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Fibroblast growth factor (FGF) and its receptor (FGFR) are thought to be negative regulators of chondrocytic growth, as exemplified by achondroplasia and related chondrodysplasias, which are caused by constitutively active mutations in FGFR3. To understand the growth-inhibitory mechanisms of FGF, we analyzed the effects of FGF2 on cell cycle-regulating molecules in chondrocytes. FGF2 dramatically inhibited proliferation of rat chondrosarcoma (RCS) cells and arrested their cell cycle at the G 1 phase. FGF2 increased p21 expression in RCS cells, which assembled with the cyclin E-Cdk2 complexes, although the expression of neither cyclin E nor Cdk2 increased. In addition, the kinase activity of immunoprecipitated cyclin E or Cdk2, assessed with retinoblastoma protein (pRb) as substrate, was dramatically reduced by FGF-2. Moreover, FGF2 shifted pRb to its underphosphorylated, active form in RCS cells. FGF2 not only induced p21 protein expression in proliferating chondrocytes in mouse fetal limbs cultured in vitro but also decreased their proliferation as assessed by the expression of histone H4 mRNA, a marker for cells in S phase. Furthermore, inhibitory effects of FGF2 on chondrocytic proliferation were partially reduced in p21-null limbs, compared with those in wild-type limbs in vitro. Taken together, FGF's growth inhibitory effects of chondrocytes appear to be mediated at least partially through p21 induction and the subsequent inactivation of cyclin E-Cdk2 and activation of pRb. FGFs1 are a large family of at least 23 related polypeptides that bind to and activate a family of four tyrosine kinase receptors, FGFRs. They play important roles in regulating proliferation and differentiation of various types of cells, including those involved in limb development and long bone formation (1, 2). Long bones form by endochondral ossification, which is characterized by mesenchymal condensation, chondrogenic differentiation, chondrocytic proliferation, synthesis of cartilage matrix, hypertrophic differentiation, and replacement by bone. These sequential growth and differentiation processes are regulated by numerous growth factors and their receptors, such as parathyroid hormone-related protein, Indian hedgehog, and insulin-like growth factor-I (3, 4). Recently, achondroplasia, thanatophoric dysplasia, and hypochondroplasia have been shown to be caused by constitutively active mutations in the FGFR3 gene (5). Also, FGFR3-deficient mice displayed overgrowth of long bones (6, 7), and mice carrying dominant active FGFR3 genes exhibited dwarfism similar to that in patients with achondroplasia and thanatophoric dysplasia (8 -13). Moreover, targeted overexpression of FGF9 in cartilage results in dwarfism in mice similar to the dwarfism in achondroplasia (14). Although these findings support the hypothesis that FGF and its receptors are negative regulators of endochondral bone development, little is known about the mechanisms by which FGF inhibits chondrocytic growth. Sahni et al. recently reported that FGF inhibited chondrocytic ...

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ABSTRACT

Snail family genes are conserved among species during evolution and encode transcription factors expressed at different stages of development in different tissues. These genes are involved in a broad spectrum of biological functions: cell differentiation, cell motility, cell cycle regulation, and apoptosis. However, little is known about the target genes involved in these functions. Here we show that mouse Snail family members, Snail (Sna) and Slug (Slugh), are involved in chondrocyte differentiation by controlling the expression of type II collagen (Col2a1) and aggrecan. In situ hybridization analysis of developing mouse limb demonstrated that Snail and Slug mRNAs were highly expressed in hypertrophic chondrocytes. Inversely, the expression of collagen type II mRNA disappeared during hypertrophic differentiation. Snail and Slug mRNA expression was down-regulated during differentiation of the mouse chondrogenic cell line ATDC5 and overexpression of exogenous Snail or Slug in ATDC5 cells inhibited expression of collagen type II and aggrecan mRNA. Reporter analysis revealed Snail and Slug suppressed the promoter activity of Col2a1, and the E-boxes in the promoter region were the responsible element. Gel shift assay demonstrated the binding of Snail to the E-box. Because type II collagen and aggrecan are major functional components of extracellular matrix in cartilage, these results suggest an important role for Snailrelated transcription repressors during chondrocyte differentiation.During skeletal development, condensed mesenchymal cells give rise to chondrocytes and form cartilage primordia, which serve as templates for endochondral bone formation. In cartilage primordia, chondrocytes undergo further differentiation, starting as proliferating chondrocytes, becoming prehypertrophic chondrocytes and ending as hypertrophic chondrocytes. Chondrocytes secrete abundant extracellular matrix (ECM) 1 into the extracellular space, and the composition of ECM changes during the sequential differentiation steps. Type II collagen and aggrecan are major components of the cartilage extracellular matrix produced by proliferating and prehypertrophic chondrocytes, and type X collagen is a major collagen type produced by hypertrophic chondrocytes. The differentiation into hypertrophic chondrocytes is accompanied with changes in ECM; switching of collagen types from type II to type X and the disappearance of aggrecan and link protein (1, 2

BACKGROUND AND PURPOSE:The presence of cervical lymph node metastases is an important prognostic factor for oral tongue cancer. The accurate preoperative assessment is essential for treatment. Several studies have suggested that histologic tumor thickness is related to the metastases. The aim of this study was to determine whether MR images of oral tongue tumor have the potential to predict cervical lymph node metastases.

Abstract. Fatty acid binding proteins (FABPs) are a family of small and highly conserved lipid chaperone molecules with highly varied functions. Among them, fatty acid binding protein 4 (FABP4, also known as aP2) is highly expressed by adipocytes, macrophages and dendritic cells. Although the role of FABP4 in cancer is still unclear, it has been reported to be highly expressed by human tumors such as ovarian and bladder cancers. In the present study, we investigated the expression and role of FABP4 in oral squamous cell carcinoma (SCC) and its expression in oral SCC tissues. Immunohistochemical staining revealed that FABP4 expression in the tumor tissue was much higher than that in the non-tumor area of the same specimen. In the in vitro studies, an FABP4-knockdown SCC cell line (established through FABP4-specific siRNA) showed inhibited growth, and inhibited expression and activation of mitogen-activated protein kinase (MAPK). These results indicate that expression of FABP4 plays an important role in the cell growth of oral SCC through the MAPK pathway. IntroductionOral squamous cell carcinoma (SCC) is a major neoplasm of the oral cavity with an increasing rate of incidence (1-3). The optimal therapy for early oral SCC is surgery, but the overall survival rate has exhibited only a slight change (1-3). Therefore, more effective therapies for oral SCC are needed.Fatty acid binding proteins (FABPs) are a family of small and highly conserved lipid chaperone molecules that bind long-chain fatty acids and other hydrophobic ligands. Their functions are wide ranging (4-6). Among them, fatty acid binding protein 4 (FABP4, also known as aP2) is highly expressed in adipocytes, macrophages and dendritic cells (5,7). As a result of its distribution, FABP4 is the most extensively researched FABP in endocrinology and metabolomics. FABP4 affects metabolic syndrome progression; FABP4-deficient mice were found to have reduced hyperinsulinemia and insulin resistance in obesity (7,8) and showed protection from atherosclerosis (9).However, little is known concerning the role of FABP4 in cancer, including oral SCC. Recently, Nieman et al (10) reported that adipocytes promote ovarian cancer metastasis and tumor cell growth by providing energy mediated by FABP4. Therefore, increased FABP4 expression may affect the growth of various tumor types. Our research group also reported that molecules controlled by peroxisome proliferator-activated receptor γ (PPARγ) play key roles in SCC growth (11-15). As FABP4 is known to mediate transcription with PPARγ (4,16), we hypothesized that FABP4 may regulate SCC growth. Therefore, in the present study, we investigated FABP4 expression and its effects on SCC of the tongue. Materials and methodsTissue samples. All clinical studies were approved by the Ethics Committee of Osaka University Dental Hospital, Osaka. Twenty-seven SCC specimens from resected tongue tissue were obtained at the Osaka University Dental Hospital during 1986-2008 after patient informed consent (Table I). Patients received no pre...

Background and Objectives Some patients with early‐stage oral cancer have a poor prognosis owing to the delayed neck metastasis (DNM). Tumor budding is reportedly a promising prognostic marker in many cancers. Moreover, the tissue surrounding a tumor is also considered to play a prognostic role. In this study, we evaluated whether tumor budding and adjacent tissue at the invasive front can be potential novel predictors of DNM in early tongue cancer. Methods In total, 337 patients with early‐stage tongue squamous cell carcinoma were retrospectively reviewed. The patient characteristics and histopathological factors were evaluated for association with DNM. DNM rates were calculated; items which were significant in the univariate analysis were used as explanatory variables, and independent factors for DNM were identified by the multivariate analysis. Results The univariate analysis identified T classification, depth of invasion, tumor budding, vascular invasion, and adjacent tissue at the invasive front as significant predictors of DNM; the multivariate analysis using these factors revealed all the above variables except vascular invasion, which are independent predictors of DNM. Conclusion In addition to conventional predictors, high grade tumor budding and adjacent tissue at the invasive front can serve as useful predictors of DNM in early tongue cancer.