In 2017, an estimated 17,000 individuals were diagnosed with esophageal adenocarcinoma (EAC), and less than 20% will survive 5 years. Positron emission tomography avidity is indicative of high glucose utilization and is nearly universal in EAC. TXNIP blocks glucose uptake and exhibits proapoptotic functions. Higher expression in EAC has been associated with improved disease-specific survival, lack of lymph node involvement, reduced perineural invasion, and increased tumor differentiation. We hypothesized that TXNIP may act as a tumor suppressor that sensitizes EAC cells to standard chemotherapeutics. EAC cell lines and a Barrett epithelial cell line were used. qRT-PCR, immunoblot, and immunofluorescence techniques evaluated gene expression. TXNIP was stably overexpressed or knocked down using lentiviral RNA transduction techniques. Murine xenograft methods examined growth following overexpression of TXNIP. Apoptosis and DNA damage were measured by annexin V and γH2AX assays. Activation of the intrinsic apoptosis was quantitated with green fluorescence protein-caspase 3 reporter assay. In cultured cells and an esophageal tissue array, TXNIP expression was higher in Barrett epithelia and normal tissue compared with EAC. Constitutive overexpression of TXNIP decreased proliferation, clonogenicity, and tumor xenograft growth. TXNIP overexpression increased, whereas knockdown abrogated, DNA damage and apoptosis following cisplatin treatment. An HDAC inhibitor, entinostat (currently in clinical trials), upregulated TXNIP and synergistically increased cisplatin-mediated DNA damage and apoptosis. TXNIP is a tumor suppressor that is downregulated in EACC. Its reexpression dramatically sensitizes these cells to cisplatin. Our findings support phase I/II evaluation of “priming” strategies to enhance the efficacy of conventional chemotherapeutics in EAC. Mol Cancer Ther; 17(9); 2013–23. ©2018 AACR.

中文翻译：

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组蛋白去乙酰化酶抑制剂恩替司他对硫氧还蛋白相互作用蛋白的诱导与食管腺癌中的 DNA 损伤和细胞凋亡有关

2017 年，估计有 17,000 人被诊断出患有食管腺癌 (EAC)，其中不到 20% 的人能存活 5 年。正电子发射断层扫描亲合力表明高葡萄糖利用率并且在 EAC 中几乎是普遍的。TXNIP 阻断葡萄糖摄取并表现出促凋亡功能。EAC 中的高表达与改善的疾病特异性存活率、无淋巴结受累、减少神经周围浸润和增加肿瘤分化有关。我们假设 TXNIP 可能充当肿瘤抑制因子，使 EAC 细胞对标准化疗药物敏感。使用了 EAC 细胞系和 Barrett 上皮细胞系。qRT-PCR、免疫印迹和免疫荧光技术评估了基因表达。使用慢病毒 RNA 转导技术，TXNIP 被稳定地过表达或击倒。鼠异种移植方法检查 TXNIP 过表达后的生长。通过膜联蛋白 V 和 γH2AX 测定法测量细胞凋亡和 DNA 损伤。用绿色荧光蛋白-半胱天冬酶 3 报告基因测定法对内在细胞凋亡的激活进行定量。在培养的细胞和食管组织阵列中，与 EAC 相比，TXNIP 在 Barrett 上皮和正常组织中的表达更高。TXNIP 的组成型过表达降低了增殖、克隆形成和肿瘤异种移植物的生长。顺铂治疗后，TXNIP 过表达增加，而敲低消除，DNA 损伤和细胞凋亡。HDAC 抑制剂恩替司他（目前处于临床试验阶段）上调 TXNIP 并协同增加顺铂介导的 DNA 损伤和细胞凋亡。TXNIP 是一种肿瘤抑制因子，在 EACC 中下调。它的重新表达使这些细胞对顺铂显着敏感。我们的研究结果支持对“启动”策略进行 I/II 期评估，以提高 EAC 中常规化疗药物的疗效。摩尔癌症治疗; 17(9); 2013-23。©2018 AACR。