Nagahashi Masayuki, Matsuda Yasunobu, Moro Kazuki, Tsuchida Junko, Soma Daiki, Hirose Yuki, Kobayashi Takashi, Kosugi Shin-Ichi, Takabe Kazuaki, Komatsu Masaaki, Wakai Toshifumi
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.
Department of Medical Technology, Niigata University Graduate School of Health Sciences, 2-746 Asahimachi-dori, Chuo-ku, Niigata, 951-8518, Japan.
Surg Today. 2016 Sep;46(9):995-1005. doi: 10.1007/s00595-015-1270-8. Epub 2015 Oct 29.
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.
不可切除的肝细胞癌（HCC）患者通常无法通过全身化疗或放疗治愈，因为他们对传统治疗药物反应不佳。开发新型高效的靶向治疗方法以增加他们的治疗选择，依赖于对HCC发病机制背后分子机制的阐明。DNA损伤反应（DDR）是由DNA损伤触发的细胞信号事件网络。其失调被认为是HCC发生的关键机制之一。鞘氨醇-1-磷酸（S1P）作为一种脂质介质，已成为一种重要的信号分子，被发现参与许多细胞功能。在肝脏中，S1P信号的改变可能会影响DDR途径。在本综述中，我们探讨了DDR在各种病因导致的肝癌发生中的作用，包括乙型和丙型肝炎感染以及非酒精性脂肪性肝炎。此外，我们讨论了可能影响肝脏DDR的S1P的代谢和功能。阐明S1P的致病作用可能为HCC患者的治疗策略开辟新的研究途径。
