AAV血清型8介导的肝脏特异性GNMT表达延缓肝细胞癌的进展并防

StephenW

AAV serotype 8-mediated liver specific GNMT expression delays progression of hepatocellular carcinoma and prevents carbon tetrachloride-induced liver damage

    Cheng-Chieh Fang, Ching-Fen Wu, Yi-Jen Liao, Shiu-Feng Huang, Marcelo Chen & Yi-Ming Arthur Chen

Scientific Reportsvolume 8, Article number: 13802 (2018) | Download Citation
Abstract

Glycine N-methyltransferase (GNMT) is abundantly expressed in normal livers and plays a protective role against tumor formation. GNMT depletion leads to progression of hepatocellular carcinoma (HCC). In this study, we investigated the activity of ectopic GNMT delivered using recombinant adeno-associated virus (AAV) gene therapy in mouse models of liver cirrhosis and HCC. Injection of AAV serotype 8 (AAV8) vector carrying the GNMT gene (AAV8-GNMT) in Gnmt−/− mice increased GNMT expression and downregulated pro-inflammatory responses, resulting in reduced liver damage and incidence of liver tumors. Moreover, AAV8-GNMT resulted in the amelioration of carbon tetrachloride (CCl4)-induced liver fibrosis in BALB/c mice. We showed that AAV8-GNMT protected hepatocytes from CCl4-induced liver damage.  AAV8-GNMT significantly attenuated the levels of pro-fibrotic markers and increased efficiency of hepatocyte proliferation. These results suggest that correction of hepatic GNMT by gene therapy of AAV8-mediated gene enhancement may provide a potential strategy for preventing and delaying development of liver diseases.

StephenW

AAV血清型8介导的肝脏特异性GNMT表达延缓肝细胞癌的进展并防止四氯化碳诱导的肝损伤

    方成杰，吴清芬，廖一仁，黄秀峰，陈洁莹，陈亚明，陈亚明

Scientific Reportsvolume 8，货号：13802（2018）|下载引文
抽象

甘氨酸N-甲基转移酶（GNMT）在正常肝脏中大量表达并且对肿瘤形成起保护作用。 GNMT耗竭导致肝细胞癌（HCC）的进展。在这项研究中，我们研究了使用重组腺相关病毒（AAV）基因治疗在肝硬化和HCC小鼠模型中递送的异位GNMT的活性。在Gnmt - / - 小鼠中注射携带GNMT基因（AAV8-GNMT）的AAV血清型8（AAV8）载体增加了GNMT表达和下调的促炎反应，导致肝损伤和肝肿瘤的发生率降低。此外，AAV8-GNMT导致BALB / c小鼠中四氯化碳（CCl4）诱导的肝纤维化的改善。我们发现AAV8-GNMT保护肝细胞免受CCl4诱导的肝损伤。 AAV8-GNMT显着减弱促纤维化标志物的水平并提高肝细胞增殖的效率。这些结果表明，通过AAV8介导的基因增强的基因疗法校正肝GNMT可以提供预防和延迟肝病发展的潜在策略。