title: A novel FOXM1 isoform, FOXM1D, promotes epithelial-mesenchymal transition and metastasis through ROCKs activation in colorectal cancer.
abstract: Epithelial-mesenchymal transition (EMT) is a critical event in metastasis of colorectal cancer (CRC). Rho/ROCKs signaling has a pivotal role in orchestrating actin cytoskeleton, leading to EMT and cancer invasion. However, the underlying mechanisms for ROCKs activation are not fully understood. Here, we identified FOXM1D, a novel isoform of Forkhead box M1 (FOXM1) that has a pivotal role in ROCKs activation by directly interacting with coiled-coil region of ROCK2. FOXM1D overexpression significantly polymerizes actin assembly and impairs E-cadherin expression, resulting in EMT and metastasis in xenograft mouse model and knockdown of FOXM1D has the opposite effect. Moreover, a high FOXM1D level correlates closely with clinical CRC metastasis. FOXM1D-induced ROCKs activation could be abrogated by the ROCKs inhibitors Y-27632 and fasudil. These observations indicate that the FOXM1D-ROCK2 interaction is crucial for Rho/ROCKs signaling and provide novel insight into actin cytoskeleton regulation and therapeutic potential for CRC metastasis.
authors.affiliation: Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Collaborative Innovation Center of Cancer Medicine, Shanghai Medical College, Fudan University; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Collaborative Innovation Center of Cancer Medicine, Shanghai Medical College, Fudan University; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Collaborative Innovation Center of Cancer Medicine, Shanghai Medical College, Fudan University; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Colorectal Surgery, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: H
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Collaborative Innovation Center of Cancer Medicine, Shanghai Medical College, Fudan University; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: P
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Collaborative Innovation Center of Cancer Medicine, Shanghai Medical College, Fudan University; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Colorectal Surgery, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Collaborative Innovation Center of Cancer Medicine, Shanghai Medical College, Fudan University; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Collaborative Innovation Center of Cancer Medicine, Shanghai Medical College, Fudan University; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: P
authors.initials: P
authors.lastname: Ding
authors.affiliation: Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Collaborative Innovation Center of Cancer Medicine, Shanghai Medical College, Fudan University; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: N
authors.initials: N
authors.lastname: Wang
authors.affiliation: Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: C
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Urology, Shanghai Tenth People's Hospital, Shanghai, China.
authors.forename: T
authors.initials: T
authors.lastname: Huang
authors.affiliation: Department of Urology, Shanghai Tenth People's Hospital, Shanghai, China.
authors.forename: X
authors.initials: X
authors.lastname: Yao
authors.affiliation: Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Collaborative Innovation Center of Cancer Medicine, Shanghai Medical College, Fudan University; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Qiao
authors.affiliation: Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Collaborative Innovation Center of Cancer Medicine, Shanghai Medical College, Fudan University; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: H
authors.initials: H
authors.lastname: Gu
authors.affiliation: Department of Colorectal Surgery, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: G
authors.initials: G
authors.lastname: Cai
authors.affiliation: Department of Colorectal Surgery, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: S
authors.initials: S
authors.lastname: Cai
authors.affiliation: Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Collaborative Innovation Center of Cancer Medicine, Shanghai Medical College, Fudan University; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.|Department of Immunology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: W
authors.initials: W
authors.lastname: Hu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition; D000072278:Forkhead Box Protein M1 / Q000235:genetics / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020033:Protein Isoforms; D015398:Signal Transduction; D014162:Transfection; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D020033:Protein Isoforms; C515852:ROCK2 protein, human; D054460:rho-Associated Kinases