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.

More and more evidences suggest that primary colon and rectum tumors should not be considered as a single disease entity. In this manuscript, we evaluate the metastatic patterns of colon and rectum cancers and analyze the potential distribution of metastatic disease in these two malignancies. Data queried for this analysis include colorectal adenocarcinoma (2010-2011) from the Surveillance, Epidemiology, and End Results Program (SEER) database. Metastatic distribution information was provided for liver, lung, bone and brain. All of statistical analyses were performed using the Intercooled Stata 13.0 (Stata Corporation, College Station, TX). All statistical tests were two-sided. Totally, there were 46,027 eligible patients for analysis. We found that colon cancer had a higher incident rate of liver metastasis than rectum cancer (13.8% vs 12.3%), while rectum cancer had a higher incident rate of lung (5.6% vs 3.7%) and bone (1.2% vs 0.8%) metastasis than colon cancer, P<0.001. Colorectal cancer patients with lung metastasis had a higher risk of bone (10.0% vs 4.5%) or brain metastasis (3.1% vs 0.1%) than patients without lung metastases. The 1-year cause-specific survival was not significant different for bone or brain metastasis patients with and without lung metastasis (32.9% vs 38.7%, P=0.3834 for bone, 25.8% vs 36.9%, P=0.6819 for brain). Knowledge of these differences in metastatic patterns may help to better guide pre-treatment evaluation of colorectal cancer patients, especially in making determinations regarding curative-intent interventions.

Invasion and metastasis are the major causes of death in patients with esophageal squamous cell carcinoma (ESCC). Epithelial-mesenchymal transition (EMT) is a critical step in tumor progression and transforming growth factor-β1 (TGF-β1) signaling has been shown to play an important role in EMT. In this study, we investigated how TGF-β1 signaling pathways contributed to EMT in three ESCC cell lines as well as 100 patients of nomadic ethnic Kazakhs residing in northwest Xinjiang Province of China. In vitro analyses included Western blotting to detect the expression of TGF-β1/Smad and EMT-associated proteins in Eca109, EC9706 and KYSE150 cell lines following stimulation with recombinant TGF-β1 and SB431542, a potent inhibitor of ALK5 that also inhibits TGF-β type II receptor. TGF-β-activated Smad2/3 signaling in EMT was significantly upregulated as indicated by mesenchymal markers of N-cadherin and Vimentin, and in the meantime, epithelial marker, E-cadherin, was markedly downregulated. In contrast, SB431542 addition downregulated the expression of N-cadherin and Vimentin, but upregulated the expression of E-cadherin. Moreover, the TGF-β1-induced EMT promoted invasion capability of Eca109 cells. Tumor cells undergoing EMT acquire fibroblastoid-like phenotype. Expressed levels of TGF-β1/Smad signaling molecules and EMT-associated proteins were examined using immunohistochemical analyses in 100 ESCC tissues of Kazakh patients and 58 matched noncancerous adjacent tissues. The results showed that ESCC tissues exhibited upregulated expression of TGF-β1/Smad. We also analyzed the relationship between the above proteins and the patients' clinicopathological characteristics. The TGF-β1/Smad signaling pathway in human Eca109 ESCC cells may carry similar features as in Kazakh ESCC patients, suggesting that TGF-β1/Smad signaling pathway may be involved in the regulation of EMT in ethnic Kazakh patients with ESCC from Xinjiang, China.

Nucleus accumbens-associated protein-1 (NAC1), a nuclear factor of the BTB/POZ gene family, has emerging roles in cancer. In this study, we identified the NAC1-HDAC4-HIF-1α axis as an important pathway in regulating glycolysis and hypoxic adaptation in tumor cells. We show that nuclear NAC1 binds to histone deacetylase type 4 (HDAC4), hindering phosphorylation of HDAC4 at Ser246 and preventing its nuclear export that leads to cytoplasmic degradation of the deacetylase. Accumulation of HDAC4 in the nuclei results in an attenuation of HIF-1α acetylation, enhancing the stabilization and transcriptional activity of HIF-1α and strengthening adaptive response of cells to hypoxia. We also show the role of NAC1 in promoting glycolysis in a mouse xenograft model, and demonstrate that knockdown of NAC1 expression can reinforce the antitumor efficacy of bevacizumab, an inhibitor of angiogenesis. Clinical implication of the NAC1-HDAC4-HIF-1α pathway is suggested by the results showing that expression levels of these proteins are significantly correlative in human tumor specimens and associated with the disease progression. This study not only reveals an important function of NAC1 in regulating glycolysis, but also identifies the NAC1-HDAC4-HIF-1α axis as a novel molecular pathway that promotes survival of hypoxic tumor cells.

Background:Solid fuels are widely used in China. Household air pollution from the burning of solid fuels may increase the risk of chronic obstructive pulmonary disease (COPD), but prospective evidence is limited.Objectives:We examined the association of solid fuel use for cooking and heating with the risk of COPD in a prospective cohort study.Methods:Participants were from the China Kadoorie Biobank. Current and previous fuels used for household cooking and heating were self-reported at baseline in 2004–2008. In the present study, “solid fuels” refers to coal and wood, whereas “cleaner fuels” refers to energy sources that presumably produce lower levels of indoor pollution, including electricity, gas, and central heating. A total of 475,827 adults 30–79 y of age without prevalent COPD were followed through the end of 2015. We used adjusted Cox regression models to estimate hazard ratios for COPD.Results:Over 9.1 y of follow-up, 9,835 incident COPD cases were reported. Compared with the use of cleaner fuels for cooking, using coal and wood for cooking was positively associated with COPD, with fully adjusted HRs of 1.06 (95% CI: 0.98, 1.15) and 1.14 (95% CI: 1.06, 1.23), respectively. Adjusted HRs for heating with coal and wood were 1.16 (95% CI: 1.04, 1.29) and 1.21 (95% CI: 1.09, 1.35), respectively. The positive association between cooking with solid fuel and COPD appeared to be limited to women and never- (vs. ever-) smokers. COPD risk increased with a higher number of years of solid fuel use for heating and wood use for cooking.Conclusions:The use of solid fuel for cooking and heating was associated with the increased risk of COPD in this prospective cohort study. Studies with more accurate exposure assessment are needed to confirm the association. https://doi.org/10.1289/EHP2856