Sirtuin7 致癌潜能在人肝癌和它的章程由肿瘤遏抑 MiR-125a-5p 和 MiR-125b。

Sirtuin7 oncogenic potential in human hepatocellular carcinoma and its regulation by the tumor suppressors MiR-125a-5p and MiR-125b.

机构信息

Department of Pathology, College of Medicine, Catholic University of Korea, Seoul, Korea.

出版信息

Hepatology. 2013 Mar;57(3):1055-67. doi: 10.1002/hep.26101. Epub 2013 Feb 11.

DOI:10.1002/hep.26101

PMID:23079745

Abstract

UNLABELLED

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 p21(WAF1/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 p21(WAF1/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 p21(WAF1/Cip1) by way of repression of miR-125a-5p and miR-125b. This makes SIRT7 a promising target in cancer therapy. (HEPATOLOGY 2013).

摘要

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沉默信息调节因子 7（SIRT7）是烟酰胺腺嘌呤二核苷酸氧化形式（NAD（+））依赖性脱乙酰酶，其功能涉及细胞代谢、应激抵抗和衰老。有研究提出 SIRT7 参与核糖体基因转录，但 SIRT7 在癌症中的功能尚不清楚。本研究显示，SIRT7 在大量肝癌患者中呈高表达。SIRT7 敲低影响细胞周期，使肝癌细胞显著停留在 G1/S 期并抑制生长。该治疗方案可恢复 p21（WAF1/Cip1）、诱导 Beclin-1 并抑制 cyclin D1。此外，SIRT7 持续抑制可降低小鼠异种移植模型中的体内肿瘤生长速度。为探讨 SIRT7 调控机制，进行了 microRNA（miRNA）谱分析。该分析鉴定出肝癌中 5 个显著下调的 miRNA。通过对靶位和 HCC 细胞异位表达的生物信息学分析，表明 miR-125a-5p 和 miR-125b 抑制 SIRT7 和 cyclin D1 表达，并诱导 p21（WAF1/Cip1）依赖的 G1 期细胞周期阻滞。此外，用 5-氮杂-2′-脱氧胞苷处理 HCC 细胞或异位表达野生型而非突变型 p53 可恢复 miR-125a-5p 和 miR-125b 的表达并抑制肿瘤细胞生长，表明它们受启动子甲基化和 p53 活性调控。为了证明这些发现的临床意义，研究了 p53 基因的 DNA 结合域突变和 miR-125b 的启动子甲基化。在 9 名诱导 SIRT7 的患者中，有 4 名患者的 p53 基因发生突变，1 名患者的 miR-125b 启动子区域发生高甲基化。