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Effects of Sorafenib/ZEB1 on the PI3K/AKT Signaling Pathway: Modulation of EMT Progression in Papillary Thyroid Carcinoma
Vol 37, Issue 11, 2023
Abstract
Background: Papillary thyroid carcinoma (PTC), being one of the malignant tumors, ranks as the most common thyroid tumor. Sorafenib (SFB), Zinc finger E-box binding homeobox1 (ZEB1), and the phosphatidylinositol-3-kinase and protein kinase B (PI3K/AKT) signaling pathway all play critical roles in cancer development and are involved in various biological processes within cancer cells. However, the precise mechanism of PTC remains unclear. Therefore, the objective of this study was to investigate the regulatory role of SFB/ZEB1 in the process of epithelial-mesenchymal transition (EMT) in PTC, with a focus on the PI3K/AKT signaling pathway. Methods: Quantitative Real-time polymerase chain reaction (qRT-PCR) and Western blot analysis were employed to examine the expression levels of ZEB1, phosphatidylinositol-3-kinase (PI3K), protein kinase B (AKT), pAKT, E-Cadherin (E-Ca), N-cadherin (N-Ca), and Vimentin, while regulatory mechanisms controlling these molecules were also investigated. Additionally, PTC cell viability and metastasis were assessed using scratch assays, Transwell assays, and 3-45-dimethylthiahiazo-z-y1-35-di-phenytetrazoliumromide (MTT) assays. Results: We observed that SFB effectively reduced the viability of PTC cells in a concentration-dependent manner, with an inhibitory concentration 50% (IC50) of 9.56 μmol/L. Furthermore, SFB demonstrated significant inhibitory effects on the metastasis of PTC cells when compared to the control group (p < 0.05). ZEB1 exhibited an upregulation in PTC cells, and the overexpression of ZEB1 led to a noteworthy enhancement in the viability, metastatic potential, and induction of epithelial-mesenchymal transition (EMT) in PTC cells compared to the overexpression-negative control (v-NC) group (p < 0.05). Notably, the upregulation of ZEB1 was associated with elevated protein levels of PI3K, AKT, and pAKT. However, SFB effectively reduced the expression level of ZEB1 and suppressed the promoting effects on PTC induced by ZEB1 overexpression (p < 0.05). Conclusions: In this study, our findings suggest that ZEB1 enhances the viability, metastatic potential, and EMT process of PTC cells by modulating the PI3K/AKT signaling pathway. SFB is effective in impeding the progression of PTC by inhibiting the biological effects of ZEB1 in PTC.
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Medical Genetics, University of Torino Medical School, Italy

Department of Biomedical, Surgical and Dental Sciences, University of Milan, Italy