State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China.
Institute of Nano Biomedicine and Engineering, Department of Instrument Science and Engineering, Key Laboratory for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electronic Engineering, Shanghai Jiaotong University, Shanghai, 200240, China.
J Exp Clin Cancer Res. 2020 Aug 27;39(1):170. doi: 10.1186/s13046-020-01684-x.
The 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.
Immunohistochemistry 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 Kras/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.
The clinical evidences reveal that KIAA1522 independently predicts both the overall survival and the outcome of platinum-based chemotherapy in lung adenocarcinomas. By using a Kras-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.
High 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.
铂类化疗是治疗非小细胞肺癌（NSCLC）的一线方案。然而，由于顽强的化疗耐药性，导致一部分患者预后较差，治疗效果在很大程度上受到限制。已知 KIAA1522 在多种实体肿瘤中异常表达，并与这些肿瘤有关，包括 NSCLC。目前，人们对该基因的了解相当有限。在这里，我们旨在确定 KIAA1522 在肺腺癌中的作用，以及其介导的铂类化疗耐药性的潜在分子事件。
免疫组织化学检测临床 NSCLC 样本中 KIAA1522 的表达。然后，进行生存分析以评估 KIAA1522 表达与总生存率或治疗结果之间的关系。通过腺相关病毒介导的 sgRNA/Cre 递送到条件性 Kras/Cas9 表达小鼠中，实现腺癌细胞中 KIAA1522 的体内耗竭，以鉴定 KIAA1522 在肿瘤发生和/或化疗反应中的作用。通过小鼠模型中的药理学研究和体外培养细胞中的实验研究 KIAA1522 及其下游分子事件的作用。通过来自多个队列的在线数据集的数据挖掘来检验我们研究结果的临床相关性。
临床证据表明，KIAA1522 独立预测肺腺癌的总生存率和铂类化疗的治疗结果。通过使用 Kras 驱动的小鼠肺腺癌模型并进行体外测定，我们证明 KIAA1522 是肺腺癌的关键正调节剂和顺铂反应的调节剂。KIAA1522 增强了 TNFα-TNFR2-NFκB 信号转导，从而加剧了对顺铂治疗的抵抗。这些结果通过对独立数据集的综合生物信息学分析进一步得到证实，其中 KIAA1522 与 TNFα-NFκB 通路的活性和顺铂耐药基因特征密切相关。更引人注目的是，在体内，过表达 KIAA1522 可抵抗顺铂诱导的肿瘤生长抑制，而 NFκB 活性的破坏可显著降低这种作用。
高表达 KIAA1522 表明肺腺癌患者对铂类治疗的效果不佳。KIAA1522 通过激活 TNFα-NFκB 信号通路促进对铂类药物的耐药性。通过小分子抑制剂靶向 NFκB 信号可能是克服化疗耐药性并协同增强 KIAA1522 过表达肺腺癌中铂类化疗效果的合理策略。
