衰老相关分泌模式促进肾癌肿瘤干细胞特性参与舒尼替尼抵抗的分子机制与干预策略研究

Sunitinib is a broad-spectrum small-molecular inhibitor of receptor tyrosine kinase (RTK) and has shown promising clinical efficacy in the treatment of patients with advanced renal cell carcinoma (RCC).Unfortunately, most patients develop sunitinib resistance after about one year of treatment, which is a major obstacle in RCC clinical treatment. We take the molecular mechanisms, survival assessment and newer therapeutic options of RCC as the original focus to go on the investigation and research, and our previous studies found that Notch1 (Cancer Sci 2012), Dec1 (Cancer Sci 2013), Klotho (Cancer Sci 2013), macrophage polarization (Ann Surg Oncol 2014) and CXCR4 (Brit J Cancer 2014) play an important role in tumor development and drug resistance of RCC. We demonstrated that sunitinib can induce senescence-associated secretory phenotype (SASP) in RCC cells. Our present research project intends to work on the basis of the preliminary study, we will focus on the molecular mechanism and functional significance for RCC stem cell properties conferred by CXCR2/PAK1 signal activation due to SASP chemokine IL-8, explore its important role in resistance to sunitinib, and try to establish molecular mechanisms and resistance reversal regulatory model of SASP induced sunitinib resistance in RCC treatment.

以舒尼替尼为代表的靶向药物可显著提升晚期肾癌患者的总体生存，然而治疗后迅速出现的药物抵抗是目前临床治疗的一大难题。围绕肾癌发生分子机制、术后生存评估和靶向治疗新策略展开研究，我们发现了Notch1（Cancer Sci 2012）、Dec1（Cancer Sci 2013）、Klotho（Cancer Sci 2013）、巨噬细胞极化（Ann Surg Oncol 2014）和CXCR4（Brit J Cancer 2014）在肾癌发生发展和治疗抵抗中的重要作用。我们前期研究还发现舒尼替尼可诱导肾癌细胞产生衰老相关分泌模式（SASP）。本项目拟在前期工作基础上，研究SASP中趋化因子IL-8通过活化CXCR2/PAK1信号促进肾癌肿瘤干细胞特性的功能意义，并探讨其在舒尼替尼抵抗中的重要作用，建立SASP诱导肾癌舒尼替尼抵抗发生的分子机制和耐药逆转调控模型，为临床克服舒尼替尼耐药奠定基础。

项目负责人顺利完成原定研究目标，以第一作者或共同第一作者在Oncoimmunology，Cell Death Dis，Ann Surg Oncol，Urology，Urol Oncol，Int J Urol等国际泌尿外科学和肿瘤学权威杂志发表SCI 学术论文11篇，论文总影响因子48.84分。此外，以相应的科研成果为基础，成功申请上海市卫计委人才计划项目1项。我们还发现PAK1介导NF-κB/I L-6信号异常活化决定着肾癌细胞肿瘤干细胞样表型并参与其对舒尼替尼治疗抵抗过程（ Cell Death Dis 2015；Int J Urol 2015）。我们还发现跨膜蛋白Notch1（Urology 2015）、炎症小体产物IL-1β和IL-18（Urol Oncol 2015）、趋化因子IL-8（Tumor Biol 2016）参与肾癌复发和侵袭转移；我们还发现B4GALT增加是非转移性肾透明细胞癌患者潜在独立不良预后因素（Oncotarget 2016）。我们还发现肾癌中CXCR1（Oncoimmunology 2017）、肿瘤浸润肥大细胞(Ann Surg Oncol 2017)、核连蛋白NUCB2 （Oncotarget 2017）粒细胞集落刺激因子G-CSF（Oncotarget 2017）提示患者预后不良，其可能作为肾癌生存和细胞因子治疗反应的重要评估指标，我们还发现DNA修复基因O6-甲基鸟嘌呤甲基转移酶（MGMT）可作为膀胱癌铂类化疗敏感性预测指标（Ann Surg Oncol 2018）。