LRRFS) and distant metastasis-free (DMFS) for pre-DNA >2010 vs.≤2010 were 78.1% vs. 93.6% (P < 0.001), 92.3% vs. 98.9% (P < 0.001), 90.9% vs. 96.6% (P = 0.004) and 85.5% vs. 96.6% (P < 0.001), respectively. Three-year DFS, OS, LRRFS and DMFS for post-DNA >0 vs. = 0 were 49.9% vs. 88.5% (P < 0.001), 72.1% vs. 97.5% (P < 0.001), 86.6% vs. 94.3% (P = 0.019), and 60.5% vs. 93.3% (P < 0.001), respectively. Plasma EBV DNA remains a prognostic factor in IMRT era and should be incorporated into TNM staging to guide individualized treatment strategies in NPC.
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