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.,Theranostics

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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.
Theranostics ( IF 12.4 ) Pub Date : 2019-01-01 , DOI: 10.7150/thno.32462
Yongquan Huang _{1,

2,

3} , Bin Zhou _{2,

3} , Hui Luo ₃ , Junjie Mao _{2,

3} , Yin Huang ₂ , Ke Zhang _{2,

3} , Chaoming Mei ₃ , Yan Yan ₃ , Hongjun Jin ₃ , Jinhao Gao ₄ , Zhongzhen Su _{1,

3} , Pengfei Pang _{2,

3} , Dan Li ₃ , Hong Shan _{2,

3}

Affiliation

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 (E-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.

中文翻译：

ZnAs @ SiO2纳米颗粒可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性和上皮-间质转化。

理由：由于剩余的抗治疗性肝癌干细胞（CSC），治疗失败和复发阻碍了肝细胞癌（HCC）的当前疗法。茎干和上皮-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，同时针对这两种特性的药物应能有效消除HCC并阻止复发。在这项研究中，我们开发了新的基于三氧化二砷（ATO）的纳米颗粒（NPs），并有望比目前的HCC治疗更有效，并探讨了其潜在机理。方法：采用“一锅法”逆乳化法制备ZnAs @ SiO2 NPs。HCC细胞系MHCC97L和Hep3b，通过定量细胞生长和转移来研究ZnAs @ SiO2 NPs的体内外抗肿瘤活性，以及研究其对干细胞和EMT的影响。SHP-1 siRNA用于验证SHP-1 / JAK2 / STAT3信号通路在介导ZnAs @ SiO2抑制干性和EMT方面的作用。结果：与目前的ATO处理相比，ZnAs @ SiO2 NPs促进了MHCC97L和Hep3b细胞的凋亡并显着抑制了它们的增殖，迁移和侵袭。在体内试验中，与ATO相比，ZnAs @ SiO2 NPs抑制肿瘤生长2.2倍，转移抑制3.5倍。ZnAs @ SiO2 NPs还可以在体外和体内抑制肿瘤球体的形成，并诱导干性标记（CD133，Sox-2和Oct-4）和EMT标记（E-钙粘着蛋白，波形蛋白，和Slug）。SHP-1 / JAK2 / STAT3信号介导了ZnAs @ SiO2与HCC预后相关的这些作用。结论：ZnAs @ SiO2 NPs通过调节SHP-1 / JAK2 / STAT3信号通路有效抑制肝癌细胞的肿瘤发生，生长，转移，并抑制干细胞和EMT。因此，ZnAs @ SiO2 NPs在未来的HCC处理中具有巨大的潜力。

更新日期：2019-01-01

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