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

脂质和氧化应激在消化系统癌发生中的作用

• 批准号: 18390213
• 负责人: WATANABE Sumio
• 金额: $ 11.37万
• 依托单位: Juntendo University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390213/
• 关键词: steatohepatitis; PTEN; oxidative stress; hepatic caricinogenesis; antioxidant; N-acetyleisteine

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.

非酒精性脂肪性肝炎（NASH）是一种继发于肝硬化甚至肝细胞癌的进行性肝病。目前还没有明确的NASH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类NASH几乎相同的肝脏病变，被认为代表了一些有限的NASH患者。我们首先使用DNA微阵列技术分析了10 - 35周龄Pten KO小鼠肝细胞的综合基因表达，以找出与人类NASH发展和恶化相关的候选基因。Spp1, Vnn1, Itga6。Abed2, Auh, Acox1, Pdk4, Cpt1a, Len2, Tgfbp2, Gstm6, soc3。Tgm2和Aldh9al被认为是与炎症相关的候选基因。纤维化的候选基因为Sppl、Ctgf和Cyp2c39，而Cidec和Sppl被认为是致癌的候选基因。为了证实这些基因与某些人类NASH的病因有关，需要使用人类肝脏样本进行进一步的研究。在本研究中，我们进一步研究了使用多种抗氧化剂治疗NASH的实验疗法，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，但没有脂肪变性本身。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疾病进展和随后的致癌的最佳方案。

项目成果

The role of adipokines in hepatic fibrogenesis in alcoholic and nonalcoholic fatty liver diseases.

脂肪因子在酒精性和非酒精性脂肪肝病肝纤维发生中的作用。

• 发表时间: 2006
• 作者: Ikejima K;Okumura K;Kon K;Aoyama T;Yamashina S;Enomoto N;Takei Y;Sato N
• 通讯作者: Sato N

Orthotopic hepatocellular carcinoma model with a com rolle and reproducible tumorigenicity.

具有可控且可重复致瘤性的原位肝细胞癌模型。

• 发表时间: 2007
• 期刊: J. Gastroenterol. Hepatol. 22(3)
• 作者: Oktubo H;Takei Y. Serizawa N;Enomoto N. Ikejima K. Sato N.
• 通讯作者: Enomoto N. Ikejima K. Sato N.

Infliximab as a treatment for systemic amyloidosis associeted with Crohn's disease.

英夫利昔单抗用于治疗与克罗恩病相关的系统性淀粉样变性。

• 发表时间: 2006
• 期刊: Gut 55(5)
• 作者: Iizuka M;Konno S;Horie Y;Itou H;Shindo K;Watanabe S
• 通讯作者: Watanabe S

Sucralfate prevents the delay of wound repair in intestinal epithelial cells byhydrogen peroxide through NF-kappaB pathway.

硫糖铝可通过 NF-κB 途径防止过氧化氢延迟肠上皮细胞伤口修复。

• 发表时间: 2006
• 期刊: J Gastroenterol 41(5)
• 作者: Shindo K;Iizuka M;Sasaki K;Konno S;Itou H;Horie Y;Watanabe S
• 通讯作者: Watanabe S

Hepatic gene ezpression in hepatocyte-specific Pten deficient mice showing steatohepatitis without ethanol challenge

肝细胞特异性 Pten 缺陷小鼠的肝基因表达在无乙醇攻击的情况下表现出脂肪性肝炎

• 发表时间: 2006
• 期刊: HEPATOLOGY RESEARCH 34
• 作者: Sato W;Horie Y;Kataoka E;Ohshima S;Dohmen T;Iizuka M;Sasaki J;Sasaki M;Hamada K;Kishimoto H;Suzuki A;Watanabe S
• 通讯作者: Watanabe S