MACC1介导PI3K/mTOR通路参与鼻咽癌辐射抵抗的分子机制

Radiotherapy is the primary treatment for nasopharyngeal carcinoma (NPC). However, there are still a substantial proportion of patients with NPC who fail to achieve long-term disease control and die from local recurrence and metastasis. The dismal prognosis of NPC may due to its radioresistance. In our preliminary study, we found that overexpression of MACC1 could enhance radioresistance of NPC. Furthermore, miR-218 could bind to MACC1 and decrease its expression level. Knockdown the expression of MACC1 could decrease the activity of ATM and CHK1, which play critical roles in the process of DNA damage repair caused by IR, as well as the decreased activity of PI3K/mTOR pathway. Based on our preliminary results, we first present that MACC1 could enhance radioresistance of NPC throuth modulating the process of DNA damage repair. To test this hypothesis, we firstly constructed NPC radioresistance sublines; secondly, we will deeply explore the mechanism of MACC1 in radioresistance of NPC, whether or not through the modulating PI3K/mTOR pathway and stabilization the expression of FANCD2, leading to the enhanced activity of DNA damage repair. last but not least, the effect of MACC1 will be identified by in vivo study and clinical samples in NPC. Altogether, the functional role of miR-218-MACC1-mTOR-FANCD2-CHK1 pathway in NPC radioresistance will be explored and will provide the basis for further development of MACC1 as a therapeutic target for NPC.

放疗是鼻咽癌的主要治疗手段之一，而辐射抵抗是治疗失败的主要原因之一。我们的前期研究发现，MACC1可以增强鼻咽癌的辐射抵抗；与miR-218直接靶向结合从而表达水平降低；敲除MACC1的表达可导致辐射损伤修复相关蛋白ATM和CHK1的活化水平降低，以及PI3K/mTOR通路活化水平降低。依据以上前期结果，我们首次提出：MACC1通过调节辐射损伤修复过程从而参与鼻咽癌辐射抵抗的发生。本项目拟通过构建鼻咽癌辐射抵抗细胞株，并在亲代及辐射抵抗细胞株中进行MACC1表达的干预，验证MACC1通过调控下游PI3K/mTOR，稳定FANCD2蛋白的表达，从而增强DNA损伤修复能力，引起辐射抵抗的发生，并进一步在体内实验及临床病理组织分析中验证，以证明miR-218-MACC1-mTOR-FANCD2-CHK1通路是参与鼻咽癌辐射抵抗的新机制，为探寻鼻咽癌治疗的新靶点提供充分的理论依据和实验基础。

放疗是鼻咽癌的主要治疗手段之一，而辐射抵抗是治疗失败的主要原因之一。.本项研究中，我们发现，构建的鼻咽癌辐射抵抗细胞中MACC1表达升高，在亲代细胞中过表达MACC1，细胞的辐射敏感性下降，DNA损伤修复能力增强；而在辐射抵抗细胞亚株中敲除MACC1的表达，可增强细胞的辐射敏感性，DNA的损伤修复能力减弱；敲除MACC1的表达后，mTOR通路的活化受到抑制；进一步的研究发现，miR-218可与MACC1靶向结合，过表达miR-218可逆转鼻咽癌细胞的辐射抵抗；CHIP实验发现MACC1可与MYT1基因的启动子结合，通过调节MYT1基因的表达，进而激活mTOR通路参与了鼻咽癌细胞的辐射抵抗。本研究的完成揭示了MACC1在鼻咽癌辐射抵抗中的作用，并初步探讨了MACC1参与鼻咽癌辐射抵抗的分子机制，证明miR-218-MACC1-MYT1-mTOR通路是参与鼻咽癌辐射抵抗的新机制，为探寻鼻咽癌治疗的新靶点提供充分的理论依据和实验基础。