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。

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.