FOXD1 promotes EMT and cell stemness of oral squamous cell carcinoma by transcriptional activation of SNAI2

Abstract

Background Epithelial-mesenchymal transition (EMT) and cell stemness are implicated in the initiation and progression of oral squamous cell carcinoma (OSCC). Revealing the intrinsic regulatory mechanism may provide effective therapeutic targets for OSCC. Results In this study, we found that Forkhead box D1 (FOXD1) was upregulated in OSCC compared with normal samples. Patients with a higher FOXD1 expression had a poorer overall survival and disease-free survival. Immunohistochemical staining results showed that FOXD1 expression was related to the clinical stage and relapse status of OSCC patients. When FOXD1 expression was knocked down in CAL27 and SCC25 cells, the migration, invasion, colony formation, sphere formation, and proliferation abilities decreased. Moreover, EMT and stemness-related markers changed remarkably, which indicated that the EMT process and cell stemness were inhibited. Conversely, overexpression of FOXD1 promoted EMT and cell stemness. Further study demonstrated that FOXD1 could bind to the promoter region and activate the transcription of SNAI2. In turn, the elevated SNAI2 affected EMT and cell stemness. An in vivo study showed that FOXD1-overexpressing CAL27 cells possessed a stronger tumorigenic ability. Conclusions Our findings revealed a novel mechanism in regulating EMT and cell stemness and proposed FOXD1 as a potential marker for the diagnosis and treatment of OSCC.

The Prognostic Significance of FOXD1 Expression in Head and Neck Squamous Cell Carcinoma

“…Different from what Li et al had demonstrated [ 30 ], we noted that the expression of FOXD1 was not statistically related to advanced TNM stage and N+ status, but a high expression of FOXD1 was correlated with recurrence or metastasis. Previous studies had revealed that overexpression of FOXD1 promoted the epithelial–mesenchymal transition, which might be the potential mechanism for the poorer survival that presented among patients with a higher FOXD1 expression level [ 31 ]. It was reported that high expression of FOXD1 was correlated with pathological differentiation in colorectal carcinoma; however, there was no statistical relationship between histological grade and FOXD1 expression in our study about HNSCC [ 32 ].…”

FOXD1 Is a Transcription Factor Important for Uveal Melanocyte Development and Associated with High-Risk Uveal Melanoma

“…In vitro and in vivo experiments elucidated FOXD1 as an oncogene involved in proliferation, dedifferentiation, migration, and radio- and chemoresistance [ 67 , 68 , 69 , 70 , 71 ]. For instance, in oral squamous cell carcinoma, FOXD1 promotes the epithelial–mesenchymal transition (EMT) by activation of SNAI2 [ 72 ]. Functional work on FOXD1 in cutaneous melanoma elucidated its capability to induce the expression of the tumor-specific isoform Rac Family Small GTPase 1B ( RAC1B ) to enhance melanoma migration and invasion [ 38 ].…”

Cancer cells corrupt normal epithelial cells through miR-let-7c-rich small extracellular vesicle-mediated downregulation of p53/PTEN

“…The experiments were conducted as described in previous research. 43 Briefly, the cells were evenly planted on a six-well plate and grown into a confluent monolayer. Subsequently, a scratch was made and marked on the underside of the plate to ensure that the images were observed at identical places at 0 and 48 h. The migrated areas were calculated using Image-Pro Plus 6.0 software.…”

“…The assay was carried out as previously described. 43 In summary, HIOECs were uniformly plated into 24-well plates, fixed and stained using the EdU Cell Proliferation Kit (Beyotime, China) as instructed, and finally observed and photographed under a fluorescence microscope (Keyence, Japan).…”