Abstract
Around half of all patients with oral squamous cell carcinoma (OSCC) present with lymphatic metastasis, a strong predictor of poor survival. Improving survival rates depends on preventing the first step in the “invasion-metastasis cascade,” epithelial-to-mesenchymal transition (EMT), and developing antilymphangiogenesis therapies that antagonize lymphatic metastasis. The extracellular matrix-related protein WISP-1 (WNT1-inducible signaling pathway protein-1) stimulates bone remodeling and tumor progression. We have previously reported that WISP-1 promotes OSCC cell migration and lymphangiogenesis induced by vascular endothelial growth factor C (VEGF-C). This investigation sought to determine the role of WISP-1 in regulating EMT in OSCC. Our analysis of oral cancer data from The Cancer Genome Atlas (TCGA) database revealed significant and positive associations between levels of WISP-1 expression and clinical disease stage, as well as regional lymph node metastasis. We also found higher levels of WISP-1 expression in serum samples obtained from patients with OSCC compared with samples from healthy controls. In a series of in vitro investigations, WISP-1 activated EMT signaling via the FAK/ILK/Akt and Snail signaling transduction pathways and downregulated miR-153-3p expression in OSCC cells. Our findings detail how WISP-1 promotes EMT via the miR-153-3p/Snail axis in OSCC cells.
Highlights
The vast majority of oral neoplasms are diagnosed as oral squamous cell carcinoma (OSCC) [1], which primarily affects the tongue (34.1%), palate (13.5%), buccal mucosa (13.3%), and floor of the mouth (12.2%) [2,3]
We have previously demonstrated that OSCC-derived WISP-1 increases its motility and lymphangiogenesis to facilitate lymph node metastasis [31,32]
Levels of WISP-1 mRNA expression were much higher in tumor tissue than in adjacent normal tissue (Figure 1A) and significant associations were observed between high levels of WISP-1 expression and clinical disease stage (Figure 1B) and regional lymph node metastasis (Figure 1D), but there was no such effect on clinical tumor status (Figure 1C)
Summary
The vast majority (an estimated 95%) of oral neoplasms are diagnosed as oral squamous cell carcinoma (OSCC) [1], which primarily affects the tongue (34.1%), palate (13.5%), buccal mucosa (13.3%), and floor of the mouth (12.2%) [2,3]. The epithelial-to-mesenchymal transition (EMT) phenomenon describes a process whereby the migratory capacity and invasiveness of epithelial cells is enhanced via the loss of cell–cell adhesions and polarity, enabling them to transition into cells with a mesenchymal phenotype [7,8]. During this highly dynamic process, EMT activation decreases levels of epithelial markers (e.g., E-cadherin) and increases levels of mesenchymal markers (e.g., N-cadherin, vimentin, and fibronectin) in cancers [9,10]. EMT-activated cancer cells become highly mobile, more stem cell-like (self-renew and differentiate into different tumor cell types), and are better able to infiltrate immune cell populations and become treatment-resistant [18,19,20]
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