AAV serotype 8-mediated liver specific GNMT expression delays progression of hepatocellular carcinoma and prevents carbon tetrachloride-induced liver damage.
AAV serotype 8-mediated liver specific GNMT expression delays progression of hepatocellular carcinoma and prevents carbon tetrachloride-induced liver damage.
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DOI：
10.1038/s41598-018-30800-3
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发表时间：
2018-09-14
影响因子：
4.6
通讯作者：
Chen YA
中科院分区：
文献类型：
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作者：
Fang CC;Wu CF;Liao YJ;Huang SF;Chen M;Chen YA
甘氨酸n -甲基转移酶（Glycine N-methyltransferase， GNMT）在正常肝脏中大量表达，对肿瘤的形成起保护作用。GNMT缺失导致肝细胞癌（HCC）的进展。在这项研究中，我们研究了重组腺相关病毒（AAV）基因治疗小鼠肝硬化和HCC模型的异位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GNMT的表达，下调促炎反应，减少肝损伤和肝脏肿瘤的发生率。此外，AAV8-GNMT可改善四氯化碳（CCl4）诱导的BALB/c小鼠肝纤维化。我们发现AAV8-GNMT保护肝细胞免受ccl4诱导的肝损伤。AAV8-GNMT显著降低促纤维化标志物水平，提高肝细胞增殖效率。这些结果表明，通过aav8介导的基因增强基因治疗来纠正肝脏GNMT可能为预防和延缓肝脏疾病的发展提供了一种潜在的策略。
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.
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DOI：
10.1007/978-3-0348-0837-8_16
发表时间：
2014-01-01
期刊：
INFLAMMATION AND CANCER
影响因子：
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作者：
Bishayee, Anupam
通讯作者：
Bishayee, Anupam
影响因子：
3.8
作者：
Bell, Peter;Wang, Lili;Wilson, James M.
通讯作者：
Wilson, James M.
影响因子：
13.5
作者：
Liu, Shih-Ping;Li, Ying-Shiuan;Chen, Yi-Ming Arthur
通讯作者：
Chen, Yi-Ming Arthur
影响因子：
9.2
作者：
Mao Y;Pei N;Chen X;Chen H;Yan R;Bai N;Li A;Li J;Zhang Y;Du H;Chen B;Sumners C;Wang X;Wang S;Li H
通讯作者：
Li H
影响因子：
82.9
作者：
通讯作者：
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