The LIM-only protein, LMO4, and the LIM domain-binding protein, LDB1, expression in squamous cell carcinomas of the oral cavity

Abstract

Carcinoma cells can lose their epithelial cell characteristics and dedifferentiate into a fibroblast-like cell during progression of a neoplasm. Aberrant expression of oligomeric transcriptional complexes contributes to progression of carcinomas. Although individual transcription factors initiating progression remain unknown, LIM-only protein (LMO) and LIM-domain binding protein (LDB) negatively regulate breast carcinoma cell differentiation. In this study, we investigated the expression of LMO4 and LDB in squamous cell carcinomas of the oral cavity. LMO4 mRNA was amplified in four of six carcinoma tissues and eight of 12 carcinoma cell lines, and LDB1 in three carcinoma tissues and 11 cell lines examined. Immunoprecipitation studies revealed that LMO4 and LDB1 interact with each other in the nuclear milieu of the carcinoma cells indicating the presence of an LMO4-LDB1-mediated transcription complex. Both LMO4 and LDB1 proteins were preferentially localised in the nuclei of carcinoma cells at the invasive front and the immunoreactivity was increased in less-differentiated carcinoma tissues (Po0.01). Carcinoma cells metastasised to the cervical lymph nodes with increased immunoreactivity compared to the primary site of neoplasm (Po0.05). These data suggest that the LMO4 -LDB1 complexes may be involved in carcinoma progression possibly through dedifferentiation of squamous carcinoma cells of the oral cavity.

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

“…Consistent with a role in mammary epithelial cells, we have shown that overexpression of a dominantnegative LMO4 inhibits ductular and lobuloalveolar development in the mammary glands of transgenic mice (Wang et al, 2004), and others have demonstrated that mammary gland-specific deletion of the LMO4 gene leads to impaired lobuloalveolar development during pregnancy (Sum et al, 2005c). LMO4 has also been shown to be upregulated at the invasive fronts of oral cancers, suggesting a role in cancer cell invasion (Mizunuma et al, 2003). In the prostate, LMO4 was downregulated during tumor progression and lowered in hormone refractory tumors (Mousses et al, 2002).…”

LMO4 is a prognostic marker involved in cell migration and invasion in non-small-cell lung cancer

“…LMO2 regulates angiogenesis and hematopoiesis (8,9), and LMO1 and LMO3 are expressed during embryogenesis (10). LMO proteins have important roles in cell growth, apoptosis, and differentiation (11)(12)(13). A previous study showed that LMO4 is overexpressed during the differentiation of mammary epithelial cells (14), implicating it as an oncogene.…”

The LIM-only factor LMO4 regulates expression of the BMP7 gene through an HDAC2-dependent mechanism, and controls cell proliferation and apoptosis of mammary epithelial cells

“…LMO4 has been implicated in the cause or progression of breast cancers (Sum et al, 2005b), squamous cell carcinomas of oral cavity (Mizunuma et al, 2003) and primary prostate cancers (Mousses et al, 2002). The LMO4 gene is most highly expressed in mammary epithelial cells during midpregnancy (Wang et al, 2004), a stage of active proliferation and invasion; interference with the protein (Wang et al, 2004) or deletion of the gene (Sum et al, 2005c) leads to impaired lobuloalveolar development of the mammary gland.…”