Stoyanov Evgeniy, Mizrahi Lina, Olam Devorah, Schnitzer-Perlman Temima, Galun Eithan, Goldenberg Daniel S
The Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Oncotarget. 2017 May 30;8(62):104772-104784. doi: 10.18632/oncotarget.18300. eCollection 2017 Dec 1.
Chronic inflammation precedes the majority of hepatocellular carcinoma (HCC) cases. We investigated the chemopreventive potential of S-adenosylmethionine (SAM), an essential donor for all methylation reactions in the cell, at the late precancerous stage of HCC development using the Mdr2-knockout (Mdr2-KO, Abcb4) mice, a model of inflammation-mediated hepatocarcinogenesis. Previously, we revealed down-regulation of the genes regulating SAM metabolism in the liver of these mice at the precancerous stages. Now, we have supplied Mdr2-KO mice at the late precancerous stage with SAM during either a short-term (17 days) or a long-term (51 days) period and explored the effects of such supplementation on tumor development, DNA methylation and gene expression in the liver. The short-term SAM supplementation significantly decreased the number of small tumor nodules, proliferating hepatocytes and the total DNA methylation level, while it increased expression of the tumor suppressor proteins Mat1a and p21. Surprisingly, the long-term SAM supplementation did not affect tumor growth and hepatocyte proliferation, while it increased the total liver DNA methylation. Our results demonstrate that the short-term SAM supplementation in the Mdr2-KO mice inhibited liver tumor development potentially by increasing multiple tumor suppressor mechanisms resulting in cell cycle arrest. The long-term SAM supplementation resulted in a bypass of the cell cycle arrest in this HCC model by a yet unknown mechanism.
大多数肝细胞癌（HCC）病例之前都存在慢性炎症。我们使用Mdr2基因敲除（Mdr2-KO，Abcb4）小鼠（一种炎症介导的肝癌发生模型），在肝癌发生的癌前晚期阶段研究了S-腺苷甲硫氨酸（SAM，细胞中所有甲基化反应的必需供体）的化学预防潜力。此前，我们发现这些小鼠在癌前阶段肝脏中调节SAM代谢的基因表达下调。现在，我们在癌前晚期阶段为Mdr2-KO小鼠短期（17天）或长期（51天）提供SAM，并探讨这种补充对肝脏肿瘤发展、DNA甲基化和基因表达的影响。短期补充SAM显著减少了小肿瘤结节的数量、增殖的肝细胞数量以及总DNA甲基化水平，同时增加了肿瘤抑制蛋白Mat1a和p21的表达。令人惊讶的是，长期补充SAM并未影响肿瘤生长和肝细胞增殖，但增加了肝脏总DNA甲基化。我们的结果表明，在Mdr2-KO小鼠中短期补充SAM可能通过增加多种肿瘤抑制机制导致细胞周期停滞，从而抑制肝脏肿瘤发展。在这个肝癌模型中，长期补充SAM通过一种未知机制导致细胞周期停滞被绕过。
