Abstract
Hyaluronic acid (HA) is a glycosaminoglycan of extracellular matrix related to cell surface which interacts with various cell types. To understand the role of HA during hepatocarcinogenesis, we assessed the effect of the inhibition of HA deposition and its association with heterogeneous hepatocellular carcinoma (HCC) cells. In this study, we used transgenic mice C57BL/6J-Tg(Alb1HBV)44Bri/J (HBV-TG) and normal C57BL/6 J (WT) for in vivo study, while HCC cells Huh7 and JHH6 as in vitro models. Both models were treated with an HA inhibitor 4-methylumbelliferone (4MU). We observed that 4MU treatments in animal model down-regulated the mRNA expressions of HA-related genes Has3 and Hyal2 only in HBV-TG but not in normal WT. As observed in vivo, in HCC cell lines, the HAS2 mRNA expression was down-regulated in Huh7 while HAS3 in JHH6, both with or without the presence of extrinsic HA. Interestingly, in both models, the expressions of various cancer stem cells (CD44, CD90, CD133, and EpCAM) were also decreased. Further, histological analysis showed that 4MU treatment with dose 25 mg/kg/day reduced fibrosis, inflammation, and steatosis in vivo, in addition to be pro-apoptotic. We concluded that the inhibition of HA reduced the expressions of HA-related genes and stem cells markers in both models, indicating a possible modulation of cells-to-cells and cells-to-matrix interaction.
Highlights
Hepatocellular carcinoma (HCC) is a major health problem, being the second most common cause of cancer-related death worldwide[1]
Hyaluronic acid (HA) deposition was evident in the liver of hepatitis B virus (HBV)-transgenic mice (HBV-TG), especially in the hepatic periportal area while this accumulation was not noticed in wild-type mice (WT)
No animals showed any adverse reactions during treatment; only in a group of 50 mg/kg/day HBV-TG mice, a slight increase (10%) of body weight was observed (Table 1)
Summary
Hepatocellular carcinoma (HCC) is a major health problem, being the second most common cause of cancer-related death worldwide[1]. HA is found in almost all tissues but it is especially increased in those with active cell proliferation, regeneration, and repair, such as embryonic, inflamed, and tumor stroma tissues[4,5]. It is one of the markers of fibrosis in liver diseases[6,7] and high preoperative serum HA levels can be used to predict poor prognosis in patients with HCC after hepatic resection[8]. Many species of plants, especially umbelliferae, fabaceae, and oleaceae It is dietary supplement since the 1990s to support liver function and detoxification, as well as in clinical trials in patients with chronic hepatitis B and C. Tumors systemically treated with 4MU show extensive areas of necrosis, inflammatory infiltrates and a 2–3-fold reduction in the number of tumor satellites[10]
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