重金属镉诱发TARS2/HMGA1复合体介导ND2干预线粒体电子传递链激活EGFR相关通路在非小细胞肺癌增殖中的作用及机制研究

Non-small-cell lung cancer has a high-occurrence in the world. Heavy metal cadmium is one of the main reason, but its target and nosogenesis mechanisms are unclear. We used gene chip to pick out the differential gene TARS2 from non-small-cell lung cancer tissues.In the preliminary investigation , we found that the TARS2 is highly expressed in non-small-cell lung cancer, and significantly correlated with T stage, and the interaction with HMGA1 can caused the increased transcription of mtDNA. Studies have shown that ND2 have influences on mitochondrial electron transport chain, which can increase the the production of ROS, and ROS can activate the EGFR pathways to promote cell proliferation in non-small cell lung cancer. Through the protein structure analysis of PDB Data Bank, the unique ligands zinc may exist in TARS2, and cadmium can replace zinc within the protein to execute biological function. Taken together, we hypothesize that the new mechanism by which cadmium inducing non-small-cell lung cancer: cadmium replaces zinc in TARS2, promoting TARS2 to interact with HMGA1, thus increasing the ND2 level, then the ND2 interferes with mitochondrial transport chain, raises the level of ROS, and activates EGFR pathways to promote cell proliferation in non-small-cell lung cancer. This project aims to obtain reliable evidence that cadmium induces TARS2/HMGA1 complex to promote the proliferation of non-small-cell lung cancer and provide scientific evidence for the pathogenesis of cadmium-induced non-small-cell lung cancer.

非小细胞肺癌（NSCLC）全球高发。镉是导致肺癌发生的一种重要原因之一，但其作用靶标和发病机制尚不清楚。我们利用基因芯片，从NSCLC组织中选出差异基因TARS2。初步研究发现，TARS2在肺癌中高表达，且与T分期相关，与HMGA1互作可促使mtDNA的转录增加，导致ND2表达增多。研究显示ND2可影响线粒体电子传递链，促进ROS产生，进而激活EGFR及下游通路，促进细胞增殖。进一步蛋白结构分析显示，TARS2极有可能存在独特配体锌，研究发现镉可以替换蛋白内的锌，发挥生物学功能。由此，我们提出重金属镉促进肺癌增殖新机制：镉通过替换TARS2的配体锌，使TARS2与HMGA1互作，上调ND2，干预线粒体电子传递链，促进ROS产生，进而激活EGFR相关通路，促进NSCLC细胞增殖。本项目旨在获得镉诱导TARS2/HMGA1复合体促进NSCLC增殖的可靠证据，为镉诱发肺癌的发病机制提供科学证据。

非小细胞肺癌（NSCLC）是全球高发恶性肿瘤，重金属污染是其发病的一个重要因素。流行病学调查显示重金属镉(Cd)暴露与肺癌发生率增加有关，但是其机制尚不明确。为此，这项研究的目的是采用NSCLC患者的临床标本，利用组织芯片测序、免疫组化等方法，探索重金属镉可能存在的作用网络，同时在细胞及动物水平进行验证。经过对前序实验样本的补充，目前总计纳入NSCLC临床石蜡组织样本176例，新鲜NSCLC癌组织样本及血液样本60例，正常人血液样本60例，通过对这些样本进行分析发现，TARS2和HMGA1在NSCLC组织中高表达，在非癌肺组织中低表达。Cd在NSCLC患者血液中含量较正常人血液高，但是Cd含量与患者TARS2和HMGA1表达未见明显相关性，TARS2和HMGA1表达也未见相关性。细胞实验证实，TARS2和HMGA1相互不是上下游关系，免疫沉淀（IP）结合质谱检测发现TARS2和HMGA1有互作。Cd与锌（Zn）属于元素周期同族并且位置相邻，可能具有相似的理化性质，已有的研究显示，Cd通过Zn离子通道进行细胞。对TARS2蛋白结构分析发现其三维结构上存在结合锌的结构域。敲减TARS2/HMGA1可以减弱低剂量Cd对细胞增殖的促进作用。我们猜测Cd可能通过结合在TARS2上发挥生物学作用。后续的机制研究显示，Cd可能通过HMGA1/TARS2复合物调控线粒体mtDNA的表达，从而干预线粒体电子传递链，影响细胞内活性氧平衡，促进细胞增殖。

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