Deregulated Lysophosphatidic Acid Metabolism and Signaling in Liver Cancer

Abstract

Liver cancer is one of the leading causes of death worldwide due to late diagnosis and scarcity of treatment options. The major risk factor for liver cancer is cirrhosis with the underlying causes of cirrhosis being viral infection (hepatitis B or C), metabolic deregulation (Non-alcoholic fatty liver disease (NAFLD) in the presence of obesity and diabetes), alcohol or cholestatic disorders. Lysophosphatidic acid (LPA) is a bioactive phospholipid with numerous effects, most of them compatible with the hallmarks of cancer (proliferation, migration, invasion, survival, evasion of apoptosis, deregulated metabolism, neoangiogenesis, etc.). Autotaxin (ATX) is the enzyme responsible for the bulk of extracellular LPA production, and together with LPA signaling is involved in chronic inflammatory diseases, fibrosis and cancer. This review discusses the most important findings and the mechanisms related to ATX/LPA/LPAR involvement on metabolic, viral and cholestatic liver disorders and their progression to liver cancer in the context of human patients and mouse models. It focuses on the role of ATX/LPA in NAFLD development and its progression to liver cancer as NAFLD has an increasing incidence which is associated with the increasing incidence of liver cancer. Bearing in mind that adipose tissue accounts for the largest amount of LPA production, many studies have implicated LPA in adipose tissue metabolism and inflammation, liver steatosis, insulin resistance, glucose intolerance and lipogenesis. At the same time, LPA and ATX play crucial roles in fibrotic diseases. Given that hepatocellular carcinoma (HCC) is usually developed on the background of liver fibrosis, therapies that both delay the progression of fibrosis and prevent its development to malignancy would be very promising. Therefore, ATX/LPA signaling appears as an attractive therapeutic target as evidenced by the fact that it is involved in both liver fibrosis progression and liver cancer development.

Development and Validation of a Metabolic Gene-Based Prognostic Signature for Hepatocellular Carcinoma

“…6 Increasing evidence has confirmed that aberrant metabolisms of glucose, lipid, amino acid, acylcarnitine, and lysophosphatidic acid, as well as several metabolic enzymes and metabolites, are involved in HCC progression. 5,[7][8][9][10] For example, in HCC cells, lipid synthesis is enhanced, and increased fatty acids can serve as the energy sources and signaling molecules to promote HCC proliferation. 7,11 Besides, a ketogenesis rate-limiting enzyme is downregulated in HCC to decrease the amount of intracellular ketone, promoting HCC progression.…”

Could Protein Content of Urinary Extracellular Vesicles be Useful to Detect Alcoholic Liver Disease and Assess Hepatocarcinoma Risk?

“…Indeed, ferroptosis-inducing therapy is being applied as treatment in many cancers by using drugs such as sorafenib, erastin and RSL3 [89], and new formulations with erastin-loaded exosomes are been explored [90]. Other upregulated uEV-proteins involved in homeostasis of molecules are RHCG, that plays a major role in transporting ammonia and accumulates in acute liver failure, resulting in brain damage [91,92]; and GDPD3, responsible for lysophosphatidic acid synthesis that, in turns, is involved in liver disease development [93][94][95].…”

Screening of Early Diagnostic Biomarkers and Prognostic Biomarkers for Liver Cancer Based on GEO and TCGA Databases and Studies on Pathways and Biological Functions Affecting the Survival Time of Liver Cancer

“…Modern medical research has shown that there is no pain sensation in the liver, and even if the liver disease had happened, the body does not feel it. Therefore, no matter from the perspective of traditional Chinese medicine or modern medicine, the clinical manifestation of liver disease is very slight, Therefore, in clinical practice, most patients with liver cancer are diagnosed at a late stage [20][21][22][23]. The cure rate of early-stage liver cancer is very optimistic, so if we can make a diagnosis in stage III, stage II or even stage I, then the treatment of tumour will not be as desperate as it is now.…”