沉默信息调节因子2（SIRT2）在肝细胞癌侵袭中的重要作用及机制研究

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. In China, HCC is the second most common cause of cancer mortality. Despite its high prevalence and inferior prognosis in general, our understanding of the pathogenesis of this cancer is very limited. Treatment of HCC is complicated by the fact that the disease is often diagnosed at an advanced stage when it is no longer amenable to curative surgery, and that current systemic chemotherapeutics are mostly inefficacious. A better understanding on the molecular basis of HCC is therefore urgently required to facilitate development of new therapeutic strategies. Sirtuin 2 (SIRT2) is a class III histone deacetylase implicated in cell cycle progression and apoptosis, yet its role in carcinogenesis remains uncertain. We showed that SIRT2 expression is upregulated in the majority of human HCC cell lines and tumors. Functional studies revealed that gene silencing of SIRT2 significantly suppresses migration and invasion of HCC cells that is associated with a remarkable reduction in beta-catenin level. Our preliminary data therefore revealed a novel role of SIRT2 in the aberrant activation of Wnt/beta-catening signaling pathway, which plays a major role in HCC metastasis. The central theme of this proposal is thus to elucidate the molecular basis of SIRT2 in regulating the abundance and activity of beta-catenin. We will also use animal model to evaluate if suppression of SIRT2 will mitigate HCC growth and metastasis. Our proposed studies therefore hold value in providing a better understanding on the role of SIRT2 in HCC tumorigenesis, and will impact on the future development of SIRT2 inhibitors as HCC therapeutics.

沉默信息调节因子2相关酶2 ( SIRT2)是烟碱胺腺嘌呤二核苷酸(NAD + )依赖的组蛋白去乙酰化酶,参与细胞周期调节及细胞凋亡等生理活动，并在肿瘤的发生发展中发挥着重要的作用。我们的前期研究发现SIRT2 在肝癌细胞系和人类肝细胞癌组织中表达明显增高，并且SIRT2沉默能抑制肝癌细胞侵袭能力。更为重要的是SIRT2沉默能显著抑制Wnt信号通路最关键分子beta-catenin的蛋白水平。因此我们推测SIRT2在肝癌细胞中异常高表达与Wnt/beta-catenin信号通路的异常活化密切相关，SIRT2基因沉默通过抑制β-catenin的表达或活性，从而调节下游靶基因的转录，最终抑制肝癌细胞的迁移及侵袭。因此本项目进一步研究SIRT2对beta-catenin 细胞定位及转录活性等的影响及相关的分子机制，并在裸鼠肿瘤模型上验证SIRT2抑制因子的抗肿瘤效力。

沉默信息调节因子 2 相关酶 2 (SIRT2)是烟碱胺腺嘌呤二核苷酸(NAD + )依赖的组蛋白去乙酰化酶,参与细胞周期调节及细胞凋亡等生理活动，并在肿瘤的发生发展中发挥着重要的作用。我们的前期研究发现 SIRT2 在肝癌细胞系和人类肝细胞癌组织中表达明显增高，并且 SIRT2 沉默能抑制肝癌细胞侵袭能力。更为重要的是 SIRT2 沉默能显著抑制 Wnt 信号通路最关键分子 beta-catenin 的蛋白水平。通过我们的研究发现 SIRT2 在肝癌细胞中异常高表达与 Wnt/beta-catenin 信号通路的异常活化密切相关，SIRT2 基因沉默通过抑制beta-catenin 的表达和活性，从而调节下游靶基因的转录，最终抑制肝癌细胞的迁移及侵袭。同SIRT2在同一家族的SIRT1基因在肝癌的发生过程中也发挥了重要作用，SIRT1可以保护端粒，调节端粒酶的活性。进一步研究发现SIRT1可以调节TERT启动子的组蛋白乙酰化和甲基化，从而通过远程的反应或者是目前还不知道的组蛋白修饰的方法来调节TERT的表达。同时我们还发现作为SIRT2的上游调控因子CTCF在肝癌的发生过程中也起了一定功能。CTCF在肝癌细胞系和人类肝细胞癌组织中表达明显增高，同肝癌病人的不良预后显著相关，并且CTCF可以通过直接调控TERT和FOXM1基因的转录水平来影响肝癌细胞的增殖和迁移。我们的实验结果揭示了SIRT2，SIRT1，CTCF在肝癌发生发展过程中发挥重要的分子，阐明详细的分子机制和信号通路，对于肝癌的早期诊断以及寻找有效的肝癌治疗方案起到了至关重要的作用。