FOXM1新型异构体FOXM1D促进肿瘤进展的分子机制

Cancer metastasis and drug resistance remain the key questions in cancer research field. FOXM1 (FOXM1B/C) has been widely recognized as a nuclear transcription factor, which is overexpressed in most types of cancer and highly associated with cancer poor prognosis. Interestingly, FOXM1 is greatly correlated to “ten characters” of cancer that were summarized by Dr. Weinberg. Very recently, we have identified a novel isoform of FOXM1, named FOXM1D that is produced by alternative splicing. FOXM1D, locating in cytoplasm without transcription effect, is also highly expressed in metastatic cancer tissues. It plays the roles mainly through the protein-protein interaction with ROCKs, PKM2 and PI3K, resulting in the high association with cancer metastasis and drug resistance. Moreover, FOXM1D can be degraded via isgylation modified by typer I interferons. In this proposal, using the biochemical and molecular biological approaches we will investigate the molecular mechanisms in the levels of molecule, cell, animal and human specimen, by which FOXM1D is highly expressed, FOXM1D promotes metastasis and drug resistance via protein-protein interaction, and FOXM1D is degraded by isgylation. We hope that these findings may provide evidence for FOXM1D as cancer prognosis and drug target in cancer treatment.

肿瘤侵袭转移与治疗耐药机制仍然是肿瘤研究领域的重要问题。既往认为FOXM1（FOXM1B/C）在核内发挥转录因子功能，几乎高表达于所有类型肿瘤组织，与肿瘤预后密切相关，其功能与Weinberg提出的肿瘤十大特征高度吻合。我们最近首次鉴定出一种新的通过可变剪切产生的FOXM1异构体，并命名为FOXM1D。FOXM1D位于胞浆，高表达于高转移性肿瘤组织，无转录功能，主要通过与ROCKs，PKM2和PI3K等蛋白质相互作用而发挥功能，与肿瘤侵袭转移与耐药密切相关，且I型干扰素可Isgylation修饰并降解FOXM1。本课题将利用生化和分子生物学等手段，在分子、细胞、动物和临床水平深入研究FOXM1D高表达、FOXM1通过蛋白相互作用发挥促肿瘤进展与耐药、以及I型干扰素Isgylation修饰降解FOXM1的分子机制，为FOXM1D作为肿瘤预后预测的标志物和肿瘤治疗的药物靶点提供理论依据。

FOXM1是一种与肿瘤发生发展关系异常密切的转录因子，它负责调控参与细胞周期的60余种蛋白的基因转录，故曾被认为是增殖特异的转录因子。后续发现FOXM1更直接或间接参与调控与肿瘤发生发展共220余种基因的转录，FOXM1几乎高表达于所有肿瘤组织及其各个阶段。大数据分析也表明FOXM1是失调的七个关键转录因子之一，而且FOXM1高表达与大多数实体瘤的不良预后呈显著正相关。FOXM1由于具有作为预测肿瘤预后的独立标记物以及成为重要肿瘤治疗靶点的潜力，但是FOXM1参与肿瘤发生发展和耐药治疗的机制还尚未完全阐明，因此，深入研究FOXM1的功能与调控具有重要的理论与潜在的应用价值。我们前期发现并命名了一种FOXM1的新的转录异构体FOXM1D（Oncogene, 2018），并初步揭示了FOXM1D通过与ROCKs相互作用促进上皮间质转化（EMT）而增强直结肠癌肝转移的分子机制。后续申请了本项目资助，拟深入研究FOXM1D参与肿瘤进展与耐药形成的功能与分子机制，为肿瘤预后预测和治疗靶点提供理论依据。通过本项目的实施，我们发现FOXM1D与PI3K的p110催化亚基和p85调节亚基同时发生相互作用，激活PI3K而促进肿瘤的多种生物学行为，包括EMT，研究结果发表于Signal Transduction and Targeted Therapy（2020）。我们还深入研究了FOXM1D参与肿瘤代谢和血管生成的作用与机制，结果表明代谢重要激酶PKM2通过与FOXM1D相互作用，促进肿瘤细胞的糖酵解，以及VEGF的合成与分泌进而促进血管生成，最终促进肿瘤的增殖，研究结果发表于Molecular Oncology（2021）。另外，我们还发现FOXM1D在肿瘤患者T细胞中表达水平下调，促进肿瘤免疫逃避，正深入研究其分子机制。项目获批授权专利3项，另外培养中青年研究人员两名，博士后1名，博士3名，硕士1名，顺利地完成了相应的研究计划。