ZnAs@SiO2 nanoparticles as a potential anti-tumor drug for targeting stemness and epithelial-mesenchymal transition in hepatocellular carcinoma via SHP-1/JAK2/STAT3 signaling
ZnAs@SiO2 nanoparticles as a potential anti-tumor drug for targeting stemness and epithelial-mesenchymal transition in hepatocellular carcinoma via SHP-1/JAK2/STAT3 signaling
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ZnAs@SiO2纳米粒子作为潜在的抗肿瘤药物，通过SHP-1/JAK2/STAT3信号传导靶向肝细胞癌的干细胞性和上皮间质转化
DOI：
10.7150/thno.32462
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Shan, Hong
中科院分区：
文献类型：
--
作者：
Huang, Yongquan;Zhou, Bin;Shan, Hong
基本原理：目前肝细胞癌（HCC）的治疗受到治疗失败和复发的阻碍，这是由于剩余的耐药肝癌干细胞（CSC）。干细胞和上皮-间质转化（EMT）被认为是癌症进展所必需的肝CSC的两个基本特征;因此，同时靶向这两个特征的药物应被证明在消除HCC和阻止复发方面有效。在这项研究中，我们开发了新的三氧化二砷（ATO）为基础的纳米粒子（NPs），这是预计比目前的肝癌治疗更有效，并探讨其潜在的mechanism.Methods：一锅法“反相乳化法制备ZnAs@SiO2纳米粒子。使用HCC细胞系MHCC 97 L和Hep 3b，通过定量细胞生长和转移以及研究对干性和EMT的影响来分析ZnAs@SiO2 NPs在体外和体内的抗肿瘤活性。利用SHP-1 siRNA验证SHP-1/JAK 2/STAT 3信号通路在ZnAs@SiO2抑制MHCC 97 L和Hep 3b细胞干细胞和EMT中的作用。结果：与ATO处理相比，ZnAs@SiO2纳米粒促进了MHCC 97 L和Hep 3b细胞的凋亡，并显著抑制了细胞的增殖、迁移和侵袭。在体内测定中，与ATO相比，ZnAs@SiO2 NPs抑制肿瘤生长2.2倍，转移3.5倍。ZnAs@SiO2纳米颗粒还在体外抑制肿瘤球体形成和在体内抑制肿瘤起始，并在体外和体内诱导干细胞标志物（CD 133、Sox-2和Oct-4）和EMT标志物（ε-钙粘蛋白、波形蛋白和Slug）表达的显著变化。结论：ZnAs@SiO2纳米粒通过调控SHP-1/JAK 2/STAT 3信号通路，在体内外均能有效抑制肝癌细胞的发生、生长、转移，抑制肿瘤干细胞化和EMT。因此，ZnAs@SiO2纳米颗粒在未来肝癌治疗方面具有巨大的潜力。
Rationale: Current therapies for hepatocellular carcinoma (HCC) are hampered by treatment failure and recurrence due to the remaining treatment-resistant liver cancer stem cells (CSCs). Stemness and epithelial-mesenchymal transition (EMT) are regarded as two fundamental characteristics of liver CSCs necessary for cancer progression; thus, drugs that simultaneously target both characteristics should prove effective in eliminating HCC and impeding recurrence. In this study, we developed new arsenic trioxide (ATO)-based nanoparticles (NPs), which are expected to be more effective than the current HCC therapy, and explored their potential mechanism.Methods: A "one-pot" reverse emulsification approach was employed to prepare the ZnAs@SiO2 NPs. HCC cell lines, MHCC97L and Hep3b, were used to analyze the antitumor activity of ZnAs@SiO2 NPs in vitro and in vivo by quantifying cell growth and metastasis as well as to study the effect on stemness and EMT. SHP-1 siRNA was used to validate the role of the SHP-1/JAK2/STAT3 signaling pathway in mediating inhibition of stemness and EMT by ZnAs@SiO2.Results: Compared with the current ATO treatment, ZnAs@SiO2 NPs promoted apoptosis and significantly inhibited proliferation, migration, and invasion of both MHCC97L and Hep3b cells. In the in vivo assay, ZnAs@SiO2 NPs inhibited tumor growth by 2.2-fold and metastasis by 3.5-fold as compared to ATO. The ZnAs@SiO2 NPs also inhibited tumor spheroid formation in vitro and tumor initiation in vivo and induced significant changes in the expression of stemness markers (CD133, Sox-2, and Oct-4) and EMT markers (epsilon-cadherin, Vimentin, and Slug) both in vitro and in vivo. These effects of ZnAs@SiO2 that correlated with prognosis of HCC were mediated by the SHP-1/JAK2/STAT3 signaling.Conclusions: ZnAs@SiO2 NPs can effectively suppress tumor initiation, growth, metastasis, and inhibit stemness and EMT through regulation of SHP-1/JAK2/STAT3 signaling pathway in liver cancer cells in vitro and in vivo. Thus, ZnAs@SiO2 NPs have immense potential for HCC treatment in the future.