HCC (hepatocellular carcinoma) is the second leading cause of cancer deaths worldwide, with several etiologic causes, mostly inflammation-associated. Different inflammatory responses in the liver can be triggered by different etiological agents. The inflammatory process can be resolved or be persistent, depending on the etiology and multiple other factors. Chronic inflammation, tissue remodeling, genetic alterations, and modifications in cellular signaling are considered to be key processes promoting immunosuppression. The progressive immunosuppression leads to the inactivation of anti-tumor immunity involved in HCC carcinogenesis and progression. Tumor cellular processes including DNA damage, necrosis, and ER (endoplasmic reticulum) stress can affect both immune-surveillance and cancer-promoting inflammation, supporting a mutual interdependence. Here, we review the current understanding of how chronic liver injury and inflammation is triggered and sustained, and how inflammation is linked to HCC. The identification of many hepatic microenvironmental inflammatory processes and their effector molecules, has resulted in extensive translational work and promising clinical trials of new immunomodulatory agents.

Thrombocytopenia has been reported to be associated with small size HCCs, and thrombocytosis to be associated with large size HCCs. The aim was to examine the effects of platelets in relation to HCC cell growth.

Chlorogenic acid (CGA) is a polyphenol present in many human dietary foods. Several studies indicated a beneficial role of CGA in the prevention of cancer and an enhancement of chemotherapy when combined with CGA in the treatment of human hepatocarcinoma (HCC). Drug toxicity, resistance and subsequent disease progression represent a problem in HCC management, although treatment with the multikinase inhibitor Regorafenib improved overall survival. This study focused on the evaluation of the effects of combined treatment using both low Regorafenib concentrations and CGA as natural compound in HCC cells. The analysis of cell proliferation by Ki67 staining and cell cycle progression showed that CGA enhanced Regorafenib-mediated cell growth inhibition. Moreover, CGA potentiated the apoptotic effect of Regorafenib by the activation of the pro-apoptotic Annexin V, Bax and Caspase 3/7 and the inhibition of anti-apoptotic Bcl2 and Bcl-xL. Combined treatments were also effective in inhibiting cell motility. The mechanisms underlying the positive effects of combining CGA and Regorafenib were also addressed and an increased inhibition of MAPK (mitogen-activated protein kinase)and PI3K/Akt/mTORC (phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling was observed. Overall, these data demonstrated that co-treatment with Regorafenib and CGA enhanced Regorafenib action, reducing its cytotoxicity in HCC cells. In conclusion, this drug combination could be considered as a safe and more effective approach in HCC therapy.

Background: n-3 and n-6 polyunsaturated fatty acids (PUFAs) are the two major classes of PUFAs encountered in the diet, and both classes of fatty acids are required for normal human health. Moreover, PUFAs have effects on diverse pathological processes impacting chronic disease, such as cardiovascular and immune disease, neurological disease, and cancer. Aim: To investigate the effects of eicosapentaenoic acid (EPA) and arachidonic acid (ARA) on the proliferation and apoptosis of human hepatoma cell line HepG2 after exposure to increasing concentrations of EPA or ARA for 48 h. Moreover, in the same cells the gene expression of Fatty Acid Synthase (FAS) and 3-Hydroxy-3-Methyl-Glutaryl Coenzyme A Reductase (HMG-CoAR) was also investigated. Method: Cell growth and apoptosis were assayed by MTT and ELISA test, respectively after cell exposure to increasing concentrations of EPA and ARA. Reverse-transcription and real-time PCR was used to detect FAS and HMG-CoAR mRNA levels in treated cells. Results: Our findings show that EPA inhibits HepG2 cell growth in a dose-dependent manner, starting from 25 μM (P < 0.01, one-way ANOVA test and Dunnett's post test) and exerts a statistically significant pro-apoptotic effect already at 1 μM of EPA. Higher doses of ARA were need to obtain a statistically significant inhibition of cell proliferation and a pro-apoptotic effect in these cells (100 μM, P < 0.01, one-way ANOVA test and Dunnett's post test). Moreover, a down-regulation of FAS and HMG-CoAR gene expression was observed after EPA and ARA treatment in HepG2 cells, starting at 10 μM (P < 0.05, one-way ANOVA test and Dunnett's post test). Conclusion: Our results demonstrate that EPA and ARA inhibit HepG2 cell proliferation and induce apoptosis. The down-regulation of FAS and HMG-CoAR gene expression by EPA and ARA might be one of the mechanisms for the anti-proliferative properties of PUFAs in an in vitro model of hepatocellular carcinoma.