Dulcitol suppresses proliferation and migration of hepatocellular carcinoma via regulating SIRT1/p53 pathway
Dulcitol suppresses proliferation and migration of hepatocellular carcinoma via regulating SIRT1/p53 pathway
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卫矛醇通过调节 SIRT1/p53 通路抑制肝细胞癌的增殖和迁移
DOI：
10.1016/j.phymed.2019.153112
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发表时间：
2020-01-01
期刊：
影响因子：
7.9
通讯作者：
Zhang, Tao
中科院分区：
文献类型：
--
作者：
Lin, Xiao Lin;Li, Kai;Zhang, Tao
背景：肝细胞癌（Hepatocellular carcinoma，HCC）是一种恶性程度高、易转移的肿瘤，其发病率呈持续上升趋势。因此，在肝癌的治疗中，应研究更有效的阻断癌细胞增殖和转移的策略。卫矛醇是从翅羽卫矛中提取的一种天然产物，有报道其能诱导C6胶质瘤细胞凋亡。目的：本研究采用MTT法、Ki-67和Hoechst 33258/PI双染色法检测Dulcitol对肝癌细胞增殖和凋亡的影响，并探讨Dulcitol对肝癌细胞增殖和凋亡的作用机制。通过伤口愈合实验和transwell实验检测HepG 2细胞的迁移和侵袭能力。采用HE染色和免疫组化方法观察肿瘤组织的病理变化。结果：半乳糖醇通过下调SIRT 1、Bcl-2、沿着上调p53、乙酰化p53（K382）、cleaved-caspase 9、cleaved-caspase 3、Bax和细胞色素c蛋白表达，抑制HepG 2细胞增殖，呈剂量依赖性。Dulcitol通过降低MMP-2、uPA和MMP-9的表达，增加与肿瘤侵袭相关的E-cadherin，从而抑制HepG 2细胞的迁移和侵袭。结论：Dulcitol可通过抑制SIRT 1/p53信号通路抑制HepG 2细胞的生长，其作用机制可能与调节MMPs、SIRT 1/p53信号通路有关。
Background: Hepatocellular carcinoma (HCC) spreads further with continuance and increasing incidence due to its high-grade malignancy and metastasis. More effectual strategies on blocking proliferation and metastasis of cancer cells should be studied in HCC. Dulcitol, a natural product extracted from euonymus alatus, was reported that it could induce apoptosis of C6 glioma cells. However, the underlying mechanism of Dulcitol on HCC remains unclea.Purpose: In this study, we aimed to reveal the effect and potential mechanisms of Dulcitol on hepatocellular carcinoma in vitro and in vivo.Study design and methods The cell proliferation and apoptosis were evaluated by MTT, Ki-67 and Hoechst 33258/PI double staining. The migratory and invasive abilities of HepG2 cells were measured by wound-healing and transwell assays. Pathological changes of tumor tissue were observed by HE staining and IHC methods. The expression levels of protein were detected using Western Blot analysis.Results: The results showed that Dulcitol inhibited HepG2 cells proliferation by down-regulating the protein expression of SIRT1, Bcl-2, along with up-regulating p53, acetylated-p53 (K382), cleaved-caspase9, cleaved-caspase3, Bax, and cytochrome c in a dose-dependent manner. Furthermore, Dulcitol surpressed the migration and invasion of HepG2 cells through decreasing the levels of MMP-2, uPA and MMP-9 and increasing E-cadherin associated with tumor invasion. In vivo, Dulcitol distinctly inhibited the growth of HepG2 cancer xenograft tumors via inhibiting SIRT1/p53 pathway.Conclusions: Our findings suggested that Dulcitol acted as a SIRT1 inhibitor, inducing apoptosis and inhibiting proliferation, migration and invasion of HepG2 cells and its modulatory mechanism seemed to be associated with regulation of MMPs, SIRT1/p53 pathways.