PC4介导的IL-1βm6A修饰在低氧诱导结直肠癌侵袭转移中的作用和机制研究

低氧微环境可以促进CRC（结直肠癌）侵袭转移，然而其中的分子机制尚未完全阐明。寻找低氧促进CRC转移的分子并加以阻断，是改善CRC预后的关键。我们近期在CRC中发现了一个新的受低氧调控的转录辅因子PC4，可以促进CRC细胞侵袭，并引起下游IL-1β的mRNA表达和m6A（腺嘌呤6位N原子甲基化）修饰增加，以及甲基化转移酶METTL3的表达增加。因此我们提出假设：低氧诱导PC4表达增加，促进METTL3的转录表达，使得IL-1β mRNA发生m6A修饰，稳定性增加，从而加快CRC侵袭转移。课题将通过CRC临床样本、裸鼠转移瘤及CRC细胞模型，探索PC4对低氧CRC侵袭转移的影响；在低氧CRC细胞中，通过质谱分析、DNA/RNA-蛋白结合实验等阐明Hif-1α对PC4、PC4对METTL3的转录调控，以及下游IL-1β的m6A修饰和稳定性的变化和分子机制，有望为抑制CRC转移提供新的治疗靶点。

Hypoxic microenvironment could promote the invasion and metastasis of colorectal cancer (CRC), while the underlying molecular mechanisms have not been fully elucidated. Exploring the molecules during the hypoxic metastasis of CRC and blocking them is crucial for the prognosis improvement of CRC. Our recent work found a new hypoxia-regulated transcriptional coactivator PC4 (transcriptional positive coactivator 4), which could enhance the invasiveness of CRC cells, together with upregulated mRNA expression and m6A (N6-methyladenosine) modification of downstream IL-1β. Meanwhile, the expression of METTL3 (Methyltransferase Like 3) was also increased. Thereafter, we propose the hypothesis that “Hypoxia induces the expression of PC4, which enhances the transcription of METTL3, thus bring the m6A modification and enhanced stability of IL-1β mRNA, then the invasion and metastasis of CRC cells are accelerated”. This project will explore the impact of PC4 on the invasion and metastasis of CRC under hypoxia through CRC clinical specimens, nude mice metastatic tumor and CRC cell models. In addition, the transcription regulation of PC4 by Hif-1α, the transcription regulation of METTL3 by PC4, the alteration of downstream IL-1β m6A modification and molecular mechanisms in hypoxic CRC cells will be elucidated through spectrum analysis and DNA/RNA-protein binding assays. Hopefully, this study will provide new therapeutic targets for inhibiting the metastasis of CRC.