非小细胞肺癌（NSCLC）是发病率和死亡率最高的恶性肿瘤。UNC5同源蛋白C（UNC5C）是潜在的抑癌基因，可调控肿瘤细胞的增殖、迁移和克隆形成等重要生物学行为。UNC5C在多种恶性肿瘤中发生缺失，然而其机制尚不明确。我们前期研究首次发现：在突变型NSCLC细胞中抑制KRAS能够显著上调UNC5C，KRAS活性与UNC5C之间存在明显的负向调控关系。另有研究显示：KRAS突变能驱动DNA甲基化并沉默特定抑癌基因从而造成细胞转化；UNC5C缺失可能与其启动子甲基化密切相关。据此，我们提出假设：KRAS突变可能通过诱导UNC5C基因启动子区CpG岛超甲基化介导UNC5C缺失，进而促进NSCLC的发生和发展。在本课题中，我们将首次探究KRAS突变介导的UNC5C缺失在NSCLC中的作用，解析KRAS突变诱导UNC5C缺失的分子机制，以期为临床上KRAS突变型NSCLC的治疗提供新思路和新靶点。

Non-small cell lung cancer (NSCLC) is the most common malignant tumors with highest incidence of morbidity and mortality worldwide. Uncoordinated-5-homolog C (UNC5C) is a potential tumor suppressor gene participating in the regulation of critical biological behaviors of cancer cells such as proliferation, migration and colony formation. UNC5C is downregulated in multiple malignant tumors, but the mechanism of UNC5C loss is not clear. Our preliminary study found for the first time that inhibition of oncogenic KRAS significantly upregulated UNC5C and the activity of oncogenic KRAS was negatively correlated with the expression of UNC5C. Moreover, it has been reported that mutation of KRAS proto-oncogene drives cell transformation by DNA hypermethylation and subsequent silencing of specific tumor suppressor genes and UNC5C loss was correlated with the hypermethylation of CpG islands in its promoter regions. On the basis of our preliminary result and current research progress, we hypothesized that the KRAS mutation could induce UNC5C loss through hypermethylation of CpG islands of UNC5C promoter regions and thereby promote the initiation and progression of NSCLC. In the current project, we will first investigate the role of oncogenic KRAS-mediated UNC5C loss in NSCLC and decipher the exact molecular mechanism of KRAS mutation-mediated UNC5C deletion, thus providing novel therapeutic strategies and targets for the treatment of KRAS-driven NSCLC in clinic.