移动元件L1-FGGY通过12-LOX/Wnt通路促进肺鳞癌增殖侵袭和免疫逃逸的机制研究

肺鳞癌（LUSC）进展快，预后差，从常规化疗和靶向治疗中获益甚微，因此开发新的LUSC治疗方案至关重要。我们前期发现LUSC中存在一种高频的染色体重排结构——LINE-1逆转录转座，其通过干扰代谢基因FGGY转录，启动花生四烯酸（AA）代谢重编程，导致12-LOX/12S-HETE代谢途径过度活化，通过上调Wnt通路促进肿瘤增殖侵袭和免疫逃逸。Wnt通路促进肿瘤发生发展，并调控免疫细胞分化和发育，但其与LINE-1，以及12-LOX代谢途径的相关研究尚无报道。本课题拟从组织、细胞、动物等多角度，深入探讨移动元件L1-FGGY驱动LUSC细胞中12-LOX代谢途径激活Wnt通路的分子机制，阐明LINE-1插入对12S-HETE受体GPR31蛋白的去泛素化调控作用，探索靶向12-LOX/Wnt通路的干预措施在LUSC中的治疗价值，以期为筛选LUSC新的治疗靶点提供有力的理论和实验依据。

Lung squamous cell carcinoma (LUSC) has the characteristics of rapid progress and poor prognosis, which benefits little from the conventional chemotherapy and targeted therapy. Therefore, it is important to find new therapeutic methods for LUSC patients. In our previous studies, we developed a novel algorithm and detected a high-frequency chromosomal rearrangement in LUSC samples: Long interspersed elements-1 (LINE-1) retrotransposition. And we found that the LINE-1 insertion into FGGY, which is a metabolism-related gene, interfered with FGGY transcription and initiated the arachidonic acid (AA) metabolism reprogramming to activate the 12-LOX/12S-HETE metabolic pathway, followed by up-regulation of the Wnt signaling pathway. The Wnt signaling pathway could promote the proliferation and invasion of tumor cells, as well as regulate the differentiation of immunocytes. But there was none report on the relationship among the Wnt pathway, LINE-1, and the 12-LOX pathway. In this study, we intend to investigate the molecular mechanisms of L1-FGGY driven activation of the 12-LOX/12S-HETE pathway and upregulation of the Wnt signaling pathway in tissue, cell, and animal models, and elucidate the role of LINE-1 insertion in the regulation of the deubiquitination of GPR31 protein (the receptor of 12S-HETE). Furthermore we will explore the therapeutic value by targeting the 12-LOX/Wnt pathway in LUSC in order to provide a solid theoretical and experimental basis for screening new therapeutic targets for LUSC patients in the future.