Aspirin in hepatocellular carcinoma: Is it an out-of-date or promising treatment?

Abstract

Hepatocellular carcinoma (HCC) is one of the most aggressive human malignancies with a dismal survival rate. Few strategies can effectively prevent the occurrence of HCC. Although immunotherapy has significantly improved HCC-related survival in recent years, this systemic therapy is very expensive and lays a heavy burden on most HCC patients. Aspirin, which is currently one of the most widely used medications in analgesic and cardiovascular diseases, is reported to have anti-tumor effects on HCC. Most importantly, long-term administration of low-dose aspirin does not significantly increase the risk of gastrointestinal bleeding. Owing to its cost-effectiveness and wide use, aspirin can be easily applied as an HCC treatment and is affordable for a wide range of patients. Therefore, deeper understanding and more attention are needed to extend the frontline of aspirin's preventive and therapeutic potential into cancer research and management. In this review, we discuss the preventive effect of aspirin on HCC in the context of different etiological factors, including hepatitis B or hepatitis C virus infection, non-alcoholic fatty liver disease, and alcohol-associated liver disease. The therapeutic role of aspirin in resectable or unresectable HCC management is also discussed. Furthermore, the mechanisms underlying the anti-cancer effects of aspirin on HCC are fully reviewed and discussed in the following two aspects: the effect of aspirin on multi-oncogenic signaling pathways in HCC (e.g., AMPK, Wnt/β-catenin, NF-κB) and aspirin-mediated immunometabolic responses in liver diseases. These findings indicate aspirin is a promising agent for populations at risk and HCC patients to prevent or treat HCC.

Keywords: Aspirin; Cancer therapy; Chemoprevention; Hepatocellular carcinoma; Immunometabolic response; Oncogenic signaling.

Fig. 1

Molecular mechanism of aspirin repression of tumor-related characteristics. By targeting several molecules (e.g., β-catenin, NF-κB) that are critical in the progression of HCC, aspirin exerts a broad-spectrum anti-cancer effect on key tumor cell functions, including proliferation, apoptosis, and invasion. Abbreviations: AMPK, adenosine 5′-monophosphate-activated protein kinase; AP-1, activator protein-1; CCK-18, caspase-cleaved cytokeratin-18; COX-2, cyclooxygenase-2; DHA, docosahexaenoic acid; EGFR, epidermal growth factor receptor; EP2, prostaglandin E-receptor 2; ERK, extracellular signal-regulated kinase; Gαs, stimulatory G alpha protein; GLUT1, glucose transporter 1; HIF-1α, hypoxia inducible factor-1α; MMP9, mTOR, matrix metalloproteinase 9; mammalian target of rapamycin; NF-κB, nuclear factor kappa-B; P4HA2, collagen prolyl 4-hydroxylase A subunit 2; PGE2, prostaglandin E2; SDF1-α, stromal-derived factor 1-alpha; TSC, tuberous sclerosis complex; YAP, Yes-associated protein.

Fig. 2

The immunometabolic response mediated by aspirin in the liver. Aspirin regulates lipid metabolism in several types of cells (e.g., hepatocyte, HCC cells) in the liver. Furthermore, aspirin and aspirin-triggered anti-inflammatory lipids, which include LXA4, RvD1, RvD2, MaR1, and PD1, modulate the activity (e.g., trafficking, secretion, differentiation, infiltration) of certain immune cells (e.g., PMN, monocyte, macrophage), thus reprogramming the HCC immune microenvironment. Abbreviations: ACC, acetyl-CoA carboxylase; Acox1, acyl-coenzyme A oxidase; ACSL1, acyl-CoA synthetase long-chain family member 1; AMPK, adenosine 5′-monophosphate-activated protein kinase; Atg5, autophagy-related proteins 5; Atg7, autophagy-related proteins 7; Cpt1a, carnitine palmitoyltransferase; CX3CL1, chemokine (CX3C motif) ligand 1; CX3CR1, chemokine (CX3C motif) receptor 1; ER, endoplasmic reticulum; FPR2, formyl peptide receptor 2; GPIbα, platelet-derived glycoprotein ibalpha; IL-1β, interleukin-1β; IL-4, interleukin-4; IL-8, interleukin-8; KC, Kupffer cell; LXA4, lipoxin A4; MAPK, mitogen-activated protein kinase; MaR1, maresin 1; MCP-1, monocyte chemoattractant protein-1; MIP-2, macrophage inflammatory peptide-2; M-CSF, macrophage colony-stimulating factor; NKT, natural killer T cell; NF-κB, nuclear factor kappa-B; PGC-1α, proliferator-activated receptor gamma coactivator 1-alpha; PMN, polymorphonuclear neutrophil; PD1, protectin 1; RvD1, resolvin D1; RvD2, resolvin D2; ROS, reactive oxygen species; STAT3, signal transducer and activator of transcription-3.

Fig. 3

The therapeutic and preventive effects of aspirin on HCC. When the healthy liver is exposed to various risk factors (e.g., HCV, HBV), the liver will be damaged to different degrees. If patients with liver disease take low-dose aspirin for a long time, aspirin can significantly modulate some biological molecules to suppress the biological characteristics of HCC cells and affect lipid metabolism and immune modulation in liver, thus reducing the occurrence of HCC and HCC-related mortality. In contrast, patients without any treatment may eventually develop HCC.