3-羟基丁酸脱氢酶2异常失活抑制乙酰乙酸生成影响鼻咽癌恶性进展及肿瘤微环境的机制研究

能量代谢异常是鼻咽癌（nasopharyngeal carcinoma，NPC）的重要特征之一。前期研究中初步发现，生酮路径中的关键基因BDH2在NPC中表达下调，导致酮体中的乙酰乙酸生成减少，并促进了NPC细胞的增殖与转移能力，提示乙酰乙酸代谢异常在NPC发病中可能扮演一定角色。而近期研究更提示乙酰乙酸参与调控肿瘤相关巨噬细胞的招募。本研究拟进一步探究BDH2基因在NPC中的转录和表达异常，BDH2对酮体生成的调控和藉此对NPC细胞恶性生物学行为的影响，及其通过调节乙酰乙酸代谢对肿瘤间质免疫微环境的影响，以期揭示其中可能的分子机制。该研究成果将为肿瘤发病机制的探索提供了一个新的思路，也可为肿瘤的代谢治疗手段的开发和新药开发提供新的靶点。

Abnormal energetic metabolism is a hallmark of nasopharyngeal carcinoma (NPC). Our preliminary studies found that BDH2, a key gene in ketogenic pathway, is down-regulated in NPC, resulting in a decrease in acetoacetate production, which is a main component of ketone bodies, and promoting the proliferation and metastasis of NPC cells. This suggests that abnormal acetoacetate metabolism may play a role in the pathogenesis of NPC. Recently, acetoacetic acid has been found to involve in regulating the recruitment of tumor-associated macrophages (TAM). Therefore, we aim to further explore the abnormal transcription and expression of BDH2 in NPC and its effect on malignant biological behavior of NPC cells by regulating acetoacetate metabolism. In addition, to understand the effect of acetoacetate in immune microenvironment in NPC stroma, and reveal the possible molecular mechanism involved. Our research outcome will provide a new insight into the pathogenesis of cancer, and may also promote the development of metabolic therapy and offer new target for drug discovery.