KIAA1522 potentiates TNFα-NFκB signaling to antagonize platinum-based chemotherapy in lung adenocarcinoma
KIAA1522 potentiates TNFα-NFκB signaling to antagonize platinum-based chemotherapy in lung adenocarcinoma
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KIAA1522 增强 TNFα-NFκB 信号传导以拮抗肺腺癌中的铂类化疗
DOI：
10.1186/s13046-020-01684-x
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发表时间：
2020-08-27
影响因子：
11.3
通讯作者：
Liu, Yizhen
中科院分区：
文献类型：
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作者：
Wang, Boshi;Jing, Tiantian;Liu, Yizhen
以铂为基础的化疗方案是治疗非小细胞肺癌的一线方案。然而，治疗效率在很大程度上受到顽固的化疗不敏感的限制，这导致了一组患者预后较差。已知KIAA1522在包括非小细胞肺癌在内的多种实体瘤中异常表达并参与其中。如今，人们对这种基因的了解相当有限。在此，我们旨在确定KIAA1522在肺腺癌中的作用，以及KIAA1522介导的铂类药物耐药的分子事件。然后，进行生存分析，以评估KIAA1522表达与总体生存或治疗结果之间的联系。通过腺相关病毒介导的sgRNA/Cre导入条件表达KrasG12D/Cas9的小鼠体内KIAA1522的耗竭，以确定KIAA1522在肿瘤发生和/或化疗反应中的作用。KIAA1522及其下游分子事件的作用通过小鼠模型药理学和体外培养细胞检测来研究。结果临床证据显示，KIAA1522可以独立预测肺腺癌患者的总体生存率和铂类化疗的结果。通过使用KrasG12D驱动的小鼠肺腺癌模型和体外实验，我们证明KIAA1522是肺腺癌的关键正向调节因子和顺铂反应的调节器。KIAA1522增强肿瘤坏死因子α-肿瘤坏死因子2-核因子κB信号转导，进而加强对顺铂治疗的抵抗。这些结果进一步通过对独立数据集的综合生物信息学分析得到证实，其中KIAA1522与肿瘤坏死因子α-核因子κB途径的活性和顺铂耐药基因特征密切相关。更显著的是，KIAA1522的高表达可拮抗体内顺铂诱导的肿瘤生长停滞，这种作用可被NFκB活性阻断而显著减弱。结论KIAA1522的高表达是以铂为基础的治疗肺腺癌疗效差的一个指标。KIAA1522可高度激活肿瘤坏死因子α-核因子κB信号，以促进对铂类试剂的耐药性。在KIAA1522过表达的肺腺癌中，通过小分子抑制剂靶向NFκB信号转导可能是克服化疗耐药和协同铂类化疗的合理策略。
BackgroundThe platinum-based chemotherapy is the first-line regimen for the treatment of Non-small cell lung cancer (NSCLC). However, the therapeutic efficiency is largely limited by tenacious chemo-insensitivity that results in inferior prognosis in a cohort of patients. It has been known that KIAA1522 is aberrantly expressed and implicated in several types of solid tumors including NSCLC. Nowadays, knowledge about this gene is quite limited. Here, we aimed to identify the role of KIAA1522 in lung adenocarcinomas, and the molecular events that underlie KIAA1522-mediated chemoresistance to the platinum.MethodsImmunohistochemistry were used to detect KIAA1522 expression in clinical NSCLC samples. Then, the survival analyses were performed to assess the link between KIAA1522 expression and overall survival or therapeutic outcome. In vivo depletion of KIAA1522 in adenocarcinoma cells were achieved by adeno-associated virus-mediated sgRNA/Cre delivery into the conditional KrasG12D/Cas9 expressed mice, which were designated to identify the roles of KIAA1522 in tumorigenesis and/or chemotherapy responses. The effects of KIAA1522 and downstream molecular events were studied by pharmacology in mice model and assays using in vitro cultured cells. The clinical relevance of our findings was examined by data-mining of online datasets from multiple cohorts.ResultsThe clinical evidences reveal that KIAA1522 independently predicts both the overall survival and the outcome of platinum-based chemotherapy in lung adenocarcinomas. By using aKrasG12D-driven murine lung adenocarcinoma model and performing in vitro assays, we demonstrated that KIAA1522 is a critical positive regulator of lung adenocarcinoma and a modulator of cisplatin response. KIAA1522 potentiates the TNFα-TNFR2-NFκB signaling which in turn intensifies recalcitrance to cisplatin treatment. These results were further manifested by integrative bioinformatic analyses of independent datasets, in which KIAA1522 is tightly associated with the activity of TNFα-NFκB pathway and the cisplatin-resistant gene signatures. More strikingly, overexpression of KIAA1522 counteracts the cisplatin-induced tumor growth arrest in vivo, and this effect can be remarkably diminished by the disruption of NFκB activity.ConclusionHigh expression of KIAA1522 is turned out to be an indicator of dismal effectiveness of platinum-based therapy in lung adenocarcinomas. KIAA1522 hyperactivates TNFα-NFκB signaling to facilitate resistance to platinum reagents. Targeting NFκB signaling through small molecule inhibitors may be a rational strategy to conquer chemoresistance and synergize platinum-based chemotherapy in KIAA1522 overexpressed lung adenocarcinomas.