丝氨酰tRNA合成酶在乳腺癌糖代谢异常中的作用及机制研究

糖代谢方式的异常转变是乳腺癌细胞恶性转化和转移的重要原因。许多癌基因都能通过促进乳腺癌细胞的糖代谢转变而发挥促癌作用。然而对机体如何抑制能量代谢方式恶性转换的分子机制的研究还非常欠缺，这极大限制了针对乳腺癌异常代谢的抗癌药物的研发。我们的前期研究发现了一种调控糖酵解等代谢途径异常转换的新抑癌基因SerRS，本项目拟在此基础上，（1）深入研究SerRS在小鼠乳腺癌肿瘤模型和乳腺癌临床样本中表达水平与糖酵解及三羧酸循环等能量代谢途径异常之间的相关性，并利用细胞核SerRS敲除小鼠明确SerRS在调控乳腺癌能量代谢中的作用；（2）研究SerRS调控乳腺癌细胞能量代谢转变的分子机制，鉴定受SerRS调控的乳腺癌能量代谢途径中重要的酶及通道蛋白质；（3）探索乳腺癌细胞调控SerRS以实现恶性转移的信号通路及分子机制。本项目有助于深入阐明乳腺癌能量代谢异常的病理机制，并为乳腺癌防治提供新策略。

The dysregulation of glucose metabolism is a driving force for the malignant transformation and metastasis of breast cancer. Many oncogenes can promote tumor progression through oncogenic alteration of glucose metabolism. However, the molecular mechanisms of how cells prevent this malignant metabolic shift remain largely unknown, which hinders the development of anti-cancer drugs targeting energy metabolism. Our previous studies revealed a novel transcriptional repressor, namely SerRS, which may directly regulate the key genes in glycolysis, such as PDK3, HK1, and MCT4 etc. Based on these findings, this project is proposed (1) to investigate the correlation between SerRS expression level and the alteration of glucose and energy metabolisms in mouse breast cancer models and human breast cancer samples, testing the involvement of SerRS in metabolic abnormality in breast cancer. Evaluate the importance of SerRS in malignant metabolic reprogramming by using nuclear SerRS knockout mice (SarsΔNLS); (2) to identify key target genes of SerRS in breast cancer metabolism, elucidating the molecular mechanisms of how SerRS regulates glucose metabolism in breast cancer; (3) to investigate the signaling pathways through which the cancer cells modulate SerRS activity for their malignant transformation. This project will not only broaden our understandings on how the energy metabolism is dysregulated in breast cancer, but also provide new strategy for the prevention and therapy of breast cancer.