MYC/FTO/m6A通路对胰腺癌放射敏感性的影响及机制研究

Radiotherapy is an important approach in pancreatic cancer treatment. However, radiation resistance of pancreatic cancer is a challenge in radiotherapy of pancreatic cancer. MYC may be one of the most important factors that mediate radiation resistance, but the molecular network that was influenced by MYC during radiation resistance remains unclear. Our preliminary experiment showed that MYC could activate FTO, one of the most important m6A demethylases. Our data also uncovered that MYC mRNA has m6A modification. To this end, we propose the hypothesis that MYC transcriptionally activates FTO and decreases the m6A modification on MYC mRNA, which stabilizes MYC mRNA and results in upregulation of MYC protein and radiation resistance in pancreatic cancer. In order to confirm this hypothesis, western blot, PCR and luciferase assay will be used to investigate the activation of MYC/FTO/m6A pathway after irradiation. Next, clonogenic assay, apoptosis assay and tumor xenograft model will be used to reveal whether activation of MYC/FTO/m6A pathway is associated with radiation resistance, both in vitro and in vivo. Finally, approaches inhibiting FTO protein will be used to increase the radiosensitivity of pancreatic cancer. This study will provide us with new ideas in better understanding the radiation resistance of pancreatic cancer and with new strategies to find effective radiosensitizers that can be used in radiotherapy of pancreatic cancer.

放射治疗是胰腺癌治疗的重要手段，但是胰腺癌的辐射抵抗是胰腺癌放射治疗面临的挑战。既往的研究表明MYC蛋白可以介导辐射抵抗，但分子机制仍不明确，我们的预实验表明MYC蛋白可以激活去甲基化酶FTO，而MYCmRNA受到m6A修饰。为此，我们提出假说：MYC蛋白可以转录激活FTO基因，清除MYCmRNA的m6A修饰，并增加其稳定性，从而增加MYC蛋白，引起辐射抵抗。为了验证该假说，首先我们使用western blot、PCR和荧光素酶报告基因等手段明确辐射后MYC/FTO/m6A通路活化的分子机制；其次使用克隆形成、细胞凋亡等实验和荷瘤裸鼠模型，在体内和体外水平揭示MYC/FTO/m6A通路的活化与胰腺癌辐射抗性之间的关系；最后我们通过下调FTO的手段实现胰腺癌放射增敏的目的。本项目可以为更深入的理解胰腺癌辐射抵抗的机制提供新思路，为寻找有效的放射增敏的新靶点提供理论依据。

放射治疗是胰腺癌治疗的重要手段，但是胰腺癌的辐射抵抗是胰腺癌放射治疗面临的挑战。既往的研究表明MYC蛋白可以介导辐射抵抗，但分子机制仍不明确，我们的预实验表明MYC蛋白可以激活去甲基化酶FTO，而MYCmRNA受到m6A修饰。为此，我们提出假说：MYC蛋白可以转录激活FTO基因，清除MYCmRNA的m6A修饰，并增加其稳定性，从而增加MYC蛋白，引起辐射抵抗。为了验证该假说，首先我们使用western blot、PCR和荧光素酶报告基因等手段明确辐射后MYC/FTO/m6A通路活化的分子机制；其次使用克隆形成、细胞凋亡等实验和荷瘤裸鼠模型，在体内和体外水平揭示MYC/FTO/m6A通路的活化与胰腺癌辐射抗性之间的关系；最后我们通过下调FTO的手段实现胰腺癌放射增敏的目的。本项目可以为更深入的理解胰腺癌辐射抵抗的机制提供新思路，为寻找有效的放射增敏的新靶点提供理论依据。

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