Oncogene database

2274

FHL2

four and a half LIM domains 2;FHL2;four and a half LIM domains 2

LIM domain protein DRAL|aging-associated gene 11|down-regulated in rhabdomyosarcoma LIM protein|four and a half LIM domains protein 2|skeletal muscle LIM-protein 3

2q12.2

protein-coding

Four-and-a-half-LIM protein 2 (FHL2) is a member of FHL protein family, which plays a crucial role in regulating gene expression, cell survival, and migration. Although its function in oncogenesis appears to be tumor type-specific, its roles in glioma formation and development are yet to be elucidated. In the present study, we demonstrated that the mRNA level of FHL2 was elevated in both low- and high-grade glioma samples. Overexpression of FHL2 stimulated the proliferation, anchorage-independent growth, and migration of human glioblastoma cells. Conversely, FHL2 knockdown by short hairpin RNA (shRNA-FHL2) inhibited glioblastoma cell proliferation and migration. Overexpression of FHL2 increased the tumorigenicity of glioblastoma cells in nude mice and decreased the mRNA levels of p53 and its downstream proapoptotic genes, including p21, Bcl2-associated protein X (Bax), and p53-upregulated modulator of apoptosis. It also enhanced the promoter activities of activator protein-1 (AP-1), human telomerase reverse transcriptase, and survivin genes. Together, these results provide the first evidence that FHL2 contributes to glioma carcinogenesis.

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.

BACKGROUND: The molecular mechanisms that are involved in the growth and invasiveness of osteosarcoma, an aggressive and invasive primary bone tumor, are not fully understood. The transcriptional co-factor FHL2 (four and a half LIM domains protein 2) acts as an oncoprotein or as a tumor suppressor depending on the tissue context. In this study, we investigated the role of FHL2 in tumorigenesis in osteosarcoma model. METHODOLOGY/PRINCIPAL FINDINGS: Western blot analyses showed that FHL2 is expressed above normal in most human and murine osteosarcoma cells. Tissue microarray analysis revealed that FHL2 protein expression is high in human osteosarcoma and correlates with osteosarcoma aggressiveness. In murine osteosarcoma cells, FHL2 silencing using shRNA decreased canonical Wnt/beta-catenin signaling and reduced the expression of Wnt responsive genes as well as of the key Wnt molecules Wnt5a and Wnt10b. This effect resulted in inhibition of osteosarcoma cell proliferation, invasion and migration in vitro. Using xenograft experiments, we showed that FHL2 silencing markedly reduced tumor growth and lung metastasis occurence in mice. The anti-oncogenic effect of FHL2 silencing in vivo was associated with reduced cell proliferation and decreased Wnt signaling in the tumors. CONCLUSION/SIGNIFICANCE: Our findings demonstrate that FHL2 acts as an oncogene in osteosarcoma cells and contributes to tumorigenesis through Wnt signaling. More importantly, FHL2 depletion greatly reduces tumor cell growth and metastasis, which raises the potential therapeutic interest of targeting FHL2 to efficiently impact primary bone tumors.