Sirtuin7 oncogenic potential in human hepatocellular carcinoma and its regulation by the tumor suppressors MiR-125a-5p and MiR-125b
Sirtuin7 oncogenic potential in human hepatocellular carcinoma and its regulation by the tumor suppressors MiR-125a-5p and MiR-125b
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DOI：
10.1002/hep.26101
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发表时间：
2013-03-01
期刊：
影响因子：
13.5
通讯作者：
Nam, Suk Woo
中科院分区：
文献类型：
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作者：
Kim, Jeong Kyu;Noh, Ji Heon;Nam, Suk Woo
sirtuins是烟酰胺腺嘌呤二核苷酸氧化形式（NAD+）依赖性脱乙酰酶，在细胞代谢、应激抵抗和衰老中发挥作用。对于sirtuin7（SIRT7），提出了在核糖体基因转录中的作用，但其在癌症中的功能尚不清楚。在这项研究中，我们发现SIRT7的表达在一个大的人类肝细胞癌（HCC）患者队列中上调。SIRT7基因敲低影响细胞周期，导致肝癌细胞显著增加，保持在G1/S期并抑制生长。这种处理恢复了p21WAF 1/Cip 1，诱导了Beclin-1，并抑制了细胞周期蛋白D1。此外，SIRT7的持续抑制降低了小鼠异种移植模型中的体内肿瘤生长速率。为了探索SIRT7调节的机制，进行了microRNA（miRNA）分析。这在HCC中鉴定了五种显著下调的miRNA。对靶位点和肝癌细胞异位表达的生物信息学分析显示，miR-125a-5p和miR-125b抑制SIRT7和cyclin D1的表达，诱导p21 WAF 1/Cip1依赖的G1期细胞阻滞。此外，用5-氮杂-2-脱氧胞苷或野生型而非突变型p53的异位表达处理HCC细胞恢复了miR-125 a-5p和miR-125 b的表达并抑制肿瘤细胞生长，表明它们通过启动子甲基化和p53活性进行调节。为了显示这些发现的临床意义，研究了p53的DNA结合结构域的突变和miR-125 b的启动子甲基化。9名SIRT7诱导患者中有4名携带p53基因突变，1名患者显示miR-125b启动子区域超甲基化。结论：我们的研究结果表明SIRT7在肝癌发生中的致癌潜力。提出了一种调节环，其中SIRT7通过抑制miR-125a-5p和miR-125b来抑制p21 WAF 1/Cip1的转录激活。这使得SIRT7成为癌症治疗中有希望的靶点。（肝脏学2013）
Sirtuins are nicotinamide adenine dinucleotide oxidized form (NAD+)-dependent deacetylases and function in cellular metabolism, stress resistance, and aging. For sirtuin7 (SIRT7), a role in ribosomal gene transcription is proposed, but its function in cancer has been unclear. In this study we show that SIRT7 expression was up-regulated in a large cohort of human hepatocellular carcinoma (HCC) patients. SIRT7 knockdown influenced the cell cycle and caused a significant increase of liver cancer cells to remain in the G1/S phase and to suppress growth. This treatment restored p21WAF1/Cip1, induced Beclin-1, and repressed cyclin D1. In addition, sustained suppression of SIRT7 reduced the in vivo tumor growth rate in a mouse xenograft model. To explore mechanisms in SIRT7 regulation, microRNA (miRNA) profiling was carried out. This identified five significantly down-regulated miRNAs in HCC. Bioinformatics analysis of target sites and ectopic expression in HCC cells showed that miR-125a-5p and miR-125b suppressed SIRT7 and cyclin D1 expression and induced p21WAF1/Cip1-dependent G1 cell cycle arrest. Furthermore, treatment of HCC cells with 5-aza-2-deoxycytidine or ectopic expression of wildtype but not mutated p53 restored miR-125a-5p and miR-125b expression and inhibited tumor cell growth, suggesting their regulation by promoter methylation and p53 activity. To show the clinical significance of these findings, mutations in the DNA binding domain of p53 and promoter methylation of miR-125b were investigated. Four out of nine patients with induced SIRT7 carried mutations in the p53 gene and one patient showed hypermethylation of the miR-125b promoter region. Conclusion: Our findings suggest the oncogenic potential of SIRT7 in hepatocarcinogenesis. A regulatory loop is proposed whereby SIRT7 inhibits transcriptional activation of p21WAF1/Cip1 by way of repression of miR-125a-5p and miR-125b. This makes SIRT7 a promising target in cancer therapy. (HEPATOLOGY 2013)