Aberrant activation/expression of AP-1/Fra-2 and NF-κB/c-Rel was observed in most aggressive poorly differentiated tongue cancer with worst prognosis and the specific siRNA based silencing of c-Rel or Fra-2 further strengthened the functional role of c-Rel and Fra-2 and their possible cross-talk and interaction with other critical genes during aggressive tongue carcinogenesis. This evidence concerns the gene FOSL2 and tongue cancer.