A human oncogene formed by the fusion of truncated tropomyosin and protein tyrosine kinase sequences. the suppression of TRKB phosphorylation in PD-OSCC but not in WD-OSCC and genes, respectively. Although it is well-known that TRK proteins play a wide variety of roles in neuronal function during developmental, physiological, and disease processes, they were initially identified in cancer [17C19]. In central and peripheral nervous systems, TRK proteins serve as high-affinity receptors for the nerve growth factor, a type CB-1158 of neurotrophins (brain-derived neurotrophic factor, BDNF; neurotrophin-3, NT-3; and neurotrophin-4, NT-4), and play a critical role in regulating neuronal cell survival, neurite growth, cell migration, spine and dendritic growth, and synapse formation [20C23]. Overexpression of TRK proteins and gene fusion were found in many types of cancer [21, 24C28]. Especially, TRKB is well investigated in many types of cancer. TRKB promotes tumor cell CB-1158 proliferation through the activation of the RAS/MAPK, the PI3K/PDK1/AKT, and the PLC pathways  and induces anoikis suppression and epithelial-mesenchymal transition through the induction of Twist and Snail [30C33]. It has also been established that TRKB promotes tumor metastasis in some types of tumors, such as lung adenocarcinoma [34, 35], breast cancer, and neuroblastoma , using tumor transplantation mouse models. Overexpression of TRKB and its specific ligand, BDNF, in OSCC, was also reported CB-1158 by several research groups [22, 32, 37, 38]. However, regardless of these accumulating findings, the correlation between TRKB overexpression and clinicopathological characteristics in patients with OSCC is not fully elucidated. In this study, we used the human OSCC tissues to examine the correlations between TRKB/BDNF expression, tumor differentiation, and clinicopathologic features in patients with OSCC. We also used two different types of human OSCC cell lines (well differentiated and poorly differentiated) to study the CB-1158 FLJ23184 effect of a TRKB-specific inhibitor for tumor therapy in tumor cell-transplanted mouse models and cell culture systems. We describe a new correlation between TRKB/BDNF overexpression and OSCC tumor differentiation, and propose that TRKB is a potential therapeutic target for OSCC, especially for poorly differentiated OSCC. RESULTS Clinicopathologic features in patients with OSCC The preferential site of the OSCC was the tongue (31/44 cases, 70.5%), followed by the mouth floor (5/44 cases, 11.4%), gingiva (5/44 cases, 11.4%), buccal mucosa (2/44 cases, 4.5%), and hard palate (1/44 case, 2.3%). All 44 patients were classified as either stage I (25/44 cases, 56.8%), stage II (15/44 cases, 34.1%), stage III (2/44 cases, 4.55%), or stage IV (2/44 cases, 4.55%). According to the Tumor-Node-Metastasis (TNM) clinical classification, 25 cases were classified as T1 (56.8%) and 19 as T2 (43.2%). Tumor grading showed that 25 cases were well differentiated (56.8%), 12 cases were moderately differentiated (27.3%), and 7 cases were poorly differentiated (15.9%). Correlation between the expression levels of TRKB, BDNF, or both, and clinicopathological features in patients with OSCC Despite the accumulating understanding of the basic molecular functions of TRKB, the correlation between the expression levels of TRKB, BDNF, or both, and the clinical significance in patients with OSCC is not well understood. First, we analyzed the expression levels of TRKB and its specific ligand, BDNF, in OSCCs from 44 CB-1158 patients who had not received any previous treatment, by immunohistochemistry. In most cases, the expression levels of TRKB and BDNF were both low (TRKBlow/BDNFlow) in WD-OSCC tumor cells, whereas they were both higher (TRKBhigh/BDNFhigh) in MD and PD-OSCC tumor cells (Figure ?(Figure1).1). The expression.