基于KRAS/REG4/NQO-1的β-lapachone肺癌化学预防作用及机制研究

肺癌的药物治疗虽然取得了较大进展，但病人死亡率仍居高不下。化学预防应是更为有效的方法。β-lapachone(LPC)是一种植物来源的天然萘醌，在美国曾进入II期临床用于肺癌治疗，因其静脉注射制剂和毒性的问题未能上市。本课题组前期研究发现，在NNK诱导以及KRASG12D突变小鼠肺癌模型中，肺组织NQO1的表达水平均随肿瘤的发生而上调。口服LPC能够显著抑制这两种小鼠肺癌的恶性进展，无明显毒副作用。KRAS可能通过上调REG4，促进其竞争性结合Hrd1泛素连接酶上Nrf2的结合域而抑制Nrf2降解，提高NQO1的表达水平。本项目旨在运用恶性转化人支气管上皮细胞等体外模型以及NQO1敲除小鼠、慢病毒选择性敲低小鼠肺部REG4等体内模型，研究LPC基于NQO1和KRAS的肺癌化学预防作用及机理，以及KRAS调控Nrf2转录后水平的具体机制，具有十分重要的理论意义和潜在的临床价值。

Although the chemotherapy for lung cancer have made great progress, the death rate for this disease remains relatively high. Chemoprevention might be a better way to fight cancer. β-lapachone (LPC), a natural product, can inhibit the growth of a broad range of NQO1 overexpressing cancer cells. LPC has been evaluated in phase II clinical trial against lung cancer, but failed due to its formulation challenge and toxicity. Our study found that LPC has chemopreventive effect against lung cancer, and the mechanism may involve NQO1. The expression of NQO1 increase with the development of lung cancer in carcinogen-induced lung cancer mice. KRASG12D may upregulate REG4，increase its binding with the Nrf2 binding domain on Hrd1, therefore decrease the degradation of Nrf2，and increase the expression level of NQO1. Here we plan to use human and mouse lung precancerous cell lines as in vitro cell model, together with carcinogen-induced and transgenic animal models as in vivo model, to study the efficacy and mechanism of the chemopreventive effect of LPC, and the mechanism of post-transcriptional regulation of Nrf2 by KRAS. The result of this study would shed light on the chemoprevention of lung cancer.