LMO3 Interacts with Neuronal Transcription Factor, HEN2, and Acts as an Oncogene in Neuroblastoma

Abstract

LIM-only proteins (LMO), which consist of LMO1, LMO2, LMO3, and LMO4, are involved in cell fate determination and differentiation during embryonic development. Accumulating evidence suggests that LMO1 and LMO2 act as oncogenic proteins in T-cell acute lymphoblastic leukemia, whereas LMO4 has recently been implicated in the genesis of breast cancer. However, little is known about the role of LMO3 in either tumorigenesis or development. In the present study, we have identified LMO3 and HEN2, which encodes a neuronal basic helix-loop-helix protein, as genes whose expression levels were higher in unfavorable neuroblastomas compared with those of favorable tumors. Immunoprecipitation and immunostaining experiments showed that LMO3 was associated with HEN2 in mammalian cell nucleus. Human neuroblastoma SH-SY5Y cells stably overexpressing LMO3 showed a marked increase in cell growth, a promotion of colony formation in soft agar medium, and a rapid tumor growth in nude mice compared with the control transfectants. More importantly, the increased expression of LMO3 and HEN2 was significantly associated with a poor prognosis in 87 primary neuroblastomas. These results suggest that the deregulated expression of neuronal-specific LMO3 and HEN2 contributes to the genesis and progression of human neuroblastoma in a lineage-specific manner. (Cancer Res 2005; 65(11): 4587-97)

Expressions of SH3BP5, LMO3, and SNAP25 in diffuse large B‐cell lymphoma cells and their association with clinical features

“…LMO3, a member of the LMO family, was originally described as expressed only in the brain and spinal cord 25, and LMO3 overexpression predicts a poor prognosis in neuroblastoma 26. Recently, aberrant LMO3 expression in other various types of malignant cells has been reported 27, 28, 29.…”

CD133 suppresses neuroblastoma cell differentiation via signal pathway modification

“…Every 24 h, cell viability was determined by water-soluble tetrazolium salt (WST-8) assay using Counting kit-8 (Dojindo, Kumamoto, Japan) according to the manufacturer's protocol. For soft agar assay, 2 Â 10 3 cells of stable infectants TGW or SH-SY5Y cells were seeded in soft agar as described previously (Aoyama et al, 2005). Viable colonies were stained with 0.05 mg/ml MTT.…”

“…For tumor formation, 6-week-old female athymic BALB/c AJcl nu/nu mice (CLEA Japan, Shizuoka, Japan) were injected into the femur with 1 Â 10 7 TGW cells as described previously (Aoyama et al, 2005). The handling of animals was in accordance with the guidelines of Chiba Cancer Center Research Institute.…”

LMO4 can interact with Smad proteins and modulate transforming growth factor-β signaling in epithelial cells

“…The four LMOs play roles in mammalian development (Yamada et al, 1998;Hahm et al, 2004;Tse et al, 2004;Lee et al, 2005). In addition, LMO1 and LMO2 act as oncogenes in acute lymphoblastic leukemia (Rabbitts, 1998), and recent studies have defined LMO3 as an oncogene in neuroblastoma (Aoyama et al, 2005) and LMO4 as a protumorigenic factor in breast cancer (Visvader et al, 2001;Sum et al, 2005b). LMOs interact strongly with transcriptional coregulators referred to as Co-factors of LIM domains (Clims)/LIM domain-binding proteins (Ldb)/nuclear LIM interactors (Nli) (Agulnick et al, 1996;Jurata et al, 1996;Bach et al, 1997Bach et al, , 1999Visvader et al, 1997;Matthews and Visvader, 2003).…”