Oncogene functions of FHL2 are independent from NF-kappaBIalpha in gastrointestinal cancer.

Four and a half of LIM-only protein 2 (FHL2) is an adaptor protein that can interact with many transcription factors and thus plays a variety of biological functions. Previous studies by our group have demonstrated that suppression of FHL2 was capable of inducing tumor cell differentiation, and inhibiting the growth of experimental gastric and colon cancers. Therefore, FHL2 appears to function as an oncogene. In order to further explore the mechanisms of how FHL2 is involved in tumorigenesis, we attempted to test whether FHL2 has any direct association with nuclear factor (NF-kappaB), the most important transcription factor involved in apoptosis, inflammation, and carcinogenesis. Using an Yeast Two Hybrid (Y2H) screening system, we have shown that FHL2 may have an interaction with NF-kappaBIalpha, the coding gene for IkappaBalpha which is the most potent endogenous inhibitor for NF-kappaB activation. However, subsequent studies using co-immunoprecipitation and co-localization failed to confirm the Y2H finding. Down-regulation of FHL2 by FHL2-siRNA down-regulated the expression of NF-kappaB p65. We therefore concluded that under the physiological condition, FHL2 may activate NF-kappaB pathway, even though such an activation may not be mediated by a direct binding of FHL2 to NF-kappaB inhibitor protein IkappaB.