IRF1通过调节自噬抑制结直肠癌生长和转移的机制研究

In recent years, it has been found that the autophagy can help tumor cells tolerate the tumor microenvironment with ischemia and hypoxia. Autophagy makes tumor cells more liable to survive and metastasize. The function in autophagy of IRF1 was reported recently, but IRF1 played different roles in kinds of tumors. Our previous studying indicated that: (1) autophagy occured in colorectal cancer (CRC) cells under starvation states, and IRF1 can inhibit autophagy of CRC and reduce the expression of ATG13 which was a key member of autophagy associated Complex(ULK1-Complex). (2) IRF1 was down-regulated in CRC tissues and the expression of IRF1 were associated with the size of CRC tissues, lymph metastasis and TNM stage. (3)Up-regulate IRF1 could inhibit the migrate and growth of CRC cells. So we propose a hypothesis that IRF1negatively regulate ATG13 in transcriptional level, thus reduce the formation of autophagy associated complex (ULK1-complex), make CRC cells difficult to adapt the jejune tumor microenvironment, consequently, the growth and metastasis ability of CRC is declined. This study will explore the regulation of IRF1 in autophagy, and declare the molecular mechanism of IRF1 in the growth and metastasis of CRC and provide possible molecular targets for the therapy of CRC.

近年研究发现自噬的发生能帮助肿瘤细胞耐受缺血缺氧的肿瘤微环境，使得肿瘤细胞更易于存活和转移。IRF1在肿瘤细胞中关于自噬的功能多次被报道，其在各种类型的肿瘤中对自噬的调控不同甚至完全相反。我们在前期研究中发现：（1）IRF1能抑制自噬并下调自噬相关复合物（ULK1-complex1）成员之一ATG13的表达；（2）IRF1在结直肠癌组织中表达降低，其表达水平与结直肠癌的大小，淋巴结转移及TNM分期相关；（3）过表达IRF1能抑制结直肠癌细胞的生长、迁移。因此我们提出了IRF1负向调控ATG13，减少自噬复合体ULK1-complex1的形成，抑制结直肠癌细胞自噬的发生，肿瘤细胞对缺血缺氧的肿瘤微环境适应力减弱，进而生长和转移能力下降的假说。本研究将探讨IRF1对自噬调节作用，以阐明IRF1通过自噬的抑制结直肠癌生长和转移的机制，为抗结直肠癌生长和转移提供可能的分子靶点。

干扰素调节因子1(IRF1)是结合到可干扰素基因调控序列上游的录调控因子，其在细胞中关于自噬的功能多次被报道，在乳腺癌中，自噬调节因子ATG7和Beclin1可负向调控IRF1，下调IRF1诱导细胞自噬。在肝细胞癌中，通过敲除IRF1可抑制IFNγ诱导的自噬。然而，IRF1介导的结直肠癌自噬的潜在机制尚未确定。在本课题中，我们证实了结直肠癌细胞在饥饿应激环境下也存在自噬，IRF1能抑制自噬并下调自噬相关复合物ULK1-Complex中的ATG13的表达，此外我们还发现IRF1在正常组织中的表达水平显著高于结直肠癌组织并与肿瘤大小呈负相关，IRF1与ATG13的表达水平呈负相关。我们还通过回复实验来明确了ATG13参与了饥饿条件下IRF1介导的自噬。ATG13的上调显著增加了IRF1过表达细胞中LC3B蛋白表达水平。这些结果表明，IRF1通过ATG13/ULK1通路直接参与了自噬的调控，抑制自噬使结直肠癌细胞对缺血缺氧的肿瘤微环境适应力减弱，进而影响生长和转移能力。本研究探讨了IRF1调控的自噬抑制结直肠癌生长和转移的分子机制，为抗结直肠癌转移提供可能的分子靶点。