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）是一种进行性肝病，其次是肝硬化，甚至是肝细胞癌。纳什没有确切的治疗方案。肝细胞特异性的PTEN缺乏（PTEN KO）小鼠在组织学上与人NASH具有几乎相同的肝病变，并且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至35周龄的PTEN KO小鼠的肝细胞的全面基因表达，以找出与人NASH的发育和加剧有关的候选基因。 SPP1，VNN1，ITGA6。 ABED2，AUH，ACOX1，PDK4，CPT1A，LEN2，TGFBP2，GSTM6，SOCS3。 TGM2和ALDH9AL被视为与炎症有关的候选基因。纤维化的候选基因是SPPL，CTGF和CYP2C39，而且CIDEC和SPPL被视为癌变的候选基因。为了确认这些基因有助于某些人NASH的病因，需要使用人肝样品进行进一步的研究。在本研究中，我们进一步研究了纳什的实验疗法，使用多种抗氧化剂，尤其是侧重于肝细胞癌化学预防。我们的研究表明，N-乙酰半胱氨酸降低了炎症的变化，但不能减少脂肪变化。因此，我们建议使用几种抗氧化剂的组合方案可能是预防NASH中疾病进展和随后的致癌作用的最佳选择。

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

Non-alcoholic steatohepatitis and hepatocellular carcinoma : lessons from hepatoeyte-specific phosphatase and tensin homolog (PTEN)-defient mice.

非酒精性脂肪性肝炎和肝细胞癌：肝细胞特异性磷酸酶和张力蛋白同源物 (PTEN) 缺陷小鼠的教训。

• 发表时间: 2007
• 期刊: J. Gastroenterol. Hepatol 22 (Suppl 1)
• 作者: Sato.Y.;Sonoda;H.;Watanabe S. Horie Y. Kataoka E. Sato W. Dohmon T. Ohshima S. Goto T. Suzuki A.
• 通讯作者: Watanabe S. Horie Y. Kataoka E. Sato W. Dohmon T. Ohshima S. Goto T. Suzuki A.

Liver disorders associated with metabolic syndrome : disease susceptibility and therapeutic resistance.

与代谢综合征相关的肝脏疾病：疾病易感性和治疗耐药性。

• 发表时间: 2006
• 作者: Yoshida;S;Ikehara;N;Aoyama;N;Shirasaka;D;Sakashita;M;Semba;S;Hasuo;T;Mild;I;Morita;Y;Tamura;T;Azuma;T;Yokozaki;H;Kasuga;M;Ikejima K
• 通讯作者: Ikejima K