title: Sphingosine-1-phosphate receptor type 1 regulates glioma cell proliferation and correlates with patient survival.
abstract: Sphingosine-1-phosphate (S1P) is a bioactive lipid that signals through a family of G protein-coupled receptors consisting of 5 members termed S1P(1-5), and it regulates cellular proliferation, migration and survival. We investigated the expression and role of S1P receptors in glioma. Human glioma expressed S1P(1), S1P(2), S1P(3), and S1P(5) by quantitative real-time PCR analysis. Expression of the S1P(1) was significantly lower in glioblastoma than in the normal brain (p < 0.01) and diffuse astrocytoma (p < 0.05). Immunoblotting showed that normal brain expressed more S1P(1) protein than did glioblastoma. Immunohistochemistry showed that S1P(1) was localized predominantly in the astrocytes in the normal brain, but no staining was observed in glioblastoma. Downregulation of S1P(1) expression correlated with poor survival of patients with glioblastoma (p < 0.05). S1P(1) small interfering RNA promoted cell proliferation in high-expressor glioma cell lines (T98G, G112). Cell proliferation was promoted by the pertussis toxin, which deactivates G(i/o) type of G proteins; the S1P(1) is exclusively coupled to these proteins. Forced expression of the S1P(1) in low-expressor cell lines (U87, U251) resulted in decreased cell growth and led to suppressed tumor growth in transplanted gliomas in vivo. Furthermore, we found a significant association between the S1P(1) expression and early growth response-1, a transcriptional factor that exhibits tumor suppression in glioblastoma cells (p < 0.05). These data indicate that the downregulation of S1P(1) expression enhances the malignancy of glioblastoma by increasing cell proliferation and correlates with the shorter survival of patients with glioblastoma.
authors.affiliation: Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Nakada
authors.forename: Naotoshi
authors.initials: N
authors.lastname: Sugimoto
authors.forename: Tomoya
authors.initials: T
authors.lastname: Harada
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kita
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Uchiyama
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yachie
authors.forename: Yoh
authors.initials: Y
authors.lastname: Takuwa
authors.forename: Jun-Ichiro
authors.initials: J
authors.lastname: Hamada
mesh_terms: D001254:Astrocytoma / Q000378:metabolism / Q000401:mortality; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D015536:Down-Regulation; D019204:GTP-Binding Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D005910:Glioma / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D037342:Pertussis Toxin / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D049349:Receptors, Lysosphingolipid; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins