title: A role of the sphingosine-1-phosphate (S1P)-S1P receptor 2 pathway in epithelial defense against cancer (EDAC).
abstract: At the initial step of carcinogenesis, transformation occurs in single cells within epithelia, where the newly emerging transformed cells are surrounded by normal epithelial cells. A recent study revealed that normal epithelial cells have an ability to sense and actively eliminate the neighboring transformed cells, a process named epithelial defense against cancer (EDAC). However, the molecular mechanism of this tumor-suppressive activity is largely unknown. In this study, we investigated a role for the sphingosine-1-phosphate (S1P)-S1P receptor 2 (S1PR2) pathway in EDAC. First, we show that addition of the S1PR2 inhibitor significantly suppresses apical extrusion of RasV12-transformed cells that are surrounded by normal cells. In addition, knockdown of S1PR2 in normal cells induces the same effect, indicating that S1PR2 in the surrounding normal cells plays a positive role in the apical elimination of the transformed cells. Of importance, not endogenous S1P but exogenous S1P is involved in this process. By using FRET analyses, we demonstrate that S1PR2 mediates Rho activation in normal cells neighboring RasV12-transformed cells, thereby promoting accumulation of filamin, a crucial regulator of EDAC. Collectively these data indicate that S1P is a key extrinsic factor that affects the outcome of cell competition between normal and transformed epithelial cells.
authors.affiliation: Division of Molecular Oncology, Hokkaido University Graduate School of Chemical Sciences and Engineering, Sapporo 060-0815, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Division of Molecular Oncology, Hokkaido University Graduate School of Chemical Sciences and Engineering, Sapporo 060-0815, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Yako
authors.affiliation: Department of Cell Physiology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Fujioka
authors.affiliation: Division of Molecular Oncology, Hokkaido University Graduate School of Chemical Sciences and Engineering, Sapporo 060-0815, Japan.
authors.forename: Mihoko
authors.initials: M
authors.lastname: Kajita
authors.affiliation: Signaling in Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University Graduate School of Chemical Sciences and Engineering, Sapporo 060-0815, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kameyama
authors.affiliation: Division of Molecular Oncology, Hokkaido University Graduate School of Chemical Sciences and Engineering, Sapporo 060-0815, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kon
authors.affiliation: Division of Molecular Oncology, Hokkaido University Graduate School of Chemical Sciences and Engineering, Sapporo 060-0815, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Ishikawa
authors.affiliation: Department of Cell Physiology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ohba
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ohno
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Kihara
authors.affiliation: Division of Molecular Oncology, Hokkaido University Graduate School of Chemical Sciences and Engineering, Sapporo 060-0815, Japan yasu@igm.hokudai.ac.jp.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Fujita
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D004285:Dogs; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism; D064448:Filamins / Q000378:metabolism; D006801:Humans; D008246:Lysophospholipids / Q000502:physiology; D061985:Madin Darby Canine Kidney Cells; D020125:Mutation, Missense; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000502:physiology; D000081025:Sphingosine-1-Phosphate Receptors; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D064448:Filamins; C471998:JTE 013; C117307:KRAS protein, human; D008246:Lysophospholipids; D011720:Pyrazoles; D011725:Pyridines; D049349:Receptors, Lysosphingolipid; C477522:S1PR2 protein, human; D000081025:Sphingosine-1-Phosphate Receptors; C060506:sphingosine 1-phosphate; D054460:rho-Associated Kinases; D016283:Proto-Oncogene Proteins p21(ras); D013110:Sphingosine