BDNF

Gene Summary

Gene:BDNF; brain-derived neurotrophic factor
Aliases: ANON2, BULN2
Location:11p13
Summary:The protein encoded by this gene is a member of the nerve growth factor family. It is induced by cortical neurons, and is necessary for survival of striatal neurons in the brain. Expression of this gene is reduced in both Alzheimer's and Huntington disease patients. This gene may play a role in the regulation of stress response and in the biology of mood disorders. Multiple transcript variants encoding distinct isoforms have been described for this gene. [provided by RefSeq, Jan 2009]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:brain-derived neurotrophic factor
HPRD
Source:NCBIAccessed: 27 February, 2015

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 February 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: BDNF (cancer-related)

Alonso-Alconada L, Eritja N, Muinelo-Romay L, et al.
ETV5 transcription program links BDNF and promotion of EMT at invasive front of endometrial carcinomas.
Carcinogenesis. 2014; 35(12):2679-86 [PubMed] Related Publications
Myometrial infiltration represents a main clinical determinant of endometrial carcinomas (EC) presenting as aggressive high-grade deeply invasive neoplasms, substantially associated with risk of recurrence and death. The up-regulation of ETV5 transcription factor linked to the promotion of epithelial to mesenchymal transition is considered as a basic mechanism underlying the initial steps of EC invasion. In this work, we aimed to investigate the transcription program of tumor invasion regulated by ETV5. We performed a comparative Chip-on-chip analysis at invasive front and superficial area of human EC. ETV5 specific binding to promoter regions of genes related to cellular migration, adhesion and invasion at deep invasion tumor areas highlighted the relevance of neural networks associated with cellular plasticity. Interestingly, brain-derived neurotrophic factor (BDNF) demonstrated a principal role orchestrating ETV5-mediated epithelial-to-mesenchymal transition in endometrial cancer. Impairment of the BDNF/tropomyosin-related kinase B (TrkB)/extracellular signal-regulated kinase axis in endometrial cancer cell lines reversed the aggressive and invasive phenotype promoted by the up-regulation of ETV5 at the invasive front of EC. Likewise, BDNF directly impacted on the efficiency of ETV5 promoted metastasis in a mice model of endometrial distant dissemination. These results translate the recognized role of BDNF/TrkB on neural plasticity into a relevant cancer metastasis event; suggest common mechanisms shared by neural development and tumor invasion; and offer new therapeutic opportunities specifically directed against disseminated disease in endometrial cancer.

Lin CY, Hung SY, Chen HT, et al.
Brain-derived neurotrophic factor increases vascular endothelial growth factor expression and enhances angiogenesis in human chondrosarcoma cells.
Biochem Pharmacol. 2014; 91(4):522-33 [PubMed] Related Publications
Chondrosarcomas are a type of primary malignant bone cancer, with a potent capacity for local invasion and distant metastasis. Brain-derived neurotrophic factor (BDNF) is commonly upregulated during neurogenesis. The aim of the present study was to examine the mechanism involved in BDNF-mediated vascular endothelial growth factor (VEGF) expression and angiogenesis in human chondrosarcoma cells. Here, we knocked down BDNF expression in chondrosarcoma cells and assessed their capacity to control VEGF expression and angiogenesis in vitro and in vivo. We found knockdown of BDNF decreased VEGF expression and abolished chondrosarcoma conditional medium-mediated angiogenesis in vitro as well as angiogenesis effects in vivo in the chick chorioallantoic membrane and Matrigel plug nude mouse models. In addition, in the xenograft tumor angiogenesis model, the knockdown of BDNF significantly reduced tumor growth and tumor-associated angiogenesis. BDNF increased VEGF expression and angiogenesis through the TrkB receptor, PLCγ, PKCα, and the HIF-1α signaling pathway. Finally, we analyzed samples from chondrosarcoma patients by immunohistochemical staining. The expression of BDNF and VEGF protein in 56 chondrosarcoma patients was significantly higher than in normal cartilage. In addition, the high level of BDNF expression correlated strongly with VEGF expression and tumor stage. Taken together, our results indicate that BDNF increases VEGF expression and enhances angiogenesis through a signal transduction pathway that involves the TrkB receptor, PLCγ, PKCα, and the HIF-1α. Therefore, BDNF may represent a novel target for anti-angiogenic therapy for human chondrosarcoma.

Sinkevicius KW, Kriegel C, Bellaria KJ, et al.
Neurotrophin receptor TrkB promotes lung adenocarcinoma metastasis.
Proc Natl Acad Sci U S A. 2014; 111(28):10299-304 [PubMed] Free Access to Full Article Related Publications
Lung cancer is notorious for its ability to metastasize, but the pathways regulating lung cancer metastasis are largely unknown. An in vitro system designed to discover factors critical for lung cancer cell migration identified brain-derived neurotrophic factor, which stimulates cell migration through activation of tropomyosin-related kinase B (TrkB; also called NTRK2). Knockdown of TrkB in human lung cancer cell lines significantly decreased their migratory and metastatic ability in vitro and in vivo. In an autochthonous lung adenocarcinoma model driven by activated oncogenic Kras and p53 loss, TrkB deficiency significantly reduced metastasis. Hypoxia-inducible factor-1 directly regulated TrkB expression, and, in turn, TrkB activated Akt signaling in metastatic lung cancer cells. Finally, TrkB expression was correlated with metastasis in patient samples, and TrkB was detected more often in tumors that did not have Kras or epidermal growth factor receptor mutations. These studies demonstrate that TrkB is an important therapeutic target in metastatic lung adenocarcinoma.

Koh MJ, Jeung HC, Namkoong K, et al.
Influence of the BDNF Val66Met polymorphism on coping response to stress in patients with advanced gastric cancer.
J Psychosom Res. 2014; 77(1):76-80 [PubMed] Related Publications
OBJECTIVE: Coping with cancer is an important determinant of psychological morbidity, quality of life, and treatment adherence in cancer patients. The aim of this study was to elucidate the association between the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and coping response to stress in patients diagnosed with advanced gastric cancer.
METHODS: Ninety-one subjects (60 males, 31 females) recently diagnosed with advanced gastric cancer were recruited. Coping style and distress level were examined using the Mini-Mental Adjustment to Cancer (Mini-MAC) scale and Hospital Anxiety and Depression Scale, and genotyping was evaluated. To examine the temporal stability of the Mini-MAC scores, a 6-week follow-up evaluation was conducted in 72 patients, after completion of two chemotherapy cycles.
RESULTS: Coping style to cancer significantly differed between the Met carriers of BDNF Val66Met and the Val/Val homozygotes. The Met carriers were significantly more anxious than the Val/Val homozygotes.
CONCLUSION: The present findings suggest that the BDNF Val66Met polymorphism may be involved in individual coping responses to cancer. The Met allele of BDNF Val66Met may be predictive of an anxious coping style in patients with advanced cancer.

Forsyth PA, Krishna N, Lawn S, et al.
p75 neurotrophin receptor cleavage by α- and γ-secretases is required for neurotrophin-mediated proliferation of brain tumor-initiating cells.
J Biol Chem. 2014; 289(12):8067-85 [PubMed] Article available free on PMC after 21/03/2015 Related Publications
Malignant gliomas are highly invasive, proliferative, and resistant to treatment. Previously, we have shown that p75 neurotrophin receptor (p75NTR) is a novel mediator of invasion of human glioma cells. However, the role of p75NTR in glioma proliferation is unknown. Here we used brain tumor-initiating cells (BTICs) and show that BTICs express neurotrophin receptors (p75NTR, TrkA, TrkB, and TrkC) and their ligands (NGF, brain-derived neurotrophic factor, and neurotrophin 3) and secrete NGF. Down-regulation of p75NTR significantly decreased proliferation of BTICs. Conversely, exogenouous NGF stimulated BTIC proliferation through α- and γ-secretase-mediated p75NTR cleavage and release of its intracellular domain (ICD). In contrast, overexpression of the p75NTR ICD induced proliferation. Interestingly, inhibition of Trk signaling blocked NGF-stimulated BTIC proliferation and p75NTR cleavage, indicating a role of Trk in p75NTR signaling. Further, blocking p75NTR cleavage attenuated Akt activation in BTICs, suggesting role of Akt in p75NTR-mediated proliferation. We also found that p75NTR, α-secretases, and the four subunits of the γ-secretase enzyme were elevated in glioblastoma multiformes patients. Importantly, the ICD of p75NTR was commonly found in malignant glioma patient specimens, suggesting that the receptor is activated and cleaved in patient tumors. These results suggest that p75NTR proteolysis is required for BTIC proliferation and is a novel potential clinical target.

Louwers YV, Rayner NW, Herrera BM, et al.
BMI-associated alleles do not constitute risk alleles for polycystic ovary syndrome independently of BMI: a case-control study.
PLoS One. 2014; 9(1):e87335 [PubMed] Article available free on PMC after 21/03/2015 Related Publications
INTRODUCTION: Polycystic Ovary Syndrome (PCOS) has a strong genetic background and the majority of patients with PCOS have elevated BMI levels. The aim of this study was to determine to which extent BMI-increasing alleles contribute to risk of PCOS when contemporaneous BMI is taken into consideration.
METHODS: Patients with PCOS and controls were recruited from the United Kingdom (563 cases and 791 controls) and The Netherlands (510 cases and 2720 controls). Cases and controls were of similar BMI. SNPs mapping to 12 BMI-associated loci which have been extensively replicated across different ethnicities, i.e., BDNF, FAIM2, ETV5, FTO, GNPDA2, KCTD15, MC4R, MTCH2, NEGR1, SEC16B, SH2B1, and TMEM18, were studied in association with PCOS within each cohort using the additive genetic model followed by a combined analysis. A genetic allelic count risk score model was used to determine the risk of PCOS for individuals carrying increasing numbers of BMI-increasing alleles.
RESULTS: None of the genetic variants, including FTO and MC4R, was associated with PCOS independently of BMI in the meta-analysis. Moreover, no differences were observed between cases and controls in the number of BMI-risk alleles present and no overall trend across the risk score groups was observed.
CONCLUSION: In this combined analysis of over 4,000 BMI-matched individuals from the United Kingdom and the Netherlands, we observed no association of BMI risk alleles with PCOS independent of BMI.

Nakamura Y, Suganami A, Fukuda M, et al.
Identification of novel candidate compounds targeting TrkB to induce apoptosis in neuroblastoma.
Cancer Med. 2014; 3(1):25-35 [PubMed] Article available free on PMC after 21/03/2015 Related Publications
Neuroblastoma (NB) is one of the most frequent solid tumors in children and its prognosis is still poor. The neurotrophin receptor TrkB and its ligand brain-derived neurotrophic factor (BDNF) are expressed at high levels in high-risk NBs and are involved in defining the poor prognosis of the patients. However, the TrkB targeting therapy has never been realized in the clinic. We performed an in silico screening procedure utilizing an AutoDock/grid computing technology in order to identify novel small chemical compounds targeting the BDNF-binding domain of TrkB. For the first screening, a library of three million synthetic compounds was screened in silico and was ranked according to the Docking energy. The top-ranked 37 compounds were further functionally screened for cytotoxicity by using NB cell lines. We have finally identified seven compounds that kill NB cells with the IC50 values of 0.07-4.6 μmol/L. The terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay showed that these molecules induce apoptosis accompanied by p53 activation in NB cell lines. The candidate compounds and BDNF demonstrated an antagonistic effect on cell growth, invasion, and colony formation, possibly suggesting competition at the BDNF-binding site of TrkB. The candidate compounds had tumor-suppressive activity in xenograft and in vivo toxicity tests (oral and intravenous administrations) using mice, and did not show any abnormal signs. Using in silico Docking screening we have found new candidate TrkB inhibitors against high-risk NBs, which could lead to new anti-cancer drugs.

Paczkowska E, Kaczyńska K, Pius-Sadowska E, et al.
Humoral activity of cord blood-derived stem/progenitor cells: implications for stem cell-based adjuvant therapy of neurodegenerative disorders.
PLoS One. 2013; 8(12):e83833 [PubMed] Article available free on PMC after 21/03/2015 Related Publications
BACKGROUND: Stem/progenitor cells (SPCs) demonstrate neuro-regenerative potential that is dependent upon their humoral activity by producing various trophic factors regulating cell migration, growth, and differentiation. Herein, we compared the expression of neurotrophins (NTs) and their receptors in specific umbilical cord blood (UCB) SPC populations, including lineage-negative, CD34(+), and CD133(+) cells, with that in unsorted, nucleated cells (NCs).
METHODS AND RESULTS: The expression of NTs and their receptors was detected by QRT-PCR, western blotting, and immunofluorescent staining in UCB-derived SPC populations (i.e., NCs vs. lineage-negative, CD34(+), and CD133(+) cells). To better characterize, global gene expression profiles of SPCs were determined using genome-wide RNA microarray technology. Furthermore, the intracellular production of crucial neuro-regenerative NTs (i.e., BDNF and NT-3) was assessed in NCs and lineage-negative cells after incubation for 24, 48, and 72 h in both serum and serum-free conditions. We discovered significantly higher expression of NTs and NT receptors at both the mRNA and protein level in lineage-negative, CD34(+), and CD133(+) cells than in NCs. Global gene expression analysis revealed considerably higher expression of genes associated with the production and secretion of proteins, migration, proliferation, and differentiation in lineage-negative cells than in CD34(+) or CD133(+) cell populations. Notably, after short-term incubation under serum-free conditions, lineage-negative cells and NCs produced significantly higher amounts of BDNF and NT-3 than under steady-state conditions. Finally, conditioned medium (CM) from lineage-negative SPCs exerted a beneficial impact on neural cell survival and proliferation.
CONCLUSIONS: Collectively, our findings demonstrate that UCB-derived SPCs highly express NTs and their relevant receptors under steady-state conditions, NT expression is greater under stress-related conditions and that CM from SPCs favorable influence neural cell proliferation and survival. Understanding the mechanisms governing the characterization and humoral activity of subsets of SPCs may yield new therapeutic strategies that might be more effective in treating neurodegenerative disorders.

Dakhova O, Rowley D, Ittmann M
Genes upregulated in prostate cancer reactive stroma promote prostate cancer progression in vivo.
Clin Cancer Res. 2014; 20(1):100-9 [PubMed] Article available free on PMC after 21/03/2015 Related Publications
PURPOSE: Marked reactive stroma formation is associated with poor outcome in clinically localized prostate cancer. We have previously identified genes with diverse functions that are upregulated in reactive stroma. This study tests the hypothesis that expression of these genes in stromal cells enhances prostate cancer growth in vivo.
EXPERIMENTAL DESIGN: The expression of reactive stroma genes in prostate stromal cell lines was evaluated by reverse transcriptase (RT)-PCR and qRT-PCR. Genes were knocked down using stable expression of short-hairpin RNAs (shRNA) and the impact on tumorigenesis assessed using the differential reactive stroma (DRS) system, in which prostate stromal cell lines are mixed with LNCaP prostate cancer cells and growth as subcutaneous xenografts assessed.
RESULTS: Nine of 10 reactive stroma genes tested were expressed in one or more prostate stromal cell lines. Gene knockdown of c-Kit, Wnt10B, Bmi1, Gli2, or COMP all resulted in decreased tumorigenesis in the DRS model. In all tumors analyzed, angiogenesis was decreased and there were variable effects on proliferation and apoptosis in the LNCaP cells. Wnt10B has been associated with stem/progenitor cell phenotype in other tissue types. Using a RT-PCR array, we detected downregulation of multiple genes involved in stem/progenitor cell biology such as OCT4 and LIF as well as cytokines such as VEGFA, BDNF, and CSF2 in cells with Wnt10B knockdown.
CONCLUSIONS: These findings show that genes upregulated in prostate cancer-reactive stroma promote progression when expressed in prostate stromal cells. Moreover, these data indicate that the DRS model recapitulates key aspects of cancer cell/reactive stroma interactions in prostate cancer.

Hai B, Qin L, Yang Z, et al.
Transient activation of hedgehog pathway rescued irradiation-induced hyposalivation by preserving salivary stem/progenitor cells and parasympathetic innervation.
Clin Cancer Res. 2014; 20(1):140-50 [PubMed] Article available free on PMC after 21/03/2015 Related Publications
PURPOSE: To examine the effects and mechanisms of transient activation of the Hedgehog pathway on rescuing radiotherapy-induced hyposalivation in survivors of head and neck cancer.
EXPERIMENTAL DESIGN: Mouse salivary glands and cultured human salivary epithelial cells were irradiated by a single 15-Gy dose. The Hedgehog pathway was transiently activated in mouse salivary glands, by briefly overexpressing the Sonic hedgehog (Shh) transgene or administrating smoothened agonist, and in human salivary epithelial cells, by infecting with adenovirus encoding Gli1. The activity of Hedgehog signaling was examined by the expression of the Ptch1-lacZ reporter and endogenous Hedgehog target genes. The salivary flow rate was measured following pilocarpine stimulation. Salivary stem/progenitor cells (SSPC), parasympathetic innervation, and expression of related genes were examined by flow cytometry, salisphere assay, immunohistochemistry, quantitative reverse transcription PCR, Western blotting, and ELISA.
RESULTS: Irradiation does not activate Hedgehog signaling in mouse salivary glands. Transient Shh overexpression activated the Hedgehog pathway in ductal epithelia and, after irradiation, rescued salivary function in male mice, which is related with preservation of functional SSPCs and parasympathetic innervation. The preservation of SSPCs was likely mediated by the rescue of signaling activities of the Bmi1 and Chrm1-HB-EGF pathways. The preservation of parasympathetic innervation was associated with the rescue of the expression of neurotrophic factors such as Bdnf and Nrtn. The expression of genes related with maintenance of SSPCs and parasympathetic innervation in female salivary glands and cultured human salivary epithelial cells was similarly affected by irradiation and transient Hedgehog activation.
CONCLUSIONS: These findings suggest that transient activation of the Hedgehog pathway has the potential to restore salivary gland function after irradiation-induced dysfunction.

Sun YX, Yang J, Wang PY, et al.
Cisplatin regulates SH-SY5Y cell growth through downregulation of BDNF via miR-16.
Oncol Rep. 2013; 30(5):2343-9 [PubMed] Related Publications
Brain-derived neurotropic factor (BDNF) is a member of the neurotropin family. High levels of BDNF are associated with more aggressive malignant behavior in human cancer. In the present study, we observed the effect of cisplatin on BDNF expression in SH-SY5Y cells and investigated the mechanism of cisplatin in inducing the apoptosis of SH-SY5Y cells. Our results revealed that the expression of BDNF was obviously decreased in cisplatin-treated SH-SY5Y cells. In addition, the 3'-untranslated region of BDNF was found to be targeted by miR-16 using microRNA analysis software. After miR-16 was synthesized chemically, SH-SY5Y cells were transfected with miR-16 to investigate the regulatory role of miR-16 in regards to BDNF. The results showed that the expression of BDNF was markedly decreased in the miR‑16-transfected cells when compared with that in the control cultures as determined by western blotting. Moreover, miR-16 expression was obviously upregulated in the cisplatin-treated cells when compared with the untreated controls. Furthermore, SH-SY5Y cells were xenografted subcutaneously in nude mice to study the effect of cisplatin on the growth of SH-SY5Y cells in vivo. The results further showed that cisplatin inhibited the proliferation of SH-SY5Y cells in the cisplatin-treated mice when compared with the saline-treated control. The expression of miR-16 was increased, while the expression of BDNF was decreased in the cisplatin-treated mice. Our results demonstrated that cisplatin downregulated the expression of BDNF through miR-16 to inhibit SH-SY5Y cell proliferation in vitro and in vivo. These findings provide the basis for new targets for drug design or cancer therapy.

Rogers DA, Schor NF
Kidins220/ARMS is expressed in neuroblastoma tumors and stabilizes neurotrophic signaling in a human neuroblastoma cell line.
Pediatr Res. 2013; 74(5):517-24 [PubMed] Article available free on PMC after 21/03/2015 Related Publications
BACKGROUND: Neurotrophic signaling is an important factor in the survival of developing neurons, and the expression of neurotrophic receptors correlates with prognosis in neuroblastoma. Kinase D-interacting substrate of 220 kDa (Kidins220) associates with neurotrophic receptors and stabilizes them, but the expression and function of Kidins220 in neuroblastoma are unknown.
METHODS: We study Kidins220 expression in human neuroblastoma cell lines and tumor samples by western blotting and microarray analyses. We determine the functional consequences of downregulation of Kidins220 for response of cell lines to oxidative stress, chemotherapeutic treatment, and neurotrophins using small interfering RNA silencing and by measuring cell survival, signaling, and migration.
RESULTS: Kidins220 is expressed in all neuroblastoma tumors and cell lines studied. Downregulation of Kidins220 leads to attenuation of nerve growth factor (NGF)-induced, but not brain-derived neurotrophic factor (BDNF)-induced, MAPK signaling. However, downregulation of Kidins220 does not alter the response to chemotherapeutic drugs or oxidative stress or affect cellular motility.
CONCLUSION: Kidins220 is expressed in neuroblastoma tumors and stabilizes NGF-induced, but not BDNF-induced, survival signaling in neuroblastoma cell lines.

Farrelly LA, Savage NT, O'Callaghan C, et al.
Therapeutic concentrations of valproate but not amitriptyline increase neuropeptide Y (NPY) expression in the human SH-SY5Y neuroblastoma cell line.
Regul Pept. 2013; 186:123-30 [PubMed] Related Publications
Neuropeptide Y (NPY) is a peptide found in the brain and autonomic nervous system, which is associated with anxiety, depression, epilepsy, learning and memory, sleep, obesity and circadian rhythms. NPY has recently gained much attention as an endogenous antiepileptic and antidepressant agent, as drugs with antiepileptic and/or mood-stabilizing properties may exert their action by increasing NPY concentrations, which in turn can reduce anxiety and depression levels, dampen seizures or increase seizure threshold. We have used human neuroblastoma SH-SY5Y cells to investigate the effect of valproate (VPA) and amitriptyline (AMI) on NPY expression at therapeutic plasma concentrations of 0.6mM and 630nM, respectively. In addition, 12-O-tetradecanoylphorbol-13-acetate (TPA) known to differentiate SH-SY5Y cells into a neuronal phenotype and to increase NPY expression through activation of protein kinase C (PKC) was applied as a positive control (16nM). Cell viability after drug treatment was tested with a 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. NPY expression was measured using immunofluorescence and quantitative RT-PCR (qRT-PCR). Results from immunocytochemistry have shown NPY levels to be significantly increased following a 72h but not 24h VPA treatment. A further increase in expression was observed with simultaneous VPA and TPA treatment, suggesting that the two agents may increase NPY expression through different mechanisms. The increase in NPY mRNA by VPA and TPA was confirmed with qRT-PCR after 72h. In contrast, AMI had no effect on NPY expression in SH-SY5Y cells. Together, the data point to an elevation of human NPY mRNA and peptide levels by therapeutic concentrations of VPA following chronic treatment. Thus, upregulation of NPY may have an impact in anti-cancer treatment of neuroblastomas with VPA, and antagonizing hypothalamic NPY effects may help to ameliorate VPA-induced weight gain and obesity without interfering with the desired central effects of VPA.

Bao W, Qiu H, Yang T, et al.
Upregulation of TrkB promotes epithelial-mesenchymal transition and anoikis resistance in endometrial carcinoma.
PLoS One. 2013; 8(7):e70616 [PubMed] Article available free on PMC after 21/03/2015 Related Publications
Mechanisms governing the metastasis of endometrial carcinoma (EC) are poorly defined. Recent data support a role for the cell surface receptor tyrosine kinase TrkB in the progression of several human tumors. Here we present evidence for a direct role of TrkB in human EC. Immunohistochemical analysis revealed that TrkB and its secreted ligand, brain-derived neurotrophic factor (BDNF), are more highly expressed in EC than in normal endometrium. High TrkB levels correlated with lymph node metastasis (p<0.05) and lymphovascular space involvement (p<0.05) in EC. Depletion of TrkB by stable shRNA-mediated knockdown decreased the migratory and invasive capacity of cancer cell lines in vitro and resulted in anoikis in suspended cells. Conversely, exogenous expression of TrkB increased cell migration and invasion and promoted anoikis resistance in suspension culture. Furthermore, over-expression of TrkB or stimulation by BDNF resulted in altered the expression of molecular mediators of the epithelial-to-mesenchymal transition (EMT). RNA interference (RNAi)-mediated depletion of the downstream regulator, Twist, blocked TrkB-induced EMT-like transformation. The use of in vivo models revealed decreased peritoneal dissemination in TrkB-depleted EC cells. Additionally, TrkB-depleted EC cells underwent mesenchymal-to-epithelial transition and anoikis in vivo. Our data support a novel function for TrkB in promoting EMT and resistance to anoikis. Thus, TrkB may constitute a potential therapeutic target in human EC.

Asai T, Bundo M, Sugawara H, et al.
Effect of mood stabilizers on DNA methylation in human neuroblastoma cells.
Int J Neuropsychopharmacol. 2013; 16(10):2285-94 [PubMed] Related Publications
Unraveling the epigenetic status of neuronal cells in the brain is critical to our understanding of the pathophysiology of psychiatric disorders, which may reflect a complex interaction between genetic and environmental factors. Several epigenetic studies of mood disorders have been conducted with postmortem brains. However, proper interpretation of the results is hampered by our scant understanding of the effects of mood stabilizers on the epigenetic status of neuronal cells. We performed both comprehensive and gene-specific analyses to examine DNA methylation in human neuroblastoma SK-N-SH cells treated with three mood stabilizers: lithium, valproate and carbamazepine. Measurement of the level of DNA methylation of about 27 000 CpG sites revealed a profound epigenetic effect of lithium, compared with the two other mood stabilizers. In addition, we found that the mood stabilizers have common epigenetic targets and a propensity to increase DNA methylation. Gene-specific analysis involved detailed analysis of the methylation of promoter regions of SLC6A4 and BDNF, both of which have been reported to show altered DNA methylation in bipolar disorder patients or suicide victims, by extensive bisulfite sequencing. We did not observe significant changes in DNA methylation at BDNF promoter IV. However, we found that CpG sites of SLC6A4, which were hypermethylated in patients with bipolar disorder, were hypomethylated in the neuroblastoma cells treated with mood stabilizers. Our results will contribute to a better understanding of the epigenetic changes associated with mood disorders, and they also provide new insight into the mechanisms of action of mood stabilizers.

Lin CY, Chen HJ, Li TM, et al.
β5 integrin up-regulation in brain-derived neurotrophic factor promotes cell motility in human chondrosarcoma.
PLoS One. 2013; 8(7):e67990 [PubMed] Article available free on PMC after 21/03/2015 Related Publications
Chondrosarcoma is a primary malignant bone cancer, with a potent capacity to invade locally and cause distant metastasis; it has a poor prognosis and shows a predilection for metastasis to the lungs. Brain derived neurotrophic factor (BDNF) is a small-molecule protein from the neurotrophin family of growth factors that is associated with the disease status and outcomes of cancers. However, the effect of BDNF on migration activity in human chondrosarcoma cells is mostly unknown. Here, we found that human chondrosarcoma tissues showed significant expression of BDNF, which was higher than that in normal cartilage and primary chondrocytes. We also found that BDNF increased the migration and expression of β5 integrin in human chondrosarcoma cells. In addition, knockdown of BDNF expression markedly inhibited migratory activity. BDNF-mediated migration and β5 integrin up-regulation were attenuated by antibody, inhibitor, or siRNA against the TrkB receptor. Pretreatment of chondrosarcoma cells with PI3K, Akt, and NF-κB inhibitors or mutants also abolished BDNF-promoted migration and integrin expression. The PI3K, Akt, and NF-κB signaling pathway was activated after BDNF treatment. Taken together, our results indicate that BDNF enhances the migration of chondrosarcoma by increasing β5 integrin expression through a signal transduction pathway that involves the TrkB receptor, PI3K, Akt, and NF-κB. BDNF thus represents a promising new target for treating chondrosarcoma metastasis.

Peng WM, Maintz L, Allam JP, et al.
Increased circulating levels of neurotrophins and elevated expression of their high-affinity receptors on skin and gut mast cells in mastocytosis.
Blood. 2013; 122(10):1779-88 [PubMed] Related Publications
Mastocytosis is a rare heterogeneous disease characterized by increase of mast cells (MCs) in different organs. Neurotrophins (NTs) have been shown to promote differentiation and survival of MCs, which in turn represent a major source of NTs. Thus, a contribution of NTs to mastocytosis seems highly conceivable but has not yet been investigated. We could demonstrate expression of high-affinity NT receptors tropomyosin-related kinase A (TrkA) for nerve growth factor (NGF)-β, TrkB for brain-derived neurotrophic factor, and NT-4 and TrkC for NT-3 on skin MCs; and of TrkA and TrkC on intestinal MCs of patients with mastocytosis. Moreover, increased expression of NGF-β; NT-3; TrkA, TrkB, and TrkC; and isoforms truncated TrkB-T1 and truncated TrkC were observed on skin MCs. Patients with mastocytosis featured elevated serum levels of NGF, NT-3, and NT-4. Levels of NGF-β and NT-4 correlated with tryptase levels, suggesting a link between MC load and blood levels of NGF and NT-4. Migration of CD117+ progenitor cells from the blood was enhanced toward NGF-β gradient in both mastocytosis and controls. Together with enhanced NT levels, the elevated expression of modified Trk receptors on skin and gut MCs might contribute to the pathophysiology of mastocytosis in autocrine and paracrine loops.

Alboni S, Gibellini L, Montanari C, et al.
N-acetyl-cysteine prevents toxic oxidative effects induced by IFN-α in human neurons.
Int J Neuropsychopharmacol. 2013; 16(8):1849-65 [PubMed] Related Publications
Currently IFN-α is widely used for effective treatment of viral infections and several malignancies. However, IFN-α can cause neuropsychiatric disturbances and mental impairments, including fatigue, insomnia, depression, irritability and cognitive deficits. Molecular and cellular mechanisms leading to such side-effects are still poorly understood. Neurons seem to be an important target in mediating cellular effects induced by exposure to this cytokine, but so far little is known about IFN-α-induced effects on these cells. We have investigated the ability of IFN-α (2-100 ng/ml) to induce damage and toxicity to the human neuroblastoma SH-SY5Y cell line, commonly used for studying such phenomena, and the mechanisms underlying these effects. After 24 h treatment, IFN-α increased mitochondrial activity, whereas cell density was reduced in a dose- and time-dependent manner. This effect did not depend on reduced cell proliferation, but rather the activation of apoptosis, as revealed by an increased Bax:Bcl-2 mRNA ratio after 72-h IFN-α exposure. At this time-point, IFN-α also reduced the expression of the brain-derived neurotrophic factor gene, and induced an increase in reactive oxygen species (ROS). A co-treatment with N-acetyl-cysteine (NAC; 5 mm), a potent antioxidant and mitochondrial modulator, was able to counteract all of these IFN-α-induced effects. These findings demonstrated that IFN-α induces neurotoxicity and apoptosis that is, in part, very likely due to mitochondrial damages and production of ROS. We suggest that NAC, already tested for the treatment of psychiatric disorders, may be useful to prevent IFN-α-induced central side-effects in a safe and effective way.

Nagpal N, Ahmad HM, Molparia B, Kulshreshtha R
MicroRNA-191, an estrogen-responsive microRNA, functions as an oncogenic regulator in human breast cancer.
Carcinogenesis. 2013; 34(8):1889-99 [PubMed] Related Publications
Estrogen- and microRNA-mediated gene regulation play a crucial role in breast cancer biology. However, a functional link between the two major players remains unclear. This study reveals miR-191 as an estrogen-inducible onco-miR in breast cancer, which promotes several hallmarks of cancer including enhanced cell proliferation, migration, chemoresistance and survival in tumor microenvironment. miR-191 is a direct estrogen receptor (ER) target and our results suggest existence of a positive regulatory feedback loop. We show miR-191 as critical mediator of estrogen-mediated cell proliferation. Investigations of mechanistic details of miR-191 functions identify several cancer-related genes like BDNF, CDK6 and SATB1 as miR-191 targets. miR-191 and SATB1 show inverse correlation of expression. miR-191-mediated enhanced cell proliferation and migration are partly dependent on targeted downregulation of SATB1. Further, functional validation of estrogen:miR-191:SATB1 link suggests a cascade initiated by estrogen that induces miR-191 in ER-dependent manner to target SATB1, a global chromatin remodeler, thereby contributing to estrogen-specific gene signature to regulate genes like ANXA1, PIWIL2, CASP4, ESR1/ESR2, PLAC1 and SOCS2 involved in breast cancer progression and migration. Overall, the identification of estrogen/ER/miR-191/SATB1 cascade seems to be a significant pathway in estrogen signaling in breast cancer with miR-191 as oncogenic player.

Ai LS, Sun CY, Wang YD, et al.
Gene silencing of the BDNF/TrkB axis in multiple myeloma blocks bone destruction and tumor burden in vitro and in vivo.
Int J Cancer. 2013; 133(5):1074-84 [PubMed] Related Publications
Osteolytic bone diseases are a prominent feature of multiple myeloma (MM), resulting from aberrant osteoclastic bone resorption that is uncoupled from osteoblastic bone formation. Myeloma stimulates osteoclastogenesis, which is largely dependent on an increase in receptor activator of NF-κB ligand (RANKL) and a decrease in osteoprotegerin (OPG) within the bone marrow milieu. Recently, brain-derived neurotrophic factor (BDNF) was identified as a MM-derived factor that correlates with increased RANKL levels and contributes to osteolytic bone destruction in myeloma patients. Because tyrosine receptor kinase B (TrkB), the receptor of BDNF, is abundantly expressed in osteoblasts, we sought to evaluate the role of BDNF/TrkB in myeloma-osteoblast interactions and the effect of this pathway on the RANKL/OPG ratio and osteoclastogenesis. Coculture systems constructed with noncontact transwells revealed that, in vitro, MM-derived BDNF increased RANKL and decreased OPG production in osteoblasts in a time- and dose-dependent manner. These effects were completely abolished by a specific small interfering RNA for TrkB. BDNF regulates RANKL/OPG expression in osteoblasts through the TrkB/ERK pathway. To investigate the biological effects of BDNF on myeloma in vivo, a SCID-RPMI8226 mice model was constructed using lentiviral short hairpin RNA-transfected RPMI8226 cells. In this system, stable knockdown of BDNF in MM cells significantly restored the RANKL/OPG homostasis, inhibited osteolytic bone destruction and reduced angiogenesis and tumor burden. Our studies provide further support for the potential osteoclastogenic effects of BDNF, which mediates stroma-myeloma interactions to disrupt the balance of RANKL/OPG expression, ultimately increasing osteoclastogenesis in MM.

Bakos J, Strbak V, Paulikova H, et al.
Oxytocin receptor ligands induce changes in cytoskeleton in neuroblastoma cells.
J Mol Neurosci. 2013; 50(3):462-8 [PubMed] Related Publications
Aim of the present study was to evaluate effects of ligands of oxytocin receptors on gene expression of neurofilament proteins (nestin and microtubule-associated protein 2 (MAP2)) associated with neuronal differentiation and growth factors (brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF)) related to neuronal growth. Fluorescent staining of F-actin was used to observe morphology of cells. Co-treatment with oxytocin and oxytocin receptor antagonist--atosiban--resulted in significant increase of MAP2 gene expression in SK-N-SH cells. There was no effect of oxytocin on gene expression of growth factors BDNF and NGF. Surprisingly, oxytocin with atosiban significantly increased mRNA levels for both BDNF and NGF. Gene expression of vasopressin receptor (V1aR) significantly decreased in response to vasopressin. Atosiban decreased mRNA levels for oxytocin receptor (OXTR) and V1aR. Oxytocin significantly decreased OXTR and nestin mRNA levels and increased mRNA levels for BDNF and NGF in U-87 MG cells. The densest recruitment of F-actin filaments was observed in apical parts of filopodia in SK-N-SH cells incubated in oxytocin presence. Present data demonstrate complex role of ligands of oxytocin receptors in regulation of gene expression of intermediate filaments and thus, oxytocin might be considered as a growth factor in neuronal type of cells.

Imam JS, Plyler JR, Bansal H, et al.
Genomic loss of tumor suppressor miRNA-204 promotes cancer cell migration and invasion by activating AKT/mTOR/Rac1 signaling and actin reorganization.
PLoS One. 2012; 7(12):e52397 [PubMed] Article available free on PMC after 21/03/2015 Related Publications
Increasing evidence suggests that chromosomal regions containing microRNAs are functionally important in cancers. Here, we show that genomic loci encoding miR-204 are frequently lost in multiple cancers, including ovarian cancers, pediatric renal tumors, and breast cancers. MiR-204 shows drastically reduced expression in several cancers and acts as a potent tumor suppressor, inhibiting tumor metastasis in vivo when systemically delivered. We demonstrated that miR-204 exerts its function by targeting genes involved in tumorigenesis including brain-derived neurotrophic factor (BDNF), a neurotrophin family member which is known to promote tumor angiogenesis and invasiveness. Analysis of primary tumors shows that increased expression of BDNF or its receptor tropomyosin-related kinase B (TrkB) parallel a markedly reduced expression of miR-204. Our results reveal that loss of miR-204 results in BDNF overexpression and subsequent activation of the small GTPase Rac1 and actin reorganization through the AKT/mTOR signaling pathway leading to cancer cell migration and invasion. These results suggest that microdeletion of genomic loci containing miR-204 is directly linked with the deregulation of key oncogenic pathways that provide crucial stimulus for tumor growth and metastasis. Our findings provide a strong rationale for manipulating miR-204 levels therapeutically to suppress tumor metastasis.

Rodríguez-López R, Pérez JM, Balsera AM, et al.
The modifier effect of the BDNF gene in the phenotype of the WAGRO syndrome.
Gene. 2013; 516(2):285-90 [PubMed] Related Publications
Individuals who are carriers of deletions of various sizes that cause haploinsufficiency in the contiguous WT1 and PAX6 genes, located on chromosome 11p13 approximately 4 Mb centromeric to the BDNF gene, are susceptible to Wilms tumor, aniridia, mental retardation, genitourinary anomalies and obesity (WAGRO syndrome). The molecular characterization of the wide deletion 11p15.1p12 arr (18676926-36576388) x1 dn in a child with 3 years and 4 months of age only affected by aniridia, predicts not only other serious associated diseases, but also allows us to hypothesize a specific phenotype of mental impairment, conduct alterations and childhood obesity, possibly added to the onset of metabolic alterations. The variable appearance and/or description of haploinsufficiency for obesity susceptibility in the WAGR syndrome mainly depends on the critical region located within 80 kb of exon 1 of BDNF. The relationship between genetic variation based on the genotype combinations of the 4 gene SNPs tagging the BDNF gene and the body mass index (BMI) was studied. The polymorphic variability was similarly distributed in 218 children suffering a severe and non-syndromic obesity from families at high risk for obesity, as compared with 198 controls. The corroborated role of the BDNF gene as highly susceptible to severe syndromic obesity has not already been evidenced in the molecular basis of overweight attributed to the common polygenic principles. Its potential role as risk modifier variant to provoke more severe phenotype has not yet been demonstrated. Some genetic variants of brain-derived neurotrophic factor (BDNF) have resulted in important disorders of energy balance, but it is essential to know exactly their deleterious human capacity because they play a fundamental role in the development and plasticity of the central nervous system in regulating food intake. The existence of polymorphic amino acid changes of unknown functional significance in patients carrying the haploinsufficiency of the BDNF gene could constitute an adequate model to study in depth their effects.

Shiohira H, Kitaoka A, Enjoji M, et al.
Am80 induces neuronal differentiation via increased tropomyosin-related kinase B expression in a human neuroblastoma SH-SY5Y cell line.
Biomed Res. 2012; 33(5):291-7 [PubMed] Related Publications
Am80, a synthetic retinoid, has been used in differentiation therapy for acute promyelocytic leukemia (APL). All-trans retinoic acid (ATRA) as one of natural retinoid has been also used to treat APL. ATRA treatment causes neuronal differentiation by inducing tropomyosin-related kinase B (TrkB) expression and increasing the sensitivity to brain-derived neurotrophic factor (BDNF), a TrkB ligand. In the present study, we investigated the effects of Am80 on neuronal differentiation, BDNF sensitivity and TrkB expression in human neuroblastoma SH-SY5Y cells. Treatment with Am80 induced morphological differentiation of neurite outgrowth and increased the expression of GAP43 mRNA, a neuronal differentiation marker. Additionally, TrkB protein was also increased, and exogenous BDNF stimulation after treatment with Am80 induced greater neurite outgrowth than without BDNF treatment. These results suggest that Am80 induced neuronal differentiation by increasing TrkB expression and BDNF sensitivity.

Makino K, Kawamura K, Sato W, et al.
Inhibition of uterine sarcoma cell growth through suppression of endogenous tyrosine kinase B signaling.
PLoS One. 2012; 7(7):e41049 [PubMed] Article available free on PMC after 21/03/2015 Related Publications
Uterine leiomyosarcoma is an aggressive tumor typically found at advanced stages due to difficulties with early diagnosis. Because uterine leiomyosarcoma is resistant to conventional radiation and chemotherapy, the development of more potent medical therapeutics is anticipated. Using quantitative real-time RT-PCR and immunostaining, we found the expression of brain-derived neurotrophic factor (BDNF) and neurotropin-4/5, together with their receptor, tyrosine kinase B (TrkB), in different uterine sarcoma cell lines and primary tumor samples from uterine leiomyosarcoma patients. We noted that levels of BDNF were more abundant than those of neurotropin-4/5. Moreover, the expression of TrkB and its ligands was elevated in a multidrug-resistant cell line and samples obtained from patients with leiomyosarcoma. In cultured uterine sarcoma cells, inhibition of endogenous TrkB signaling by treatment with either the soluble TrkB ectodomain or the Trk receptor inhibitor, K252a, suppressed cell proliferation and increased apoptosis based on cell viability and proliferation, in situ terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end-labeling and caspase-3/7 assays, whereas an inactive plasma membrane nonpermeable K252b was ineffective. Correspondingly, treatment with exogenous BDNF increased cell proliferation. In in vivo studies in athymic nude mice bearing multidrug-resistant uterine sarcoma cell tumors, we demonstrate suppression of tumor growth by treatment with K252a, but not K252b, as reflected by decreased cell proliferation and increased levels of apoptosis and caspase-3/7 activities without obvious side effects. Our findings indicated that endogenous signaling of the TrkB pathway contributed to uterine sarcoma cell growth, and inhibition of TrkB signaling in these tumors could provide a novel medical therapy for patients with uterine sarcomas.

Savas S, Hyde A, Stuckless SN, et al.
Serotonin transporter gene (SLC6A4) variations are associated with poor survival in colorectal cancer patients.
PLoS One. 2012; 7(7):e38953 [PubMed] Article available free on PMC after 21/03/2015 Related Publications
Prognosis in colorectal cancer patients is quite variable, even after adjustment for clinical parameters such as disease stage and microsatellite instability status. It is possible that the psychological distress experienced by patients, including anxiety and depression, may be correlated with poor prognosis. In the present study, we hypothesize that genetic variations within three genes biologically linked to the stress response, namely serotonin transporter (SLC6A4), brain-derived neurotrophic factor (BDNF), and arginine vasopressin receptor (AVPR1B) genes are associated with prognosis in colorectal cancer patients. We used a population-based cohort of 280 patients who were followed for up to 12.5 years after diagnosis. Our multivariate analysis showed that a tagSNP in the SLC6A4 gene (rs12150214) was a predictor of shorter overall survival (HR: 1.572, 95%CI: 1.142-2.164, p = 0.005) independent of stage, age, grade and MSI status. Additionally, a multivariate analysis using the combined genotypes of three polymorphisms in this gene demonstrated that the presence of any of the minor alleles at these polymorphic loci was an independent predictor of both shorter overall survival (HR: 1.631, 95%CI: 1.190-2.236, p = 0.002) and shorter disease specific survival (HR: 1.691, 95%CI: 1.138-2.512, p = 0.009). The 5-HTT protein coded by the SLC6A4 gene has also been implicated in inflammation. While our results remain to be replicated in other patient cohorts, we suggest that the genetic variations in the SLC6A4 gene contribute to poor survival in colorectal cancer patients.

Okamura K, Harada T, Wang S, et al.
Expression of TrkB and BDNF is associated with poor prognosis in non-small cell lung cancer.
Lung Cancer. 2012; 78(1):100-6 [PubMed] Related Publications
High expression levels of TrkB and BDNF are associated with aggressive malignant behavior in tumor cells and a poor prognosis in patients with various types of cancer. In this study, we aimed to identify the relationship between TrkB and BDNF expression and clinicopathological variables and prognosis in non-small cell lung cancer (NSCLC). We evaluated TrkB and BDNF expression in the tumor cells of 102 NSCLC patients by immunohistochemistry. Out of all clinicopathological factors examined, only vascular invasion was significantly correlated with TrkB (P=0.010) and BDNF (P=0.015) expression. TrkB-positive tumors had significantly worse disease-free survival (P=0.0094) and overall survival (P=0.0019) than TrkB-negative tumors, and TrkB expression was an independent prognostic factor for disease-free survival (HR 3.735, 95% CI 1.560-11.068, P=0.002) and overall survival (HR 4.335, 95% CI 1.534-15.963, P=0.004) in multivariate analysis. Finally, our analysis revealed that co-expression of TrkB and BDNF conferred poorer prognosis compared with overexpression of either protein alone. Our results indicate that expression of TrkB and BDNF is associated with poor prognosis in NSCLC patients.

Yang X, Martin TA, Jiang WG
Biological influence of brain-derived neurotrophic factor on breast cancer cells.
Int J Oncol. 2012; 41(4):1541-6 [PubMed] Related Publications
Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin superfamily which has been indicated in the pathophysiology of the nervous system and is important in a number of neurological and psychological conditions. Recently, BDNF was also shown to play a role in the development and progression of solid tumour myeloma. It has been reported that BDNF is aberrantly expressed in human breast cancer and that a raised level of BDNF is associated with poor clinical outcome and reduced survival. The present study investigated the role of BDNF in human breast cancer. A panel of human breast cancer cells was used and the expression profile of BDNF was evaluated using RT-PCR. We constructed a set of anti-BDNF transgenes which were used to transfect breast cancer cells in order to generate BDNF knocked down cells. The impact of BDNF knockdown on growth and apoptosis was evaluated. Statistical analysis was performed using SPSS. P<0.05 was considered statistically significant. BDNF gene transcripts were successfully detected in the breast cancer cell lines MCF-7, MDA-MB-231 and ZR75-1 MDA-MB-231 and MCF-7 wild-type cells were subject to transfection of anti-BDNF transgenes, followed by the establishment of BDNF knocked down sublines. Knockdown of BDNF in MDA-MB-231 and MCF-7 cell lines resulted in decreased rates of growth and proliferation. Analysis of apoptosis showed that cell apoptosis was increased in cells stably transfected with ribozymes for BDNF compared with the vector control. It is concluded that BDNF, a neurotrophic growth factor aberrantly expressed in cancers such as breast cancer, has a profound impact on the cellular behaviour of breast cancer cells and that BDNF is associated with a reduction of the apoptosis of breast cancer. BDNF is, therefore, a potential therapeutic target in breast cancer and its effect in human breast cancer requires further investigation.

Sasahira T, Ueda N, Yamamoto K, et al.
Trks are novel oncogenes involved in the induction of neovascularization, tumor progression, and nodal metastasis in oral squamous cell carcinoma.
Clin Exp Metastasis. 2013; 30(2):165-76 [PubMed] Related Publications
The function of tropomyosin receptor kinase (Trk) family including TrkA, TrkB, and TrkC in cancer remains unknown. The role of Trks in oral squamous cell carcinoma (OSCC) was examined. Knockdown of Trks provided inhibition of growth or invasion and decrease of apoptosis in OSCC cells, which expressed Trks at high levels. VEGF expression was associated with TrkA and TrkB expression; a decrease of VEGF-C and VEGF-D was observed in OSCC cells with TrkB knockdown. TrkC did not affect the expression of VEGF family. An immunohistochemical analysis of 102 OSCCs showed that TrkB expression was related to microvessel density (MVD), lymph vessel density (LVD), and poor prognosis. TrkC expression was correlated with clinical stage, lymph node metastasis, MVD, LVD, and poor prognosis. TrkA expression was associated with VEGF expression, whereas TrkB expression was associated with the expressions of VEGF, VEGF-C and VEGF-D. No significant association was found between the expression of TrkC and genes of the VEGF family. Expression of Trks was not associated with RUNX3 silencing by methylation in OSCC cells. Trks expression was inversely correlated with RUNX3 expression in the OSCC cases. These results suggested that Trks enhances progression of OSCC through angiogenesis and lymphangiogenesis.

Kawamura K, Kawamura N, Kawagoe Y, et al.
Suppression of hydatidiform molar growth by inhibiting endogenous brain-derived neurotrophic factor/tyrosine kinase B signaling.
Endocrinology. 2012; 153(8):3972-81 [PubMed] Related Publications
Brain-derived neurotrophic factor (BDNF)/tyrosine kinase B (TrkB) receptor signaling promotes trophoblast growth in normal and abnormal pregnancy. It also regulates the growth of malignant trophoblastic, choriocarcinoma cells. However, possible involvement of this signaling system in hydatidiform mole, another major gestational trophoblastic disease, has not been determined. Here, we found the expression of BDNF in syncytiotrophoblasts and its receptor, TrkB, in cytotrophoblasts of hydatidiform mole using real-time RT-PCR and immunoassays. In molar explant cultures, treatment with soluble TrkB ectodomain or a Trk receptor inhibitor K252a inhibited trophoblast outgrowth as well as decreased cytotrophoblast proliferation and cellular viability based on histopathological analyses and glucose metabolism monitoring. These inhibitors also increased apoptosis and caspase-3/7 activities. In an in vivo model of hydatidiform molar growth based on xenotransplantation of molar tissues into kidney capsules of SCID mice, treatment with K252a suppressed molar growth as reflected by decreased trophoblast proliferation and their invasion into mouse kidney, reduced tissue levels of chorionic gonadotropin-β, and increased apoptosis. Based on PCR array analyses to identify changes in expression profiles of cell cycle- and apoptosis-related genes in cultured molar explants, suppression of endogenous TrkB signaling led to decreases in key cell cycle-stimulatory and checkpoint genes together with the down-regulation of different antiapoptotic genes. Our findings demonstrate the importance of paracrine signaling by the BDNF/TrkB system in the proliferation and survival of molar trophoblasts. Inhibition of BDNF/TrkB signaling could provide a novel medical treatment for hydatidiform mole.

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