SKA3在肺腺癌肝转移以及糖代谢重编程中的作用及机制研究

肿瘤细胞要经历器官特异性代谢适应性来克服向特定器官转移的阻碍。本研究通过测序分析，发现SKA3可能是肺腺癌肝转移以及代谢重塑中发挥重要作用的分子。临床样本证实SKA3在肺腺癌肝转移组织中高表达且与不良预后相关；沉默SKA3抑制肺腺癌的肝转移以及糖代谢重塑；Co-IP实验证明SKA3与PHD2结合，PHD2是促进HIF-1α羟基化和降解的关键分子；网站预测提示SKA3可能受p53转录调控，过表达p53抑制SKA3和PDK1的表达，而PDK1是与肝转移密切相关的糖代谢分子。基于此我们提出科研假说：缺氧环境下p53转录抑制SKA3的功能受抑制，SKA3通过结合PHD2促进HIF-1α稳定，从而增强HIF-1α对PDK1的转录，最终导致肺腺癌发生肝转移和糖代谢重塑。本项目将从体内、体外临床样本三个层面深入研究SKA3促进肺腺癌肝转移的分子机制。本项目的成功实施有望为肺腺癌肝转移的诊治提供新的方向。

Cancer cells must undergo organ-specific metabolic adaptations to provide the ability to overcome the unique barriers for their colonization in foreign tissues. Our sequencing screening analysis indicated that SKA3 is an oncogene related to liver metastasis and glucose metabolism in lung adenocarcinoma. Clinical samples verification demonstrated that SKA3 is significantly overexpressed in metastatic sites of lung adenocarcinoma in liver and associated with poor prognosis. Silencing SKA3 can inhibit liver metastasis and glucose metabolism remodeling of lung adenocarcinoma. Co-IP experiment showed that SKA3 could bind to PHD2, a key molecule that promotes hydroxylation and degradation of HIF-1α. The bioinformatic analysis predicted that p53 could bind to the promoter region of SKA3, and overexpression of p53 inhibited the expressions of SKA3 and PDK1, while PDK1 is a key molecule related to liver metastasis. Based on these preliminary data, we proposed a scientific hypothesis: p53 loses the function of transcriptional inhibition of SKA3 in tumor anoxic environment, which increases SKA3 expression, enhances the binding of SKA3 with PHD2, and promotes the stabilization of HIF-1α, thereby enhancing transcription of downstream glycolytic related genes of HIF-1α, and ultimately leading to liver metastasis and glucose metabolism remodeling of lung adenocarcinoma. In this project, the molecular mechanism of how SKA3 promotes liver metastasis of lung adenocarcinoma will be further investigated from three aspects including in vitro, in vivo and clinical samples. The successful implementation of this project is expected to provide a new direction for the diagnosis and treatment of liver metastasis of lung adenocarcinoma.