AKR1C1 controls cisplatin-resistance in head and neck squamous cell carcinoma through cross-talk with the STAT1/3 signaling pathway
AKR1C1 controls cisplatin-resistance in head and neck squamous cell carcinoma through cross-talk with the STAT1/3 signaling pathway
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DOI：
10.1186/s13046-019-1256-2
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发表时间：
2019-06-10
影响因子：
11.3
通讯作者：
Hsiao, Michael
中科院分区：
文献类型：
--
作者：
Chang, Wei-Min;Chang, Yu-Chan;Hsiao, Michael
背景顺铂是用于治疗大多数上呼吸消化道癌的一线化疗药物。在头颈癌中，对顺铂的敏感性仍然是治疗反应和结果的关键问题。遗传异质性和基因表达异常可能是引起原发性顺铂耐药的内在因素。方法结合公共数据库中HNSCC基因表达数据和顺铂敏感性结果。我们发现醛酮还原酶家族 1 成员 C1 (AKR1C1) 可能与 HNSCC 治疗初始细胞的顺铂敏感性相关。我们检查了患者中 AKR1C1 的表达及其与顺铂 IC50 和预后的相关性。体外和体内 AKR1C1 分别通过过表达或敲低测定在顺铂耐药中发挥作用。 cDNA 微阵列用于鉴定调节 HNSCC 中 AKR1C1 诱导信号传导的上游调节因子。最后，我们使用香烟代谢物促进 AKR1C1 表达，并使用鲁索替尼克服 AKR1C1 诱导的顺铂耐药。结果AKR1C1 与 HNSCC 细胞的顺铂耐药呈正相关。 AKR1C1 是 HNSCC 患者复发和死亡的不良预后因素。沉默 AKR1C1 不仅会降低体外 IC50，还会增加体内顺铂反应，在过表达细胞中反之亦然。香烟代谢物也会促进 AKR1C1 表达。转录组分析显示，STAT1 和 STAT3 激活可导致 AKR1C1 诱导的顺铂耐药，并且可以通过鲁索替尼治疗来克服。结论 AKR1C1 是 HNSCC 顺铂耐药的重要调节因子，也是患者预后不良的标志物。靶向 AKR1C1-STAT 轴可能为治疗顺铂治疗难治性患者提供新的治疗策略。
BackgroundCisplatin is the first-line chemotherapy used against most upper aerodigestive tract carcinomas. In head and neck cancer, sensitivity to cisplatin remains the key issue in treatment response and outcome. Genetic heterogeneity and aberrant gene expression may be the intrinsic factors that cause primary cisplatin-resistance.MethodsCombination of the HNSCC gene expression data and the cisplatin sensitivity results from public database. We found that aldo-keto reductase family 1 member C1 (AKR1C1) may be associated with cisplatin sensitivity in HNSCC treatment of naive cells. We examined the AKR1C1 expression and its correlation with cisplatin IC50 and prognosis in patients. The in vitro and in vivo AKR1C1 functions in cisplatin-resistance through overexpression or knockdown assays, respectively. cDNA microarrays were used to identify the upstream regulators that modulate AKR1C1-induced signaling in HNSCC. Finally, we used the cigarette metabolites to promote AKR1C1 expression and ruxolitinib to overcome AKR1C1-induced cisplatin-resistance.ResultsAKR1C1 positively correlates to cisplatin-resistance in HNSCC cells. AKR1C1 is a poor prognostic factor for recurrence and death of HNSCC patients. Silencing of AKR1C1 not only reduced in vitro IC50 but also increased in vivo cisplatin responses and vise versa in overexpression cells. Cigarette metabolites also promote AKR1C1 expression. Transcriptome analyses revealed that STAT1 and STAT3 activation enable AKR1C1-induced cisplatin-resistance and can be overcome by ruxolitinib treatment.ConclusionsAKR1C1 is a crucial regulator for cisplatin-resistance in HNSCC and also poor prognostic marker for patients. Targeting the AKR1C1-STAT axis may provide a new therapeutic strategy to treat patients who are refractory to cisplatin treatment.