YTHDF1调控HIF-1α翻译在结直肠癌转移中的作用及机制研究

Deregulation of translation (protein synthesis) is closely related to tumorigenesis and tumor progression. m6A is the most abundant mRNA post-transcriptional modification, which was recently identified as an important cis-element in the regulation of translation. The m6A “reader” protein YTHDF1 promotes the translation of its target mRNAs by binding to m6A. However, the function of YTHDF1 in cancer development is unknown. Our previous studies showed that YTHDF1 is up-regulated in colorectal cancer (CRC). YTHDF1 protein level is positively correlated with CRC progression. In vitro studies showed that YTHDF1 promotes CRC cell migration and invasion. Our data also showed that YTHDF1 promotes the protein expression of HIF-1α, one of the key metastatic transcription factors. Together, those preliminary evidences suggest that YTHDF1 promotes CRC metastasis by up-regulating HIF-1α translation. Base on those, this project will systematically study the role of YTHDF1 in CRC metastasis and the underlying mechanism. First, we will consolidate the metastatic effect of YTHDF1 using cell and mouse models as well as in clinical samples. Second, we will study how YTHDF1 recognizes m6A and promotes HIF-1α translation at the molecular level. Finally, we will explore whether HIF-1α mediates YTHDF1-promoting CRC metastasis. Completion of the project will elucidate the role of YTHDF1/HIF-1α pathway in CRC metastasis, which will provide evidence that m6A modification is involved in tumor development, and potential targets for CRC therapy.

翻译异常与肿瘤发生发展密切相关。m6A是mRNA上最丰富的转录后修饰，近来被鉴定为一重要翻译调控元件。m6A识别因子YTHDF1通过结合m6A促进其靶基因翻译，但它在肿瘤中的作用不明。我们前期研究发现：1）YTHDF1在结直肠癌（CRC）中高表达，其表达水平与CRC进展正相关；2）YTHDF1促进CRC细胞迁移、侵袭能力；3）YTHDF1促进关键转移因子HIF-1α翻译。为深入研究YTHDF1调控HIF-1α翻译在CRC转移中的作用及其机制，本项目拟首先在临床病理样本中及动物、细胞水平明确YTHDF1的促CRC转移效应；随后阐明YTHDF1识别m6A从而促进HIF-1α基因翻译的分子机制；最后探索HIF-1α是否介导YTHDF1促进的CRC转移。本项目研究有望揭示YTHDF1/HIF-1α通路在CRC转移中的作用，建立m6A修饰与肿瘤的关系，并为CRC诊治提供新靶点。

m6A是mRNA最常见的转录后修饰，可作为顺式元件促进蛋白质翻译。m6A识别因子YTHDF1介导m6A对蛋白质翻译的调控，但它在肿瘤发生进展中的作用不明。通过本项目研究我们发现：1）YTHDF1在结直肠癌（CRC）中高表达，其表达水平与CRC进展正相关；2）YTHDF1促进CRC细胞迁移、侵袭能力和小鼠体内转移能力；3）YTHDF1促进WNT驱动的CRC发生过程；4）YTHDF1促进肠上皮干细胞活性；5）YTHDF1促进TCF7L2、HIF-1α等mRNA的翻译过程。基于以上结果，我们在EMBO Reports等杂志上发表SCI论文6篇。本项目研究揭示了YTHDF1在CRC发生及转移中的作用，并可能为CRC治疗提供新靶点。