title: DNA damage response and sphingolipid signaling in liver diseases.
abstract: Patients with unresectable hepatocellular carcinoma (HCC) cannot generally be cured by systemic chemotherapy or radiotherapy due to their poor response to conventional therapeutic agents. The development of novel and efficient targeted therapies to increase their treatment options depends on the elucidation of the molecular mechanisms that underlie the pathogenesis of HCC. The DNA damage response (DDR) is a network of cell-signaling events that are triggered by DNA damage. Its dysregulation is thought to be one of the key mechanisms underlying the generation of HCC. Sphingosine-1-phosphate (S1P), a lipid mediator, has emerged as an important signaling molecule that has been found to be involved in many cellular functions. In the liver, the alteration of S1P signaling potentially affects the DDR pathways. In this review, we explore the role of the DDR in hepatocarcinogenesis of various etiologies, including hepatitis B and C infection and non-alcoholic steatohepatitis. Furthermore, we discuss the metabolism and functions of S1P that may affect the hepatic DDR. The elucidation of the pathogenic role of S1P may create new avenues of research into therapeutic strategies for patients with HCC.
authors.affiliation: Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan. mnagahashi@med.niigata-u.ac.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nagahashi
authors.affiliation: Department of Medical Technology, Niigata University Graduate School of Health Sciences, 2-746 Asahimachi-dori, Chuo-ku, Niigata, 951-8518, Japan.
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Matsuda
authors.affiliation: Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Moro
authors.affiliation: Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Tsuchida
authors.affiliation: Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.
authors.forename: Daiki
authors.initials: D
authors.lastname: Soma
authors.affiliation: Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hirose
authors.affiliation: Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Kosugi
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine and the Massey Cancer Center, West Hospital 7-402, 1200 East Broad Street, Richmond, VA, 23298-0011, USA.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Takabe
authors.affiliation: Department of Biochemistry, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Wakai
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000628:therapy; D004249:DNA Damage / Q000235:genetics* / Q000502:physiology; D006509:Hepatitis B / Q000150:complications; D006526:Hepatitis C / Q000150:complications; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology* / Q000628:therapy; D008190:Lyases / Q000502:physiology; D008246:Lysophospholipids / Q000378:metabolism / Q000502:physiology*; D058990:Molecular Targeted Therapy; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000502:physiology; D000099157:Sphingosine Kinase
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008190:Lyases; D008246:Lysophospholipids; D010744:Phosphoric Monoester Hydrolases; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; C466999:SPHKAP protein, human; C060506:sphingosine 1-phosphate; C000594250:sphingosine kinase 2, human; D000099157:Sphingosine Kinase
keywords: DNA damage response; Hepatocellular carcinoma; Lipid mediator; Sphingosine-1-phosphate