良性心理应激通过调控线粒体能量代谢途径抑制肿瘤生长的机制研究

Epidemiology studies have suggested that psychological factors are associated with cancer development. However, there is few experimental evidence to support this conclusion. Enriched environment (EE) is a well-established animal model which confers benign psychological stress to the host. Recently, increasing evidence has show that EE demonstrates a broad spectrum of anti-tumor effects. We have reported before that EE Inhibited mouse pancreatic cancer growth and down-regulated the expression of mitochondria-related genes in cancer cells. Based on these findings, in the current study, we will focus on the intracellular mechanism by which EE suppresses tumor cell growth. We will first investigate whether EE influences metabolic function of mitochondria by down-regulating the genes involved in tricarboxylic acid cycle an oxidative phosphorylation in a variety of subcutaneous tumor models including pancreatic cancer, colon cancer, lung cancer, etc. Then, we will prove that Uqcrc1 gene, a mitochondrial protein coding gene whose expression level is significantly regulated by EE condition, is a novel pancreatic cancer-related gene. Lastly, we will provide both in vitro and in vivo evidence to show that EE exerts the anti-tumor effect by targeting Uqcrc1 and its associated mitochondrial energy metabolism. This study is the first to explore the mechanism underlying the inhibitory effect of EE on cancer cell growth through the direction of cellular energetics. The results from this project may provide experimental evidence for advocating bio-psycho-social medical models in cancer prevention and treatment.

流行病学研究提示良性精神情绪对肿瘤的防控具有积极意义，但长期以来缺乏实验证据支持。丰富生存环境（Enriched environment, EE）是公认的能够诱导动物产生良性心理应激的模型。最新研究表明，EE对小鼠恶性肿瘤具有广泛的抑制作用。本项目将在以往现象观察的基础上，首次探讨EE抑瘤的细胞内分子机制。根据课题组前期多组学结果发现的EE对癌细胞线粒体蛋白具有普遍下调作用的线索，我们将进一步探讨：1.EE对肿瘤线粒体形态、结构和能量代谢的影响；2.以小鼠胰腺癌模型为重点，通过一系列体内外实验，确认受EE调控最为显著的线粒体呼吸相关基因Uqcrc1为一新的胰腺癌相关基因；3.证实EE通过干扰Uqcrc1及线粒体呼吸功能发挥抑瘤作用。本研究首次从细胞能量代谢的角度，探索EE及其所诱导的良性心理反应在抗癌中的作用机制，为在肿瘤治疗和康复中倡导生物-心理-社会医学模式提供实验依据。

丰富生存环境（EE）诱导的良性心理应激，对恶性肿瘤具有普遍的抑制作用，但其机制尚未阐明。本项目基于EE抑制胰腺癌生长的同时伴有线粒体相关基因群表达差异的现象，聚焦能量代谢通路，探索胰腺癌发生发展的新机制，并提出临床干预的新靶点。项目取得的原创性结果包括：1.首次发现并证实了受EE调控的线粒体复合物III成分UQCRC1是一新的癌相关基因。UQCRC1在72.3%的胰腺癌患者中表达升高，且与疾病的不良预后相关。在细胞实验及小鼠体内皮下瘤和原位瘤模型中，UQCRC1均表现出促瘤生长的作用。2. 直接机制方面，我们发现UQCRC1过表达能导致线粒体氧化磷酸化作用增强，以及相应的ATP产量增加。ATP通过pannexin 1通道释放到细胞外基质，再以自分泌或旁分泌的作用方式，通过eATP/P2Y2-RTK/AKT轴促进肿瘤细胞的增殖。3. 间接机制方面，我们从过继性NK细胞对小鼠胰腺癌的治疗实验以及CIBERSORTx数据库人胰腺癌样本分析中，均发现肿瘤细胞UQCRC1表达对NK细胞具有抑制作用。eATP及其代谢产物腺苷一方面通过调控DNAM-1和CD96的表达，抑制NK细胞的增殖和杀伤活性；另一方面也通过减少CCL5的表达降低NK细胞的趋化性，从而实现肿瘤的免疫逃逸。4. UQCRC1敲除或ATP释放通道阻断剂可有效抑制胰腺癌的生长。线粒体呼吸抑制剂二甲双胍对UQCRC高表达的胰腺癌具有抑制作用，提示UQCRC1可作为线粒体抑制剂应用于胰腺癌治疗时的病例筛选和疗效预测标志物。此外，项目还揭示了EE对肺癌、结肠癌等的抑制作用可能也与其调控线粒体呼吸功能有关。项目在UQCRC1通过Treg细胞发挥促瘤作用方面也取得了研究进展。总之，本项目从良性心理应激抑瘤机制分析入手，筛选到了新的胰腺癌相关基因及通路，为胰腺癌的靶向治疗和综合治疗提供了新策略。