Epigenetic regulation of metastasis-related genes in gastric cancer

胃癌转移相关基因的表观遗传调控

• 批准号: 13670173
• 负责人: HIROKI Kuniyasu
• 金额: $ 2.24万
• 依托单位: Nara 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: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670173/
• 关键词: Gastric cancer; Colon cancer; DNA methylation; Histone acetylation; Epigenetics; RAGE; HMG1; エピジェネテイクス; プロモータCpGメチル化; 転移関連遺伝子; 消化器がん

Levels of protein products of 76 metastasis-related genes were examined in COLQ320 (colon cancer), MKN28 (gastric cancer), SRC29 (renal cancer), U937 (leukemia), and JEC6 (intestinal epithelium) cell lines treated with or without deoxyazacytidine (AZA) and/or trichostatine A (TSA), Alteration of protein levels by treatment with AZA and/or TSA was found in RAGE, IL-8, E-cadherin, MMP-9, MLH1 , Rho, and c-MET in cell type-specific and gene-specific manners. Next, epigenetics of RAGE and the ligand HMG1 were examined. RAGE-negative MKN45 gastric cancer cells showed DNA methylation at the Sp-1 site in the RAGE gene promoter. HMG1, originally reported as a chromatin protein, was translocated from nucleus to cytoplasm through histone acetylation by TSA treatment. Simplifying the complicating cancer epigenetics, we analyzed the mucosa adjacent to colon cancer in the athymic mice model. The mucosa showed hypoacetylation of histone H4, repression of p53 and VHL, which were associated with retention of HlF-1α protein and induction of VEGF in the mucosa. The mucosa also showed repression of p16, MLH1, and MGMT by means of promoter hypermethylation of the genes. In in vitro examination, growth factors played a role in repression of these genes.

在COLQ 320中检测了76个转移相关基因的蛋白产物水平。（结肠癌），MKN 28（胃癌），SRC 29（肾癌），U937（白血病）和JEC 6用或不用脱氧氮胞苷（AZA）和/或阿司他汀A（TSA）处理的肠上皮细胞系。MMP-9、MLH 1、Rho和c-MET以细胞类型特异性和基因特异性方式表达。接下来，检查了HMG和配体HMG 1的表观遗传学。RAGE阴性的MKN 45胃癌细胞中，在MKN 45基因启动子中的Sp-1位点存在DNA甲基化。HMG 1最初被报道为一种染色质蛋白，经TSA处理后通过组蛋白乙酰化从细胞核转位到细胞质。为了简化复杂的癌症表观遗传学，我们分析了无胸腺小鼠模型中结肠癌附近的粘膜。粘膜组织中组蛋白H4低乙酰化，p53和VHL表达受抑制，这与粘膜组织中HlF-1α蛋白的滞留和VEGF的诱导有关。粘膜也表现出抑制p16，MLH 1，和MGMT的基因启动子超甲基化的手段。在体外检测中，生长因子在这些基因的抑制中发挥作用。

项目成果

Kuniyasu H他3名: "Co-expression of CD44v3 and heparanase is correlated with metastasis of human colon cancer"International Journal of Molecular Medicine. 10(3). 333-337 (2002)

Kuniyasu H 和其他 3 人：“CD44v3 和乙酰肝素酶的共表达与人类结肠癌的转移相关”，国际分子医学杂志 10(3) 333-337 (2002)。

Kuniyasu H, Chihara Y, and Kondo H: "Differential effects between amphoterin and advances glycation end products on colon cancer cells"International Journal of Cancer. in press. (2003)

Kuniyasu H、Chihara Y 和 Kondo H：“两性蛋白和糖基化终产物对结肠癌细胞的不同作用”国际癌症杂志。

Kuniyasu H, Chihara Y, Kubozoe T, and Takahashi T: "Co-expression of CD44v3 and heparanase is correlated with metastasis of human colon cancer"International Journal of Molecular Medicine. 10(3). 333-337 (2002)

Kuniyasu H、Chihara Y、Kubozoe T 和 Takahashi T：“CD44v3 和乙酰肝素酶的共表达与人类结肠癌的转移相关”国际分子医学杂志。

Kunivasu H 他4名: "Heparan sulfate enhances metastatic potential of human colon cancer through CD44 variant exon 3 expression"Clinical Cancer Research. 7(12). 4067-4072 (2001)

Kunivasu H 和其他 4 人：“硫酸乙酰肝素通过 CD44 变异外显子 3 表达增强人类结肠癌的转移潜力”临床癌症研究 7(12) 4067-4072 (2001)。

Kunivasu H 他6名: "Interferon-alpha prevents selection of doxorubicin-resistant undifferentiated-androgen-insensitive metastatic human prostate cancer cells"Prostate. 49(1). 19-29 (2001)

Kunivasu H 和其他 6 人：“干扰素-α 阻止对多柔比星耐药的未分化雄激素不敏感的转移性前列腺癌细胞的选择”前列腺 49(1) (2001)。