The role of Cripto-1 in the tumorigenesis and progression of oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC), the most common malignancy of the oral cavity, remains a lethal disease in over 50% of cases diagnosed annually, due mostly to late detection of this cancer in its advanced stages despite the easy accessibility of the oral cavity for regular examinations. Cripto-1 is a member of the epidermal growth factor (EGF)-CFC protein family and is involved in the activation of several different signaling pathways during embryonic development and cellular transformation. Although the Cripto-1 protein is overexpressed in several human cancers including breast, colon, cervix, gastric, and pancreatic cancer, no prior study has evaluated Cripto-1 expression in OSCC. Therefore, our aims in this study were to examine Cripto-1 expression in clinical samples of OSCC patients using immunohistochemistry, to analyze the correlation between Cripto-1 expression and clinicopathologic parameters, and to identify the oncogenic roles of Cripto-1 in OSCC cell lines. Both epithelial dysplasia (73.3%) and OSCC (55.5%) tissue samples showed significantly higher expression of Cripto-1 than normal mucosa (20%) (p=0.031). In the OSCC samples, there was a significant correlation between Cripto-1 expression and the histological differentiation of OSCC (p=0.015) and a high PCNA index (p=0.011). The in vitro cell proliferation assays demonstrated that recombinant human Cripto-1 (rhCripto-1) induced both SCC-4 and SCC-25 cells to proliferate as compared with control cells (p<0.05 and p<0.01, respectively). In in vitro migration assays, treatment of SCC-4 and SCC-25 cells with rhCripto-1 protein induced a 2.4-fold and 1.7-fold-increase in cell migration, respectively (p=0.000 and p=0.008, respectively). Taken together, our data suggest that Cripto-1 plays a role in the malignant transformation of the oral mucosa and is involved in the tumorigenesis and progression of OSCC by promoting the growth and migration of malignant cells.