ACF as a marker for colon carcinogensis in patients with ulcerative colitis and its gene analysis

ACF作为溃疡性结肠炎患者结肠致癌标志物及其基因分析

• 批准号: 15590666
• 负责人: TAKAYAMA Tetsuji
• 金额: $ 2.24万
• 依托单位: Sapporo Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590666/
• 关键词: Ulcerative colitis; ACF; Carcinogenesis

Aim: we identified aberrant crypt foci (ACF) in patients with ulcerative colitis (IJC), investigated various gene alterations and clarified the significance of ACF as a biomarker in colon carcinogenesis. Methods and Results: (1) Twenty-eight patients with UC were enrolled. We observed rectal area using magnifying endoscopy with the aid of methylene blue staining as previously we described (N Engl J Med, 1998). We found ACF lesions in 27 patients out of 28. ACF in UC patients showed obscure crypt lining as compared to ACF in non-UC patients. The number of ACF in patients with dysplasia was significantly more than that without dysplasia. (2) There were positive correlations between dysplasia and ACF number or duration of disease. (3) Essentially there were no mutations of APC and K-ras in ACF and dysplasia as revealed by In vitro synthesized protein (IVSP) assay and 2-step PCR RFLP respectively. (4) Very low rates of MSI were detected in ACF and dysplasia by PCR SSCP method. (5) There was no p53 mutation in ACF although it was frequently positive in dysplasia and cancer by PCR SSCP method. Immunostaining for p53 also revealed no accumulation of p53 in ACF although it was frequently accumulated in dysplasia and cancer. (6) Hypermethylation of p16 was highly positive in ACF, dysplasia and cancer by bisulfite method. Conclusion: It was demonstrated that ACF are viable marker for detection of dysplasia and subsequent cancer. It was also strongly suggested that ACF develop by p16 hypermethylation and proceed to dysplasia by p53 mutation.

目的：在溃疡性结肠炎(IJC)患者中发现异常隐窝病灶(ACF)，研究各种基因改变，阐明ACF作为结肠癌发生的生物标志物的意义。方法和结果：(1)入选28例UC患者。我们如前所述(N Engl J Med，1998)在亚甲蓝染色的辅助下使用放大内窥镜观察直肠区域。我们发现28名患者中有27名患者有ACF损害。UC患者的ACF与非UC患者的ACF相比，隐窝衬里不明显。伴异型增生患者的ACF数量明显多于无异型增生患者。(2)异型增生与ACF数目、病程呈正相关。(3)体外合成蛋白(IVSP)检测和两步聚合酶链式反应(PCRRFLP)结果显示，ACF和异型增生组织中均未发现APC和K-ras突变。(4)用聚合酶链式反应-单链构象多态性方法检测ACF和异型增生组织中MSI的发生率很低。(5)聚合酶链式反应-单链构象多态性分析显示，非典型增生和癌组织中P53基因突变较多，但ACF中未发现P53基因突变。P53的免疫组织化学染色也显示在ACF中没有P53的积聚，尽管P53在不典型增生和癌中经常积聚。(6)亚硫酸氢法检测ACF、异型增生和癌组织中p16基因高度甲基化。结论：ACF是检测异型增生和继发性癌的有效标记物。提示ACF通过p16高甲基化发生，并通过P53突变发展为异型增生。

项目成果

Glutathione S-transferase Pl-1 protects aberrant crypt foci from apoptosis induced by deoxycholic acid

谷胱甘肽 S-转移酶 Pl-1 保护异常隐窝病灶免受脱氧胆酸诱导的细胞凋亡

• 发表时间: 2004
• 期刊: Gastroenterology 127
• 作者: Nobuoka A;Takayama T;Miyanishi K;Sato T;Hayashi T;Kukitsu T;Takanashi K;Sato Y;Takahashi M;Okamoto T;Matsunaga T;Kato J;Oda M;Azuma T;Niitsu Y.
• 通讯作者: Niitsu Y.

Prolonged survival of mice with multiple liver metastases of human colon cancer by intravenous administration of replicable 1B-55K-deleted adenovirus with E1A expressed by CEA promoter.

通过静脉内注射具有 CEA 启动子表达的 E1A 的可复制 1B-55K 缺失腺病毒，可延长患有人类结肠癌多发肝转移的小鼠的生存。

• 发表时间: 2004
• 期刊: Molecular Ther 10
• 作者: Sagawa T;Takayama;et al.
• 通讯作者: et al.

Terui T, Takayama T, Niitsu Y, et al.: "Induction of PIG3 and NOXA through acetylation of p53 at 320 and 373 lysine residues as a mechanism for apoptotic cell death by histone deacetylase inhibitors"Cancer Research. 63. 8948-8954 (2003)

Terui T、Takayama T、Niitsu Y 等人：“通过 p53 在 320 和 373 赖氨酸残基处的乙酰化诱导 PIG3 和 NOXA 作为组蛋白脱乙酰酶抑制剂导致细胞凋亡的机制”癌症研究。

Augmentation of antitumor effects of p53 Gene therapy by combination with HDAC inhibitor

• DOI: 10.4161/cbt.4.4.1620
• 发表时间: 2005-02
• 期刊: Cancer Biology & Therapy
• 影响因子: 3.6
• 作者: R. Takimoto;J. Kato;T. Terui;K. Takada;G. Kuroiwa;Jing Wu;H. Ohnuma;D. Takahari;M. Kobune;Y. Sato;T. Takayama;T. Matsunaga;Yoshiro Niistu

Glutathione-S-transferase P1-1 protects aberrant crypt foci from apoptosis induced by deoxycholic acid

• DOI: 10.1053/j.gastro.2004.05.021
• 发表时间: 2004-08-01
• 期刊: GASTROENTEROLOGY
• 影响因子: 29.4
• 作者: Nobuoka, A;Takayama, T;Niitsu, Y
• 通讯作者: Niitsu, Y