8‐Hydroxy‐2′‐deoxy‐guanosine is a risk factor for development of hepatocellular carcinoma in patients with chronic hepatitis C virus infection

Lafdil

The American Journal of Pathology

et al. 2011

Aberrantly hyperactivated STAT3 has been found in human liver cancers as an oncogene; however, STAT3 has also been shown to exert hepatoprotective effects during liver injury. The balancing act that STAT3 plays between hepatoprotection and liver tumorigenesis remains poorly defined. In this study, the diethylnitrosamine (DEN)-induced liver tumor model and the chronic carbon tetrachloride (CCl 4 )-induced liver fibrosis model were both used to investigate the role of STAT3 in liver tumorigenesis. Hepatocyte-specific STAT3 knockout mice were resistant to liver tumorigenesis induced by a single DEN injection, whose tumorigenesis was associated with minimal chronic liver inflammation, injury, and fibrosis. In contrast, long-term CCl 4 treatment resulted in severe hepatic oxidative damage, inflammation, and fibrosis but rarely induced liver tumor formation in wild-type mice. Despite the oncogenic function of STAT3 in DEN-induced liver tumor, hepatocyte-specific STAT3 knockout mice were more susceptible to liver tumorigenesis after 16 weeks of CCl 4 injection, which was associated with higher levels of liver injury, inflammation, fibrosis, and oxidative DNA damage compared with wild-type mice. These findings suggest that the hepatoprotective feature of STAT3 prevents hepatic damage and fibrosis under the condition of persistent inflammatory stress, consequently suppressing injurydriven liver tumor initiation. Once liver tumor cells have developed, STAT3 likely acts as an oncogenic factor to promote tumor growth.

Section: Potential Mechanisms Underlying Stat3 Promotion and Inhibitimentioning

confidence: 99%

Hepatoprotective versus Oncogenic Functions of STAT3 in Liver Tumorigenesis

Lafdil

The American Journal of Pathology

et al. 2011

“…In chronic hepatitis C, infiltration of activated phagocytic cells provides an additional source of ROS production that promotes oxidative stress and damage to proteins, lipids and DNA (15). Recently, it has been shown that oxidative DNA damage is associated with the increased risk of HCC and that hepatic 8-OHdG levels are considered useful markers to identify high-risk patients (16,17). Depending on the extent of DNA damage, cells may undergo apoptosis or proliferate towards tumour progression.…”

Section: Discussionmentioning

confidence: 99%

DNA oxidative damage of neoplastic rat liver lesions

Marengo

Ciusis²,

Ricciarelli³

et al. 2010

Oncol Rep

Abstract. Hepatic lesions, experimentally-induced in Fisher 344 (F344) and Brown Norway (BN) rats, respectively, susceptible and resistant to liver carcinogenesis, progress differently to hepatocellular carcinoma (HCC). The mechanisms responsible for the acquisition of the resistant phenotype are not completely clear. Herein, we show that in F344 rats subjected to carcinogenic treatment, angiogenesis and DNA oxidation markers increase in preneoplastic and neoplastic liver lesions. On the contrary, in the HCCs of treated BN rats, angiogenesis and a minor DNA oxidation are accompanied by an attempt of tissue remodelling. This study suggests that DNA oxidation might be an important factor in the initiation and promotion of the events of hepatocarcinogenesis. On the other hand, the enhancement of GSH levels and the down-regulation of superoxide dismutase (SOD) expression in both rat strains suggest that antioxidant response is not involved in the acquisition of resistant phenotype.

“…Cytokines produced by CD4+ T-helper (Th) cells are categorized as Th1 or Th2; Th1 cytokines (e.g., IL-1α, IL-1β, IL-2, IL-12p35, IL-12p40, IL-15, TNF-α and IFN-γ) and Th2 cytokines (e.g., IL-4, IL-8, IL-10, and IL-5) are generally referred to as proinflammatory and anti-inflammatory cytokines, respectively (82). In the liver, cell damage and regeneration mediated by viral hepatitis-induced immune responses can cause dysregulated hepatocyte proliferation, which may accelerate the development and progression of hepatic cancer through transcription and activation of cytokines and growth factors, oxidative DNA damage, DNA methylation, and hepatocyte injury (83)(84)(85)(86). Increasing evidence indicates the involvement of cytokines in hepatocarcinogenesis [reviewed by Bishayee (87)].…”

Section: Polysaccharides Targeting Pro-inflammatory Cytokinesmentioning

confidence: 99%

Targeting of growth factors in the treatment of hepatocellular carcinoma: The potentials of polysaccharides

et al. 2017

Abstract. Hepatocellular carcinoma (HCC) has become a leading cause of cancer-associated mortality worldwide and is thus of great concern. Although various chemotherapeutic drugs are currently used for the treatment of HCC, severe side effects associated with these treatments have prompted interest in novel therapies, including the use of certain biological macromolecules such as polysaccharides. Several studies have shown that polysaccharides have anticancer and antiproliferative effects on HCC. Vascular endothelial growth factor, transforming growth factor β, epidermal growth factor and fibroblast growth factor may be effective targets for polysaccharides and may modulate tumor growth and immunity through increasing the expression levels of cytokines. The present review focuses on the ways in which growth factors contribute to the development of HCC, and on the anti-growth factor activities of natural and synthetic polysaccharides, as well as their effect on proinflammatory cytokines.