Role of lipid and oxidative stress on carcinogenesis in the digestive system

非酒精性脂肪性肝炎（NASH）是一种进行性肝病，随后发生肝硬化甚至肝细胞癌。NASH尚无明确的治疗方案。肝细胞特异性Pten缺陷（Pten KO）小鼠在组织学上具有与人NASH几乎相同的肝脏病变，并且被认为代表一些有限的NASH患者。我们首先使用DNA微阵列技术分析了10 - 35周龄Pten KO小鼠肝细胞的全面基因表达，以寻找与人类NASH发生和加重相关的候选基因。Spp 1、Vnn 1、Itga 6。Abed2、Auh、Acox1、Pdk4、Cpt1a、Len2、Tgfbp2、Gstm6、Socs3。Tgm 2和Aldh 9al被认为是与炎症相关的候选基因。纤维化的候选基因是Sppl、Ctgf和Cyp 2c 39，并且Cidec和Sppl被认为是致癌的候选基因。为了证实这些基因对某些人类NASH的病因学有贡献，需要使用人类肝脏样本进行进一步研究。在本研究中，我们进一步研究了使用各种抗氧化剂的NASH的实验治疗，特别是关注肝细胞癌的化学预防。我们的研究表明，N-乙酰半胱氨酸减少炎症变化，但不是脂肪变性本身。因此，我们建议使用几种抗氧化剂的联合方案可能是预防NASH疾病进展和随后致癌的最佳方案。

Non-alcoholic steatohepatitis (NASH) is a progressive liver disease followed by liver cirrhosis and even hepatocellular carcinoma. There has been no definitive treatment regimen for NASH. Hepatocyte-specific Pten deficient (Pten KO) mice possess almost the same hepatic lesions histologically as human NASH and are thought to represent some limited NASH patients. We first analyzed a comprehensive gene expression of hepatocytes derived from 10 to 35-week-old Pten KO mice using the DNA microarray technology to find out the candidate gene related to development and aggravation of human NASH. Spp1, Vnn1, Itga6. Abed2, Auh, Acox1, Pdk4, Cpt1a, Len2, Tgfbp2, Gstm6, Socs3. Tgm2, and Aldh9al were regarded as the candidate genes related to inflammation. The candidate genes of fibrosis were Sppl, Ctgf, and Cyp2c39 and moreover Cidec and Sppl were regarded as the candidate genes of carcinogenesis. To confirm that these genes contribute to the etiology of some human NASH, further investigations using human liver samples are needed. In the present study we further investigated the experimental therapeutics of NASH using a variety of antioxidants especially focusing on chemoprevention of hepatocellular carcinoma. Our study demonstrated that N-acetylcysteine diminished inflammatory changes but not steatosis per se. Therefore, we propose that a combination regimen using several antioxidants may be optimal for preventing disease progression and subsequent carcinogenesis in NASH.