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

Abstract

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@SiO 2 NPs. HCC cell lines, MHCC97L and Hep3b, were used to analyze the antitumor activity of ZnAs@SiO 2 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@SiO 2 . Results : Compared with the current ATO treatment, ZnAs@SiO 2 NPs promoted apoptosis and significantly inhibited proliferation, migration, and invasion of both MHCC97L and Hep3b cells. In the in vivo assay, ZnAs@SiO 2 NPs inhibited tumor growth by 2.2-fold and metastasis by 3.5-fold as compared to ATO. The ZnAs@SiO 2 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@SiO 2 that correlated with prognosis of HCC were mediated by the SHP-1/JAK2/STAT3 signaling. Conclusions : ZnAs@SiO 2 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@SiO 2 NPs have immense potential for HCC treatment in the future.

Chronic stress promotes EMT-mediated metastasis through activation of STAT3 signaling pathway by miR-337-3p in breast cancer

“…Moreover, correlation heat map indicated that the nine genes were highly relevant to miR-337-3p ( Fig. 4c) and STAT3 was selected for further study as previous evidence proved that it was targeted by miR-337-3p 29,30 , and played a crucial role in EMT 31 .…”

Nanomaterials as Inhibitors of Epithelial Mesenchymal Transition in Cancer Treatment

“…Different nanomaterials have been exploited to deliver synthetic chemotherapeutics and chemicals inside cancer cells reverting EMT and chemoresistance, and prevent metastasis in a plethora of tumor types [68][69][70][71][72][73][74][75][76][77][78].…”

“…In this sense, zinc arsenite (ZnAs) NPs have been exploited as a molecular scaffold to deliver ATO in nasopharyngeal carcinoma (NCO) cells and hepatocarcinoma (HCC) tumor models [73,74]. ATO-loaded zinc arsenite (ZnAs) nanocomplexes inhibited EMT process via SHP-1/JAK2/STAT3 pathway and by reducing the expression of EMT-related proteins, leading to reduced tumor growth in vivo [73,74].…”

Circ‐MALAT1 Functions as Both an mRNA Translation Brake and a microRNA Sponge to Promote Self‐Renewal of Hepatocellular Cancer Stem Cells

“…Protein samples were then prepared from Hep3B cells with circ‐MALAT1 overexpression or empty vector and analyzed by western blot to verify the antibody‐array results. The most significantly increased protein correlated with circ‐MALAT1 overexpression was found to be Janus‐activated kinase 2 (JAK2), a well‐characterized protein that could induce CSC‐like characteristics (Figure C) . Conversely, Paired box 5 (PAX5), a tumor suppressor, decreased most significantly after circ‐MALAT1 overexpression among the 5 proteins (PAX5, ACTA1, ARFIP1, CLDN5, and KRT18) out of the 10 downregulated proteins in HCC cells (Figure D).…”