title: Targeted deletion of Kif18a protects from colitis-associated colorectal (CAC) tumors in mice through impairing Akt phosphorylation.
abstract: Kinesins are a superfamily of molecular motors involved in cell division or intracellular transport. They are becoming important targets for chemotherapeutic intervention of cancer due to their crucial role in mitosis. Here, we demonstrate that the kinesin-8 Kif18a is overexpressed in murine CAC and is a crucial promoter during early CAC carcinogenesis. Kif18a-deficient mice are evidently protected from AOM-DSS-induced colon carcinogenesis. Kif18A is responsible for proliferation of colonic tumor cells, while Kif18a ablation in mice promotes cell apoptosis. Mechanistically, Kif18a is responsible for induction of Akt phosphorylation, which is known to be associated with cell survival regulation. In conclusion, Kif18a is critical for colorectal carcinogenesis in the setting of inflammation by mechanisms of increased PI3K-AKT signaling. Inhibition of Kif18A activity may be useful in the prevention or chemotherapeutic intervention of CAC.
authors.affiliation: State Key Laboratory of Medical Genomics, Research Center for Experimental Medicine, Rui-Jin Hospital and Department of Medical Genetics, E-Institutes of Shanghai Universities, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Houbao
authors.initials: H
authors.lastname: Zhu
authors.forename: Wangyang
authors.initials: W
authors.lastname: Xu
authors.forename: Hongxin
authors.initials: H
authors.lastname: Zhang
authors.forename: Jianbing
authors.initials: J
authors.lastname: Liu
authors.forename: Haimin
authors.initials: H
authors.lastname: Xu
authors.forename: Shunyuan
authors.initials: S
authors.lastname: Lu
authors.forename: Suying
authors.initials: S
authors.lastname: Dang
authors.forename: Ying
authors.initials: Y
authors.lastname: Kuang
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Jin
authors.forename: Zhugang
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000818:Animals; D003092:Colitis / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000517:prevention & control*; D005260:Female; D017353:Gene Deletion; D018390:Gene Targeting / Q000379:methods*; D016547:Kinesins / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000235:genetics; D011230:Precancerous Conditions / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*
chemical_list: C578236:KIF19A protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D016547:Kinesins
keywords: AOM–DSS model; Akt; Colitis-associated cancer; Kinesin-8 Kif18a; Knock-out mice; Tumorigenesis