Department of Internal Medicine, University of Kansas Medical Center, Mailstop 1018, Kansas City, KS, 66160, USA.
Liver Center, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
J Exp Clin Cancer Res. 2019 Jun 13;38(1):252. doi: 10.1186/s13046-019-1246-4.
Optimal therapeutic strategies for hepatocellular carcinoma (HCC) patients are still challenging due to the high recurrence rate after surgical resection and chemotherapy resistance. Growing evidence shows that genetic and epigenetic alterations are involved in HCC progression and resistance to therapy, however the molecular mechanisms underlying resistance to therapy have not been fully understood.
Expression of SIRT7 in 17 paired paraffin-embedded HCC tissues and adjacent nontumoral liver tissues was examined by immunohistochemistry and Western blot. The mRNA expression of SIRT7 in 20 paired frozen HCC tissues and adjacent nontumoral liver tissues was analyzed by quantitative RT-PCR. The biologic consequences of overexpression and knockdown of SIRT7 in HCC therapy sensitivity were studied in vitro and in vivo. Interaction between SIRT7 and p53 were studied in HCC cell lines.
SIRT7 expression was frequently upregulated in clinical HCC samples, and its expression was highly associated with TACE-resistance and poor survival (P = 0.008.) Depletion of SIRT7 from multiple liver cancer cell lines significantly increased doxorubicin toxicity while overexpression of SIRT7 largely abolished doxorubicin induced apoptosis. At the molecular level, we observed that SIRT7 interacts with and induces deacetylation of p53 at lysines 320 and 373. Deacetylated p53 showed significantly less affinity for the NOXA promoter and its transcription. In mouse xenografts, SIRT7 suppression increased doxorubicin induced p53 activation, inhibited tumor growth and induced apoptosis.
The newly identified SIRT7-p53-NOXA axis partially illustrates the molecular mechanism of HCC resistance to therapy and represents a novel potential therapeutic target for HCC treatment.
由于肝癌（HCC）患者手术后复发率高和化疗耐药，因此寻找最佳的治疗策略仍然具有挑战性。越来越多的证据表明，遗传和表观遗传改变参与了 HCC 的进展和对治疗的耐药性，然而，治疗耐药的分子机制尚未完全阐明。
采用免疫组化和 Western blot 检测 17 对石蜡包埋 HCC 组织及其相邻非肿瘤肝组织中 SIRT7 的表达。采用实时定量 RT-PCR 分析 20 对冷冻 HCC 组织及其相邻非肿瘤肝组织中 SIRT7 的 mRNA 表达。在体外和体内研究 SIRT7 过表达和敲低对 HCC 治疗敏感性的生物学影响。在 HCC 细胞系中研究 SIRT7 与 p53 之间的相互作用。
SIRT7 在临床 HCC 样本中常被上调，其表达与 TACE 耐药和不良预后高度相关（P = 0.008）。从多种肝癌细胞系中敲低 SIRT7 显著增加了阿霉素的毒性，而 SIRT7 的过表达则在很大程度上消除了阿霉素诱导的细胞凋亡。在分子水平上，我们观察到 SIRT7 与 p53 相互作用，并在赖氨酸 320 和 373 处使 p53 去乙酰化。去乙酰化的 p53 与 NOXA 启动子及其转录的亲和力明显降低。在小鼠异种移植模型中，SIRT7 抑制增加了阿霉素诱导的 p53 激活，抑制了肿瘤生长并诱导了细胞凋亡。
新鉴定的 SIRT7-p53-NOXA 轴部分阐明了 HCC 对治疗耐药的分子机制，并代表了 HCC 治疗的一个新的潜在治疗靶点。
