过氧化物酶体对肺癌细胞转移的影响及分子机制

Peroxisome (PO) is a single-membrane-bound organelle and is involved in many important metabolisms. The enzymes are transported into PO matrix through the receptor, PEX5 for their metabolic functions. Our preliminary data show that some genes involved in PO biogenesis have a very high proportion of genetic alterations in lung cancer samples and PEX5 knockdown inhibits the migration and invasion of lung cancer cells and alters the expression of EMT (Epithelial-Mesenchymal Transition) functional proteins. These results suggest that lung cancer cells may utilize the enhanced PO biogenesis and metabolic functions to facilitate their EMT process and metastasis. We investigate the following to prove the hypothesis: firstly, we investigate the role of peroxisomes biogenesis in the metastasis of lung cancer cells and find the key metabolic pathway within PO for this function; Secondly we examine whether PO and the key metabolic pathway affect EMT of lung cancer cells; Lastly, we detect the expression of proteins involved in PO biogenesis and the key metabolic enzymes in lung cancer tissues and analyze their correlations with metastasis, survival of patients and EMT functional proteins. This study will reveal a novel function and molecular mechanism of PO in metastasis of lung cancer cells. As metastasis is the leading cause of lung cancer, this study will help us understand the mechanisms of metastasis of lung cancer and provide novel therapeutic targets for treating lung cancer from the perspective of PO formation and metabolism.

过氧化物酶体（PO）为单细胞膜细胞器，参与许多重要代谢过程。代谢酶由PEX5受体识别并运输入PO基质发挥代谢功能。然而PO对癌细胞转移的影响及作用机制尚不明确。预实验发现：一些PO形成基因在肺癌组织中有很高比例的遗传改变；PEX5下调抑制肺癌细胞的迁移和侵袭，并且影响EMT蛋白表达。这些提示肺癌细胞可能通过增加PO形成和增强相关代谢功能，促进癌细胞的EMT和转移。为证明该假设，首先探讨PO形成对肺癌细胞转移的影响，并找到PO发挥功能的关键代谢途径；其次，探讨PO及关键代谢途径对肺癌细胞EMT的影响；最后检测PO形成蛋白及关键代谢酶在肺癌组织中的的表达，并分析其与肺癌转移和病人存活，以及EMT蛋白的相关性。一方面，该研究将会揭示PO在肺癌转移过程中的新功能和作用机制；另一方面，癌细胞转移是引起肺癌死亡的主要原因，该研究将有助于我们理解肺癌转移的分子机制，并从PO的角度，找到治疗肺癌潜在靶标。

过氧化物酶体（PO）为单细胞膜细胞器，参与许多重要代谢过程。然而PO在癌症发生过程中的作用及机制尚不明确。我们通过在肺癌细胞中基因敲除或下调PO形成关键基因（PEX5、PEX19和PEX13），发现PO缺陷在体内外明显抑制肺癌细胞的生长和迁移。通过对PO代谢酶进行基因筛选，发现影响肺癌细胞生长和转移的6个关键代谢酶基因（ACOX1、GNPAT、PHYH、GSTK1、ECH1和FAR1），这些基因在肺癌组织中高表达，其高表达与病人生存时间负相关。这些基因主要参与脂肪酸氧化，活性氧自由基平衡及磷脂合成代谢反应，提示PO通过这些代谢途径促进肺癌细胞生长和转移。进一步，通过RNA-seq分析，我们发现PO缺陷通过激活干扰素信号通路抑制肺癌细胞生长和转移。该研究不仅揭示了PO在肺癌发生过程中的功能和作用机制，同时有助于我们从PO的角度，找到治疗肺癌潜在靶标。