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Ultrasound-Targeted Microbubble Destruction-Mediated Downregulation of EZH2 Inhibits Stemness and Epithelial-Mesenchymal Transition of Liver Cancer Stem Cells

Jie Wu,Lulu Sun,Tingting Liu,G. Dong

Published 2021 in OncoTargets and Therapy

ABSTRACT

Background Cancer cells could show the characteristics of cancer stem cells (CSCs) through epithelial-mesenchymal transition (EMT). EZH2 was associated with EMT. Ultrasound-targeted microbubble destruction (UTMD) could enhance gene transfection efficiency. Here, we explored the effect of UTMD-mediated shEZH2 on liver CSCs. Methods EZH2 expression in liver cancer and the overall survival of liver cancer patients were analyzed by bioinformatics. Liver CSCs (CD133+HuH7) were sorted by flow cytometry. After transfection of shEZH2 through UTMD (UTMD-shEZH2) or liposome (LIP-shEZH2), the viability, proliferation, sphere formation, migration, and invasion of CD133+HuH7 cells were detected by MTT, colony formation, tumor-sphere formation, wound healing, and transwell assays, respectively. A mice subcutaneous-xenotransplant tumor model was established by injecting CD133+HuH7 or CD133−HuH7 cells into the limbs of mice. Tumor weight and volume were documented. The expressions of EZH2, EMT-related factors, and STAT3/PI3K/AKT pathway-related factors in CD133+HuH7 cells or tumor tissues were detected by RT-qPCR, Western blot, or immunohistochemical. Results EZH2 was high-expressed in liver cancer, and the patients with high expression of EZH2 had a poor survival. CD133+ HuH7 cells had higher EZH2 expression, higher viability, and stronger sphere-forming and tumor-forming abilities than CD133− HuH7 cells. ShEZH2 inhibited the viability, proliferation, sphere formation, migration, and invasion of CD133+ HuH7 cells, decreased the weight and volume of the xenotransplant tumor, inhibited the expressions of EZH2, Vimentin, N-Cadherin, Twist-1, p-STAT3, p-PI3K, and p-AKT, and increased E-Cadherin expression. UTMD-shEZH2 caused a stronger effect on CD133+ HuH7 cells than LIP-shEZH2. Conclusion UTMD-mediated shEZH2 inhibited the stemness and EMT of liver CSCs in vitro and in vivo through regulating the STAT3/PI3K/AKT pathway.

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