Showing papers by "Xiaoxin Chen published in 2018"
TL;DR: It was showed that PAX9 was downregulated in human oro‐oesophageal squamous cell carcinoma (OESCC), and its downregulation was associated with alcohol drinking and promoter hypermethylation.
Abstract: PAX9 is a transcription factor of the PAX family characterized by a DNA-binding paired domain. Previous studies have suggested a potential role of PAX9 in squamous cell differentiation and carcinogenesis of the oro-oesophageal epithelium. However, its functional roles in differentiation and carcinogenesis remain unclear. In this study, Pax9 deficiency in mouse oesophagus promoted cell proliferation, delayed cell differentiation, and altered the global gene expression profile. Ethanol exposure downregulated PAX9 expression in human oesophageal epithelial cells in vitro and mouse forestomach and tongue in vivo. We further showed that PAX9 was downregulated in human oro-oesophageal squamous cell carcinoma (OESCC), and its downregulation was associated with alcohol drinking and promoter hypermethylation. Moreover, ad libitum feeding with a liquid diet containing ethanol for 40 weeks or Pax9 deficiency promoted N-nitrosomethylbenzylamine-induced squamous cell carcinogenesis in mouse tongue, oesophagus, and forestomach. In conclusion, PAX9 regulates squamous cell differentiation in the oro-oesophageal epithelium. Alcohol drinking and promoter hypermethylation are associated with PAX9 silencing in human OESCC. PAX9 downregulation may contribute to alcohol-associated oro-oesophageal squamous cell carcinogenesis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
27 citations
TL;DR: Identification and validation of Nrf2 inhibitors in esophageal squamous cell carcinoma through high-throughput screening and will test them in vitro and finally in vivo.
Abstract: Background: The Nrf2/Keap1 pathway is critical for human cells to respond to oxidative stress. In basal conditions the Keap1 homodimer is bound to Nrf2 in the cytoplasm. When stressed, Keap1 releases Nrf2 which translocates into the nucleus, binds the antioxidant response element, and activate antioxidative genes. Somatic mutations of Nrf2 or Keap1 gene can cause constitutive activation of this pathway, and thus results in chemoradioresistance and poor survival in patients with esophageal squamous cell carcinoma (ESCC). Our goal is to identify chemical Nrf2 inhibitors for targeted therapy of Nrf2high ESCC in the future. Methods: Possible Nrf2 inhibitors were identified using high throughput screening of 1,280 compounds in the Prestwick library, and 35,000 compounds in the Asinex library with Nqo1-EGFP H1299 cells stimulated by an Nrf2 activator (CDDO). Nrf2 activity was monitored via Incucyte by measuring the total normalized green fluorescence divided by the total normalized red fluorescence (tagged nuclear cherry marker). The red channel assessed cell viability and cytotoxicity of compounds. Inhibitors were identified if they met a threshold of >50% inhibition. Lead compounds will be further validated in vitro with KYSE 450 (Nrf2low+Keap1 knockdown) and KYSE 70 (Nrf2high) by examining their effects on expression of nuclear Nrf2 and its downstream target gene (Nqo1). These compounds will also be validated in vivo using Sox2CreER;Nrf2Ki/Ki mice. Results: We successfully established the in vitro assay with Nqo1-EGFP H1299 cells for high throughput screening of Nrf2 inhibitors. Eight lead compounds were identified from the Prestwick library and validated as Nrf2 inhibitors via a dose-response experiment (IC50 Conclusion: We have identified Nrf2 inhibitors through high-throughput screening and will test them in vitro and finally in vivo. Citation Format: Seth Weir, Xiaoxin Chen, Chorlada Paiboonrungruan. Identification and validation of Nrf2 inhibitors in esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5856.
1 citations