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.

Keywords: DNA damage response; Hepatocellular carcinoma; Lipid mediator; Sphingosine-1-phosphate.

Fig. 1

The various functions of hepatitis B virus X (HBX), HCV core protein and non-alcoholic steatohepatitis (NASH). HBX, HCV core protein, and NASH promote DNA damage through several different mechanisms, as shown. ATM ataxia telangiectasia mutated, ATR ataxia telangiectasia and Rad3-related, Chk1 checkpoint kinase 1, Chk2 checkpoint kinase 2, ER endoplasmic reticulum, HO1 heme oxygenase 1, Keap1 Kelch-like ECH-associated protein 1, MAPK mitogen-activated protein kinase, MRN Mre11-Rad50-Nbs1, NF-kappa B nuclear factor kappa-light-chain-enhancer of activated B cells, Nqo1 NAD(P)H: quinone oxidoreductase 1, Nrf-2 nuclear factor erythroid 2-related factor 2, PKCδ protein kinase cδ, STAT3 signal transducer and activator of transcription 3, UV-DDB UV-damaged DNA-binding protein, XAP-1 HBV X-associated protein 1, XPB xeroderma pigmentosum group B, XPD xeroderma pigmentosum group D, γH2AX phosphorylated histone H2AX

Fig. 2

Sphingosine-1-phosphate (S1P) as an important regulatory molecule in cancer. S1P produced by SphK1 is exported from cancer cells via S1P transporters. It promotes cancer cell proliferation, invasion and survival by binding to specific G protein-coupled receptors (S1P receptors) in an autocrine and paracrine manner. S1P produced by cancer cells also stimulates S1P receptors on endothelial cells and promotes tumor-related angiogenesis and lymphangiogenesis