Cellular fibronectin 1 promotes VEGF-C expression, lymphangiogenesis and lymph node metastasis associated with human oral squamous cell carcinoma

Abstract

Lymph node metastasis (LNM) is associated with poor survival in patients with oral squamous cell carcinoma (OSCC). Vascular endothelial growth factor-C (VEGF-C) is thought to be responsible for increased lymphangiogenesis and LNM. Understanding of the mechanism by which VEGF-C expression is regulated in OSCC is thus important to design logic therapeutic interventions. We showed that inoculation of the SAS human OSCC cells expressing the venus GFP (V-SAS cells) into the tongue in nude mice developed LNM. V-SAS cells in LNM were isolated by FACS and re-inoculated into the tongue. This procedure was repeated eight times, establishing V-SAS-LM8 cells. Differential metastasis PCR array between the parental V-SAS and V-SAS-LM8 was performed to identify a molecule responsible for lymphangiogenesis and LNM. Fibronectin 1 (FN1) expression was elevated in V-SAS-LM8 cells compared to V-SAS-cells. V-SAS-LM8 tongue tumor showed increased expression of FN1 and VEGF-C, and promoted lymphangiogenesis and LNM compared with V-SAS tumor. Further, phosphorylation of focal adhesion kinase (FAK), a main downstream signaling molecule of FN1, was up-regulated, and epithelial-mesenchymal transition (EMT) was promoted in V-SAS-LM8 cells. Silencing of FN1 by shRNA in V-SAS-LM8 cells decreased FAK phosphorylation, VEGF-C expression and inhibited lymphangiogenesis and LNM. EMT was also reversed. The FAK phosphorylation inhibitor PF573228 also decreased VEGF-C expression and reversed EMT in V-SAS-LM8 cells. Finally, we detected intense FN1 expression in some clinical specimens obtained from OSCC patients with LNM. These results demonstrate that elevated expression of cellular FN1 and following activation of FAK lead to increased VEGF-C expression, lymphangiogenesis and LNM and promoted EMT in SAS human OSCC cells and suggest that FN1-phosphorylated FAK signaling cascade is a potential therapeutic target in the treatment of LNM in OSCC.

Fibronectin 1 promotes migration and invasion of papillary thyroid cancer and predicts papillary thyroid cancer lymph node metastasis

“…As an EMT marker, fibronectin is involved in cell adhesion and migration, including embryogenesis,17 wound healing,18 blood coagulation,19 osteogenesis,20 and metastasis 21,22. EMT is a process involved in embryonic development, during which cells lose their epithelial features and adopt characteristics of mesenchymal cells.…”

A three‐gene signature from protein–protein interaction network of LOXL2‐ and actin‐related proteins for esophageal squamous cell carcinoma prognosis

“…Fibronectin 1 ( FN1 ) mediates a wide variety of cellular interactions with the ECM, and is involved in cell adhesion, migration processes, and metastasis . Moreover, it is reported that altered expression of fibronectin 1 exists in several squamous cell carcinomas, including ESCC, head and neck squamous cell carcinoma, and oral squamous cell carcinoma . The derivation of these three genes predictive of clinical outcome in patients with ESCC may reveal PPI anticancer targets for the development of therapy for esophageal cancer.…”

Fibronectin in Cancer: Friend or Foe

“…Attention has particularly been paid to the fact that, with a few exceptions [101][102][103][104][105][106], the role of FN expression in tumor cells was primarily thought of as a tumor suppressor prior to the 1990s, yet later the consensus switched to its role being a metastatic promoter as aforementioned. It remains obscure why there are such two cut-off phases as to the different time periods for the obviously conflicting mainstream conceptions regarding the role of FN in tumor progression.…”