Liver fibrosis occurs during wound healing after repeated liver injury and is characterized by extensive extracellular matrix deposition. We previously identified hyaluronan synthase 2 (HAS2) as a driver of liver fibrosis and hepatic stellate cell (HSC) activation. Developing strategies to suppress HSC activation is key to alleviating liver fibrosis, and HAS2 is an attractive candidate for intervention. To gain insight into the molecular function of HAS2, we investigated its posttranscriptional regulation. We found that miR-200c directly targets the 3’ untranslated regions of HAS2. Moreover, miR-200c and HAS2 were inversely expressed in fibrotic human and mouse livers. After establishing the direct interaction between miR-200c and HAS2, we investigated the functional outcome of regulating HAS2 expression in three murine models: CCl4-induced acute liver injury, CCl4-induced chronic liver fibrosis, and bile duct ligation-induced liver fibrosis. Hepatic Has2 expression was induced by acute and chronic CCl4 treatment. In contrast, miR-200c expression was decreased after CCl4 treatment. HSC-specific Has2 deletion reduced the expression of inflammatory markers and infiltration of macrophages in the models. Importantly, hyaluronidase-2 (HYAL2) but not HYAL1 was overexpressed in fibrotic human and murine livers. HYAL2 is an enzyme that can cleave the extracellular matrix component hyaluronan. We found that low-molecular-weight hyaluronan stimulated the expression of inflammatory genes. Treatment with the HA synthesis inhibitor 4-methylumbelliferone alleviated bile duct ligation-induced expression of these inflammatory markers. Collectively, our results suggest that HAS2 is negatively regulated by miR-200c and contributes to the development of acute liver injury and chronic liver inflammation via hyaluronan-mediated immune signaling.
Introduction: The aim of this systematic review is to provide evidence confirming the efficacy and safety of herbal medicines used in the treatment of liver cancer.Methods: The review will include randomized clinical trials that compared herbal medicines used as treatments for liver cancer with other therapies, such as placebos and Western medicine. Only randomized controlled trials will be included in this review, and all types of herbal medicine will be evaluated. Eleven electronic databases will be searched from the inception date: the Cochrane Database of Systematic Reviews, MEDLINE, EMBASE, AMED, CINAHL, one Chinese database (CNKI), and five Korean databases (OASIS, DBpia, RISS, KISS, and NDSL). The selection of studies, data extraction, and management will be performed independently by four researchers. Methodological quality, including the risk of bias, will be assessed using the Cochrane risk-of-bias assessment tool.Results: The review of current evidence for the effectiveness of herbal medicine for liver cancer will be summarized and quantitatively analyzed.Conclusions: Our systematic review will provide evidence of the efficacy of herbal medicines as treatments for liver cancer. This evidence will provide useful information for practitioners and patients in the fields of oncology and complementary medicine.
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