2016年11月10日，国际期刊《自由基生物学与医学》(Free Radical biology and Medicine)在线发表了中国科学院上海生命科学研究院营养科学研究所尹慧勇研究组题为Mitochondrial Control of Apoptosis through Modulation of Cardiolipin Oxidation in Hepatocellular Carcinoma: A Novel Link between Oxidation Stress and Cancer 的研究成果，文章阐述了线粒体特有的磷脂-心磷脂调节肝细胞癌 (Hepatocellular Carcinoma, HCC)凋亡的新机制。
肝癌是临床上最常见的恶性肿瘤之一，其发病率逐年增加，目前位列所有肿瘤疾病的第五位，同时其致死率也非常高，位列全球肿瘤疾病相关死亡的第二位。HCC作为原发性肝癌中最主要的一种亚型，其比例占全球肝癌的70-85%，其中新增肝癌病人55%在中国。HCC癌细胞具有区别于一般正常肝细胞的特有属性，如抗细胞凋亡、生长信号自给自足及显著激活的增殖、侵袭和转移能力等。近年来的研究表明肝癌细胞的这些特征与其代谢重构密切相关，其中糖酵解异常(Warburg Effect)和线粒体功能异常相关的分子机制研究较多，而脂代谢重构在HCC发生发展过程中所起的作用还亟待研究。
博士研究生钟慧琴等在研究员尹慧勇的指导下发现，线粒体所特有的心磷脂代谢变化在HCC发生发展过程中发挥了重要作用。研究人员利用脂质组学技术，通过系统分析不同发病阶段癌旁组织和癌组织中的心磷脂，发现癌组织中含量最丰富的心磷脂-四亚油酰心磷脂 (tetralinoleoyl cardiolipin, TLCL)和其氧化产物均显著下降，同时证明TLCL氧化产生大量的活性脂质亲电体包括4-羟基-壬烯醛(4-hydroxy-nonenal, 4-HNE)等。通过体外细胞实验证明心磷脂氧化、活性脂质亲电体的形成与细胞凋亡密切相关。该研究揭示了肝癌细胞逃避凋亡的新机制，并且证明了线粒体心磷脂氧化及4-HNE等活性脂质亲电体形成在HCC发生发展中的重要作用。
原文链接：
Mitochondrial Control of Apoptosis through Modulation of Cardiolipin Oxidation in HepatoCellular Carcinoma: A Novel Link between Oxidative Stress and Cancer
原文摘要：
Altered redox status in cancer cells has been linked to lipid peroxidation induced by reactive oxygen species (ROS) and subsequent formation of reactive lipid electrophiles, especially 4-hydroxy-nonenal (4-HNE). Emerging evidence suggests that cancer cells manipulate redox status to acquire anti-apoptotic phenotype but the underlying mechanisms are poorly understood. Cardiolipin (CL), a mitochondria-specific inner membrane phospholipid, is critical for maintaining mitochondrial function. Paradoxically, liver tissues contain tetralinoleoyl cardiolipin (TLCL) as the major CL in mitochondria yet emerging evidence suggests that ROS generated in mitochondria may lead to CL peroxidation and activation of intrinsic apoptosis. It remains unclear how CL oxidation leads to apoptosis and its relevance to the pathogenesis of hepatocellular carcinoma (HCC). We employed a mass spectrometry-based lipidomic approach to profile lipids in human tissues of HCC and found that CL was gradually decreased in tumor comparing to peripheral non-cancerous tissues, accompanied by a concomitant decrease of oxidized CL and its oxidation product, 4-HNE. Incubation of liver cancer cells with TLCL significantly restored apoptotic sensitivity accompanied by an increase of CL and its oxidation products when treated with staurosporine (STS) or Sorafenib (the standard treatment for late stage HCC patients). Our studies uncovered a novel mechanism by which cancer cells adopt to evade apoptosis, highlighting the importance of mitochondrial control of apoptosis through modulation of CL oxidation and subsequent 4-HNE formation in HCC. Thus manipulation of mitochondrial CL oxidation and lipid electrophile formation may have potential therapeutic value for diseases linked to oxidative stress and mitochondrial dysfunctions.
doi:10.1016/j.freeradbiomed.2016.10.494
作者：尹慧勇 点击：315次
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