title: TSPAN2 is involved in cell invasion and motility during lung cancer progression.
abstract: In lung cancer progression, p53 mutations are more often observed in invasive tumors than in noninvasive tumors, suggesting that p53 is involved in tumor invasion and metastasis. To understand the nature of p53 function as a tumor suppressor, it is crucial to elucidate the detailed mechanism of the alteration in epithelial cells that follow oncogenic KRAS activation and p53 inactivation. Here, we report that KRAS activation induces epithelial-mesenchymal transition and that p53 inactivation is required for cell motility and invasiveness. Furthermore, TSPAN2, a transmembrane protein, is responsible for cell motility and invasiveness elicited by p53 inactivation. TSPAN2 is highly expressed in p53-mutated lung cancer cells, and high expression of TSPAN2 is associated with the poor prognosis of lung adenocarinomas. TSPAN2 knockdown suppresses metastasis to the lungs and liver, enabling prolonged survival. TSPAN2 enhances cell motility and invasiveness by assisting CD44 in scavenging intracellular reactive oxygen species.
authors.affiliation: Division of Refractory Cancer Research, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan; Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Katsushika-ku, Tokyo 125-8585, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Otsubo
authors.affiliation: Division of Refractory Cancer Research, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan; Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Katsushika-ku, Tokyo 125-8585, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Otomo
authors.affiliation: Division of Refractory Cancer Research, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan; Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Katsushika-ku, Tokyo 125-8585, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Miyazaki
authors.affiliation: Division of Refractory Cancer Research, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Matsushima-Hibiya
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kohno
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Reika
authors.initials: R
authors.lastname: Iwakawa
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Takeshita
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Okayama
authors.affiliation: Division of Genetics, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ichikawa
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
authors.affiliation: Division of Virology, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Kiyono
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ochiya
authors.affiliation: Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Katsushika-ku, Tokyo 125-8585, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Tashiro
authors.affiliation: Division of Cancer Development System, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakagama
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Yokota
authors.affiliation: Division of Refractory Cancer Research, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan. Electronic address: menari@ncc.go.jp.
authors.forename: Masato
authors.initials: M
authors.lastname: Enari
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008819:Mice, Nude; D009154:Mutation; D009361:Neoplasm Invasiveness; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D059470:Tetraspanins / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; C117307:KRAS protein, human; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; C512650:TSPAN2 protein, human; D059470:Tetraspanins; D016159:Tumor Suppressor Protein p53; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins