Pioglitazone-mediated reversal of elevated glucose metabolism in the airway epithelium of mouse lung adenocarcinomas.
Pioglitazone-mediated reversal of elevated glucose metabolism in the airway epithelium of mouse lung adenocarcinomas.
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DOI：
10.1172/jci.insight.94220
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发表时间：
2017-07
期刊：
影响因子：
8
通讯作者：
Donghai Xiong;Jing Pan;Qi Zhang;E. Szabo;M. S. Miller;R. Lubet;Yian Wang;M. You
中科院分区：
文献类型：
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作者：
Donghai Xiong;Jing Pan;Qi Zhang;E. Szabo;M. S. Miller;R. Lubet;Yian Wang;M. You
气道上皮细胞容易受到肺癌危险因素（如吸烟）的损害。支气管气道上皮中的替代生物标志物可用于评估潜在的化学预防药物对肺腺癌形成/进展的影响，但对此知之甚少。吡格列酮已被建议作为肺癌的化学预防药物。为了研究吡格列酮在肺癌预防中的潜在作用机制，我们进行了转录组测序（RNA-Seq），发现吡格列酮治疗肺腺癌小鼠气道上皮细胞（FDR q = 9.8E-04）抑制了Kras信号传导。还发现，在肺腺癌小鼠的气道上皮中葡萄糖代谢途径升高，并被吡格列酮治疗抑制（FDR q = 0.01）。在吡格列酮治疗的小鼠肺肿瘤中也观察到葡萄糖代谢基因的下调。在多发性肺腺癌患者人群中，葡萄糖代谢升高的高危表达特征与不良生存结局相关（P值范围为1.0E-9至5.5E-5）。我们的研究结果表明，吡格列酮在预防肺腺癌的作用可能取决于抑制Kras信号和葡萄糖代谢，这可能是代理商在气道上皮细胞的作用的生物标志物。
Airway epithelial cells are prone to the damage caused by lung cancer risk factors, such as cigarette smoking. Little is known about surrogate biomarkers in the bronchial airway epithelium that can be used to assess the effect of potential chemoprevention drugs on lung adenocarcinoma formation/progression. Pioglitazone has been suggested as a chemoprevention drug for lung cancer. To study the mechanisms underlying the role of pioglitazone in lung cancer prevention, we performed transcriptome sequencing (RNA-Seq) and found that Kras signaling was repressed by pioglitazone treatment in the airway epithelial cells of mice with lung adenocarcinoma (FDR q = 9.8E-04). It was also found that glucose metabolic pathways were elevated in the airway epithelium of mice with lung adenocarcinomas and inhibited by pioglitazone treatment (FDR q = 0.01). Downregulation of glucose metabolism genes was also observed in lung tumors of mice treated with pioglitazone. The high-risk expression signature of elevated glucose metabolism was associated with poor survival outcome in multiple lung adenocarcinoma patient populations (P values ranging from 1.0E-9 to 5.5E-5). Our results suggest that the role of pioglitazone in preventing lung adenocarcinoma may depend on inhibiting Kras signaling and glucose metabolism, which may serve as biomarkers of agent action in the airway epithelium.