Lin-7C/VELI3/MALS-3: an essential component in metastasis of human squamous cell carcinoma

Using proteomic selection, functional verification, and clinical validation, we identified specific down-regulation of Lin-7C/VELI3/MALS-3 (Lin-7C), which marks oral squamous cell carcinoma (OSCC) metastasis. Despite a rarity of sequence variations in the Lin-7C gene in both primary OSCC and OSCC-derived cells, a high prevalence of hypermethylation was detected in the CpG island region that strongly correlated with its down-regulation. Inducible Lin-7C mRNA by experimental demethylation was found in all OSCC cells tested. Overexpression of the Lin-7C gene in an OSCC cell clone does not contribute to underproliferation but results in a noninvasive phenotype with elevated beta-catenin expression. Experimental metastases in multiple organs of immunodeficient mice were inhibited in cells expressing Lin-7C. Finally, the Lin-7C expression status in primary tumors afforded significantly (P<0.001) high accuracy for predicting lymph node metastasis. These results establish Lin-7C as a novel target of early detection, prevention, and therapy for OSCC metastasis.