Abstract
In this study, we present novel molecular mechanisms by which FOXO1 functions as a tumor suppressor to prevent the pathogenesis of nasopharyngeal carcinoma (NPC). First, we observed that FOXO1 not only controlled tumor stemness and metastasis, but also sensitized NPC cells to cisplatin (DDP) in vitro and in vivo. Mechanistic studies demonstrated that FOXO1-induced miR-200b expression through the GSK3β/β-catenin/TCF4 network-mediated stimulation of ZEB1, which reduced tumor stemness and the epithelial–mesenchymal transition (EMT) signal. Furthermore, we observed FOXO1 interaction with MYH9 and suppression of MYH9 expression by modulating the PI3K/AKT/c-Myc/P53/miR-133a-3p pathway. Decreased MYH9 expression not only reduced its interactions with GSK3β, but also attenuated TRAF6 expression, which then decreased the ubiquitin-mediated degradation of GSK3β protein. Increased GSK3β expression stimulated the β-catenin/TCF4/ZEB1/miR-200b network, which increased the downstream tumor stemness and EMT signals. Subsequently, we observed that chemically synthesized cinobufotalin (CB) strongly increased FOXO1-induced DDP chemosensitivity by reducing MYH9 expression, and the reduction in MYH9 modulated GSK3β/β-catenin and its downstream tumor stemness and EMT signal in NPC. In clinical samples, the combination of low FOXO1 expression and high MYH9 expression indicated the worst overall survival rates. Our studies demonstrated that CB potently induced FOXO1-mediated DDP sensitivity by antagonizing its binding partner MYH9 to modulate tumor stemness in NPC.
Highlights
Here, we found that FOXO1 significantly inhibited nasopharyngeal carcinoma (NPC) tumor stemness, migration, invasion, and metastasis in vitro and in vivo
We speculated that in gastric cancer and pancreatic ductal adenocarcinoma but are in FOXO1-suppressed MYH9 protein expression by regulating the contrast to results in glioblastoma.[9,10,11]. This discrepancy in the role PI3K/AKT/c-Myc/P53/miR-133a-3p pathway. In line with this of FOXO1 in different tumors would most likely be due to the different tissue specificities,[21] which has been reported for other genes in tumors, such as CTGF,[22] miR-374a,23 and certain members of KRTAP subfamilies.[24]
NPC cells overspeculation, we first observed that the cell abilities of cancer stemness, migration and invasion were obviously restored after cMyc was transfected into FOXO1-overexpressing NPC cells
Summary
The cancer stem cell (CSC) theory states that tumors are composed of a small group of stem cell-like cells with infinite self-renewal and heterogeneous differentiation abilities and nearby cell clusters that are unevenly differentiated.[1,2] Abnormal expression of epithelial–mesenchymal transition (EMT)-related genes often leads to tumor cells that have acquired the biological properties of migration and invasion, which eventually induces distant tumor metastases.[3,4] Numerous studies have clarified that EMT capability is a stem cell characteristic of tumor cells.[5,6] The presence of CSCs and EMT leads to significant increases in the degree of malignancy associated with tumor cells and further induces tumor cell resistance to radiotherapy and chemotherapy, reducing the efficacy of tumor treatments.[5,7] exploring stemness mechanisms in tumors and the abnormal expression of EMT-related genes in tumor cells will help to increase our understanding of tumor pathogeneses and improve the design of more effective cancer therapies. The suppressive effects that ectopic (SP) analysis showed that both NPC cell lines overexpressing FOXO1 has on stemness, migration, and invasion were reversed by FOXO1 had a dramatically decreased percentage of SP cells miR-200b expression, as shown by sphere-forming, transwell, and compared with the control groups (from 1.22% to 0.246% and Boyden assays (Supplementary Fig. 2C, D). FOXO1-overexpressing group compared with that observed in the promoter (Supplementary Fig. 2K) These results demonstrated control cells, while cell migration and invasion were induced in the that ZEB1 binds to the miR-200b promoter. Univariate we confirmed that miR-133a-3p, a tumor suppressor, and multivariate Cox regression analysis in 321 NPC patients directly downregulated MYH9 protein expression by binding to its showed that the T classifications, N classifications, M classifica- 3’UTR in NPC cells. Factor for miR-133a-3p; our experiments showed that direct binding of p53 to the miR-133a-3p promotor induced miR-133a-
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