Gene Summary

Gene:BDNF; brain derived neurotrophic factor
Aliases: ANON2, BULN2
Summary:This gene encodes a member of the nerve growth factor family of proteins. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature protein. Binding of this protein to its cognate receptor promotes neuronal survival in the adult brain. Expression of this gene is reduced in Alzheimer's, Parkinson's, and Huntington's disease patients. This gene may play a role in the regulation of the stress response and in the biology of mood disorders. [provided by RefSeq, Nov 2015]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:brain-derived neurotrophic factor
Source:NCBIAccessed: 31 August, 2019


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 (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: BDNF (cancer-related)

Antunes LCM, Cartell A, de Farias CB, et al.
Tropomyosin-Related Kinase Receptor and Neurotrophin Expression in Cutaneous Melanoma Is Associated with a Poor Prognosis and Decreased Survival.
Oncology. 2019; 97(1):26-37 [PubMed] Related Publications
OBJECTIVE: Normally, activation of tropomyosin-related kinase (TRK) receptors by neurotrophins (NTs) stimulates intracellular pathways involved in cell survival and proliferation. Dysregulation of NT/TRK signaling may affect neoplasm prognosis. Data on NT and TRK expression in melanomas are limited, and it is unclear whether NT/TRK signaling pathways are involved in the origin and progression of this neoplasm.
METHODS: We examined whether NT/TRK expression differs across different cutaneous melanoma grades and subtypes, and whether it is associated with melanoma prognosis and survival. A cross-sectional study was performed in which the expression of TrkA, TrkB, nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF) was analyzed by immunohistochemistry of 154 melanoma samples. We investigated NT/TRK expression associations with prognostic factors for melanoma, relapse-free survival (RFS), and overall survival (OS).
RESULTS: Of the 154 melanoma samples, 77 (55.4%) were TrkA immunopositive, 81 (58.3%) were TrkB immunopositive, 113 (81.3%) were BDNF immunopositive, and 104 (75.4%) were NGF immunopositive. We found NT/TRK expression associated strongly with several clinical prognostic factors, including the tumor-node-metastasis stage (p < 0.001), histological subtype (p < 0.001), and Clark level (p < 0.05), as well as with a worse OS (p < 0.05 for all, except TrkB) and RFS (p < 0.05 for all).
CONCLUSIONS: Our results show strong associations of NT/TRK expression with melanoma stage progression and a poor prognosis.

Zhi H, Lian J
LncRNA BDNF-AS suppresses colorectal cancer cell proliferation and migration by epigenetically repressing GSK-3β expression.
Cell Biochem Funct. 2019; 37(5):340-347 [PubMed] Related Publications
This study was designed to investigate the molecular mechanism and biological roles of long non-coding RNA (lncRNA) brain-derived neurotrophic factor antisense (BDNF-AS) in colorectal cancer (CRC). The quantitative real-time PCR (qRT-PCR) and western blotting were performed to detect the expressions of lncRNA BDNF-AS and glycogen synthase kinase-3β (GSK-3β) in human CRC tissues and cell lines. The cell proliferation, transwell migration, and invasion assays were carried out to evaluate the effect of lncRNA BDNF-AS on the growth of CRC cells. RNA pull-down and RNA immunoprecipitation (RIP) assays were conducted to confirm the interaction between lncRNA BDNF-AS and enhancer of Zeste Homologue 2 (EZH2). Chromatin immunoprecipitation (ChIP) assay was used to verify the enrichment of EZH2 and histone H3 lysine 27 trimethylation (H3K27me3) in the promoter region of GSK-3β in CRC cells. LncRNA BDNF-AS expression was significantly decreased, while GSK-3β was highly expressed in human CRC tissues and cell lines. Moreover, lncRNA BDNF-AS induced inhibition of proliferation, migration, and invasion of CRC cells via inhibiting GSK-3β expression. Mechanistically, BDNF-AS led to GSK-3β promoter silencing in CRC cells through recruitment of EZH2. In conclusion, lncRNA BDNF-AS functioned as an oncogene in CRC and shed new light on lncRNA-directed therapeutics in CRC. SIGNIFICANCE OF THE STUDY: LncRNA BDNF-AS is recently reported to be remarkably downregulated in a variety of tumours and served as a tumour suppressor. However, the functions and underlying mechanism of lncRNA BDNF-AS in CRC pathogenesis have not been reported yet. Our study is the first to demonstrate the effect of lncRNA BDNF-AS in CRC and revealed that lncRNA BDNF-AS expression is negatively correlated with the aggressive biological behaviour of CRC. Further investigation demonstrated that lncRNA BDNF-AS functioned as a tumour suppressor in CRC progression by suppressing GSK-3β expression through binding to EZH2 and H3K27me3 with the GSK-3β promoter, shedding light on the diagnosis and therapy for CRC.

Sapio MR, Iadarola MJ, LaPaglia DM, et al.
Haploinsufficiency of the brain-derived neurotrophic factor gene is associated with reduced pain sensitivity.
Pain. 2019; 160(5):1070-1081 [PubMed] Free Access to Full Article Related Publications
Rare pain-insensitive individuals offer unique insights into how pain circuits function and have led to the development of new strategies for pain control. We investigated pain sensitivity in humans with WAGR (Wilms tumor, aniridia, genitourinary anomaly, and range of intellectual disabilities) syndrome, who have variably sized heterozygous deletion of the 11p13 region. The deletion region can be inclusive or exclusive of the brain-derived neurotrophic factor (BDNF) gene, a crucial trophic factor for nociceptive afferents. Nociceptive responses assessed by quantitative sensory testing demonstrated reduced pain sensitivity only in the WAGR subjects whose deletion boundaries included the BDNF gene. Corresponding behavioral assessments were made in heterozygous Bdnf knockout rats to examine the specific role of Bdnf. These analogous experiments revealed impairment of Aδ- and C-fiber-mediated heat nociception, determined by acute nociceptive thermal stimuli, and in aversive behaviors evoked when the rats were placed on a hot plate. Similar results were obtained for C-fiber-mediated cold responses and cold avoidance on a cold-plate device. Together, these results suggested a blunted responsiveness to aversive stimuli. Our parallel observations in humans and rats show that hemizygous deletion of the BDNF gene reduces pain sensitivity and establishes BDNF as a determinant of nociceptive sensitivity.

Bai L, Zhang S, Zhou X, et al.
Brain-derived neurotrophic factor induces thioredoxin-1 expression through TrkB/Akt/CREB pathway in SH-SY5Y cells.
Biochimie. 2019; 160:55-60 [PubMed] Related Publications
Brain-derived neurotrophic factor (BDNF) is one of the neurotrophic factors that are vital to the survival and proliferation of neuron. Thioredoxin-1 (Trx-1) is a redox regulating protein and plays various roles in regulating transcript factors and inhibiting apoptosis. It has been reported that Trx-1 is required for nerve growth factor-mediated signal transduction and neurite outgrowth, and is involved in synaptic protein expression induced by BDNF. However, the molecular mechanism on BDNF inducing Trx-1 expression has not been fully verified. The present study investigated the expression of Trx-1 after treatment with BDNF in SH-SY5Y cells. We first demonstrated that cell viability and the expression of Trx-1 were increased by BDNF in SH-SY5Y cells, which were inhibited by the tyrosine kinase B (TrkB) inhibitor, K252a, and the phosphatidylinositol 3-kinase (PI3-K) inhibitor, LY294002. Moreover, BDNF increased the activity of cAMP response element-binding protein (CREB) through TrkB/PI3-K/Akt pathway. Whereas the expression of Trx-1 induced by BDNF was suppressed by CREB siRNA. Thus, our data suggest that BDNF induces the expression of Trx-1 through the TrkB/Akt/CREB pathway.

Dudás J, Riml A, Tuertscher R, et al.
Brain-Derived Neurotrophin and TrkB in Head and Neck Squamous Cell Carcinoma.
Int J Mol Sci. 2019; 20(2) [PubMed] Free Access to Full Article Related Publications
We hypothesized that in head and neck squamous cell carcinoma (HNSCC), the neurotrophin brain-derived neurotrophic factor (BDNF) and its high affinity receptor TrkB regulate tumor cell survival, invasion, and therapy resistance. We used in situ hybridization for

Leibovici A, Sharon R, Azoulay D
BDNF Val66Met is Associated with Pre-existing but not with Paclitaxel-induced Peripheral Neuropathy in an Israeli Cohort of Breast Cancer Patients.
Isr Med Assoc J. 2018; 20(12):746-748 [PubMed] Related Publications
BACKGROUND: Brain-derived neurotrophic factor (BDNF) is a neuronal growth factor that is important for the development, maintenance, and repair of the peripheral nervous system. The BDNF gene commonly carries a single nucleotide polymorphism (Val66Met-SNP), which affects the cellular distribution and activity-dependent secretion of BDNF in neuronal cells.
OBJECTIVES: To check the association between BDNF Val66Met-SNP as a predisposition that enhances the development of chemotherapy-induced peripheral neuropathy in an Israeli cohort of patients with breast cancer who were treated with paclitaxel.
METHODS: Peripheral neuropathy symptoms were assessed and graded at baseline, before beginning treatment, and during the treatment protocol in 35 patients, using the reduced version of the Total Neuropathy Score (TNSr). Allelic discrimination of BDNF polymorphism was determined in the patients' peripheral blood by established polymerase chain reaction and Sanger sequencing.
RESULTS: We found Val/Val in 20 patients (57.14%), Val/Met in 15 patients (42.86%), and Met/Met in none of the patients (0%). Baseline TNSr scores were higher in Met-BDNF patients compared to Val-BDNF patients. The maximal TNSr scores that developed during the follow-up in Met-BDNF patients were higher than in Val-BDNF patients. However, exclusion of patients with pre-existing peripheral neuropathy from the analysis resulted in equivalent maximal TNSr scores in Met-BDNF and Val-BDNF patients.
CONCLUSIONS: These observations suggest that BDNF Val66met-SNP has no detectable effect on the peripheral neuropathy that is induced by paclitaxel. The significance of BDNF Val66Met-SNP in pre-existing peripheral neuropathy-related conditions, such as diabetes, should be further investigated.

Siddeek B, Mauduit C, Simeoni U, Benahmed M
Sperm epigenome as a marker of environmental exposure and lifestyle, at the origin of diseases inheritance.
Mutat Res. 2018 Oct - Dec; 778:38-44 [PubMed] Related Publications
Paternal exposure to environmental challenges plays a critical role in the offspring's future health and the transmission of acquired traits through generations. This review summarizes our current knowledge in the new field of epigenomic paternal transmission of health and disease. Epidemiological studies identified that paternal ageing or challenges (imbalanced diets, stress, toxicants, cigarette smoke, alcohol) increased the risk of offspring to develop diseases such as cancer, metabolic, cardiovascular, and neurological diseases. These data were confirmed and deepened in animal models of exposure to challenges including low-protein, low-folate, high-fat diets, exposure to chemicals such as pesticides and herbicides. Even though some toxicants have mutagenic effect on sperm DNA, changes in sperm epigenome seem to be a common thread between different types of challenges. Indeed, epigenetic changes (DNA methylation, chromatin remodeling, small non-coding RNA) in sperm are described as new mechanisms of intergenerational transmission as demonstrated for dioxin, for example. Those epimutations induce dysregulation in genes expression involved in key cellular pathways such as reactive oxygen species and genome stability regulation, in brain-derived neurotrophic factor, calcium and glucocorticoid signaling, and in lipid and glucose metabolism, leading to diseases in offspring. Finally, since each type of environmental challenges has its own signature by inducing epimutations at specific genomic loci, the sperm epigenome might be used as a biomarker in toxicological and risk assessments.

Huang Q, Yang J, He X, et al.
LncRNA BDNF-AS is associated with the malignant status and regulates cell proliferation and apoptosis in osteosarcoma.
Biosci Rep. 2018; 38(6) [PubMed] Free Access to Full Article Related Publications
Long non-coding RNA (LncRNA) brain-derived neurotrophic factor antisense (BDNF-AS) has been found to be down-regulated and function in a tumor suppressive role in human cancers. However, the expression status and function of BDNF-AS is still unknown in osteosarcoma (OS). In our study, BDNF-AS expression was found to be decreased in OS tissues and cells. Moreover, BDNF-AS low expression was correlated with advanced Enneking stage, large tumor size and poor prognosis in OS patients. The multivariate analysis suggested low expression of BDNF-AS was an independent unfavorable prognostic factor for overall survival in OS patients. The

Smeele P, d'Almeida SM, Meiller C, et al.
Brain-derived neurotrophic factor, a new soluble biomarker for malignant pleural mesothelioma involved in angiogenesis.
Mol Cancer. 2018; 17(1):148 [PubMed] Free Access to Full Article Related Publications
Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer related to asbestos exposure. The discovery of soluble biomarkers with diagnostic/prognostic and/or therapeutic properties would improve therapeutic care of MPM patients. Currently, soluble biomarkers described present weaknesses preventing their use in clinic. This study aimed at evaluating brain-derived neurotrophic factor (BDNF), we previously identified using transcriptomic approach, in MPM. We observed that high BDNF expression, at the mRNA level in tumors or at the protein level in pleural effusions (PE), was a specific hallmark of MPM samples. This protein presented significant but limited diagnostic properties (area under the curve (AUC) = 0.6972, p < 0.0001). Interestingly, high BDNF gene expression and PE concentration were predictive of shorter MPM patient survival (13.0 vs 8.3 months, p < 0.0001, in PE). Finally, BDNF did not affect MPM cell oncogenic properties but was implicated in PE-induced angiogenesis. In conclusion, BDNF appears to be a new interesting biomarker for MPM and could also be a new therapeutic target regarding its implication in angiogenesis.

Yuan Y, Ye HQ, Ren QC
Proliferative role of BDNF/TrkB signaling is associated with anoikis resistance in cervical cancer.
Oncol Rep. 2018; 40(2):621-634 [PubMed] Free Access to Full Article Related Publications
Brain‑derived neurotrophic factor (BDNF) is known as one of the members of the neurotropin family. BDNF‑induced activation of its receptor tyrosine kinase B (TrkB) is associated with anoikis tolerance, tumor progression and poor prognosis in many types of malignancy. However, to the best of our knowledge, there are no reports describing the contribution of the BDNF/TrkB axis to cervical cancer. BDNF and TrKB expression in cervical cancer (CC) tissues and adjacent normal tissues from 87 patients were analyzed by immunohistochemistry, western blot analysis and quantitative PCR assays and the results showed that they were significantly higher in cancer tissues than that in normal adjacent tissues, respectively. Higher expression rates of BDNF and TrKB were observed in stage IIB or higher and BDNF expression was positively associated with lymph node metastasis. Notably, a high expression of TrKB may be contributed to poor survival time, which confirmed by Kaplan‑Meier analysis. Compared to the corresponding CC cell lines, HeLa, SiHa, CASKI, C4‑1 and C‑33a, BDNF and TrKB expression was enhanced in anoikis‑like apoptotic tolerance (AAT), a cell model established from cervical cancer cell lines. AAT cells showed a higher proliferation activity compared with CC cell lines, which was confirmed by a shorter G0/G1 phase, elevated cyclin A, cyclin D1 and c‑myc, decreased caspase‑3 and Bax, and increased Bcl‑2. By contrast, the knockdown of TrKB expression reversed these changes in AAT cells, induced G0/G1 arrest and suppressed proliferation activity. The results of the present study show that PI3K/Akt signaling is involved in the BDNF/TrKB‑induced proliferation of AAT cells in cervical cancer. These findings indicate that BDNF/TrKB pathway is a potential target for the treatment of cervical cancer.

Kimura S, Harada T, Ijichi K, et al.
Expression of brain-derived neurotrophic factor and its receptor TrkB is associated with poor prognosis and a malignant phenotype in small cell lung cancer.
Lung Cancer. 2018; 120:98-107 [PubMed] Related Publications
OBJECTIVES: TrkB is a receptor for brain-derived neurotrophic factor (BDNF) and is highly expressed in various cancers, with BDNF-TrkB signaling having been implicated in tumor progression and metastasis. The role of the BDNF-TrkB system in small cell lung cancer (SCLC), a neuroendocrine cancer, has remained unclear, however. We examined BDNF and TrkB expression in SCLC patients as well as the function of BDNF-TrkB signaling in SCLC cell lines.
MATERIALS AND METHODS: BDNF and TrkB expression in tumor specimens of 58 SCLC patients and 20 non-small cell lung cancer (NSCLC) patients was examined by immunohistochemistry and was scored on the basis of the distribution and intensity of staining. TrkB-overexpressing SCLC (SBC5
RESULTS: The staining score for TrkB in NSCLC and SCLC specimens was 2.80 ± 0.19 and 3.60 ± 0.15, respectively, whereas that for BDNF was 1.95 ± 0.32 and 2.76 ± 0.14, respectively. High levels of both TrkB and BDNF expression in SCLC tumors were significantly associated with poor overall survival in multivariate analysis (hazard ratio = 1.821, P = 0.036). BDNF activated AKT and ERK signaling pathways in and promoted the migration of SBC5
CONCLUSION: Coexpression of BDNF and TrkB was associated with poor prognosis in SCLC patients, and BDNF promoted the migration of TrkB-overexpressing SCLC cells. TrkB is thus a potential therapeutic target for SCLC.

Cheng F, Yang Z, Huang F, et al.
microRNA-107 inhibits gastric cancer cell proliferation and metastasis by targeting PI3K/AKT pathway.
Microb Pathog. 2018; 121:110-114 [PubMed] Related Publications
The present study was aimed to investigate the effect of miR-107 transfection on gastric cancer cell growth. Results from qRT-PCR revealed that level of miR-107 in SGC-7901 and MKN1 cell lines was down-regulated in comparison to the normal cells, GES-1. CCK-8 assay revealed a significant reduction in the proliferation of SGC-7901 cells on transfection with miR-107. The tumor growth was very slow in the mice implanted with SGC-7901/miR-107 compared to those bearing SGC-7901/miR-NC. In SGC-7901 cells metastasis potential after miR-107 transfection was examined using wound-healing and Transwell invasion assays. The migration as well as invasion potential of SGC-7901 cells was significantly lower on transfection with miR-107. The activity of luciferase was reduced markedly in SGC-7901 cells co-transfected with miR-107 mimic compared to miR-NC. However, miR-107 mimic co-transfection did not affect the luciferase activity in SGC-7901 cells bearing mutant-type BDNF 3'UTR. Western blot assay showed that miR-107 overexpression causes inhibition of BDNF mRNA and protein expression in SGC-7901 cells. The CCK8 assay showed that pBDNF transfection prevented miR-107 mediated inhibition of SGC-7901 cell proliferation. miR-107 mimic transfection inhibited expression of BDNF and activation of PI3K (p-PI3K) and AKT (p-AKT) in SGC-7901 cells. In order to confirm whether activation of PI3K and AKT by miR-107 mimic involves inhibition of BDNF, the cells were co-transfected with si-BDNF. The results revealed that si-BDNF transfection led to inhibition of BDNF expression and PI3K and AKT activation in SGC-7901 cells. In summary, the present study demonstrates that miR-107 expression inhibits proliferation and metastasis in gastric cancer cells. Therefore, miR-107 acts as tumor inhibitor for gastric cancer through targeting BDNF expression. Thus miR-107 can be used for treatment of gastric cancer.

Li W, Dou Z, We S, et al.
Long noncoding RNA BDNF-AS is associated with clinical outcomes and has functional role in human prostate cancer.
Biomed Pharmacother. 2018; 102:1105-1110 [PubMed] Related Publications
BACKGROUND: The underlying molecular mechanisms of prostate cancer (CaP) are largely unknown. We investigated the expression, prognostic value and functional role of long non-coding RNA (lncRNA) brain-derived neurotrophin factor antisense (BDNF-AS) in CaP.
METHODS: Clinical tumor samples were excised from patients with CaP. Their endogenous BDNF-AS expression levels were evaluated by qRT-PCR. Correlations between CaP patients' endogenous BDNF-AS expression and their clinicopathological factors, overall survival were statistically analyzed. BDNF-AS expression levels were also probed in immortal CaP cell lines. In LNCaP and PC-3 cells, BDNF-AS was ectopically overexpressed through lentiviral transduction. The functions of BDNF-AS upregulation on CaP cell development were evaluated both in vitro and in vivo.
RESULTS: BDNF-AS was downregulated in human CaP tumors. Low BDNF-AS expression was correlated with CaP patients' poor prognosis and shorter overall survival. BDNF-AS was also found to be lowly expressed in CaP cell lines. In LNCaP and PC-3 cells, lentivirus-driven BDNF-AS overexpression exerted significantly tumor-suppressing effects on hindering cancer cell proliferation and invasion in vitro, and explant growth in vivo.
CONCLUSION: Downregulated BDNF-AS in CaP patients could be a potential prognostic biomarker for predicating poor prognosis and survival. Upregulating BDNF-AS may be a novel molecular intervening target for CaP treatment.

Azoulay D, Herishanu Y, Shapiro M, et al.
Elevated serum BDNF levels are associated with favorable outcome in CLL patients: Possible link to CXCR4 downregulation.
Exp Hematol. 2018; 63:17-21.e1 [PubMed] Related Publications
Increased chemokine C-X-C receptor 4 (CXCR4) expression is related to unfavorable outcome in chronic lymphocytic leukemia (CLL). Brain-derived neurotrophic factor (BDNF) is a neuronal growth factor that has been shown previously to interact with CXCR4 in neuronal cells. Here, we studied the in vitro effect of BDNF on CXCR4 expression and chemotaxis toward stromal derived factor-1 (SDF-1) in freshly isolated CLL cells. We also explored the correlations between serum BDNF levels in CLL patients and disease characteristics and clinical course. Incubation of CLL cells with recombinant BDNF (50 ng/mL) resulted in a downregulation of CXCR4 surface expression and atenuated chemotaxis toward SDF-1. Higher serum BDNF levels were associated with a mutated immunoglobulin heavy chain variable (IGHV) gene, an early clinical stage, and a stable clinical course. Our findings suggest that increased circulating blood BDNF may be associated with a favorable effect in CLL. However, the exact mechanism of this favorable effect should be investigated further.

Sharpley CF, Christie DRH, Bitsika V, et al.
Comparing a genetic and a psychological factor as correlates of anxiety, depression, and chronic stress in men with prostate cancer.
Support Care Cancer. 2018; 26(9):3195-3200 [PubMed] Related Publications
PURPOSE: Some prostate cancer (PCa) patients become clinically anxious or depressed after diagnosis and treatment. Some also show the physiological signs of chronic stress. However, there are currently no data describing how these particular patients might be identified at intake. This study tested the individual and combined predictive power of a psychological factor and a genetic factor as potential predictors of anxiety, depression, and chronic stress in a sample of PCa patients.
METHODS: Ninety-five PCa patients completed psychological inventories for anxiety, depression, and psychological resilience (PR) and also gave a saliva sample for cortisol and a mouthwash sample for genetic testing for the presence of the BDNF Val66Met polymorphism.
RESULTS: High PR patients had significantly lower anxiety and depression than low PR patients, but showed no significant differences in their salivary cortisol. Carriers of the Met allele of the BDNF Val66Met polymorphism had significantly higher salivary cortisol concentrations than patients who did not carry this allele.
CONCLUSIONS: Each of these two factors may provide valuable information regarding the vulnerability of PCa patients to anxiety, depression, or chronic stress. Suggestions are made for their inclusion in clinical settings.

Zhang H, Liu C, Yan T, et al.
Long noncoding RNA BDNF-AS is downregulated in cervical cancer and has anti-cancer functions by negatively associating with BDNF.
Arch Biochem Biophys. 2018; 646:113-119 [PubMed] Related Publications
PURPOSE: We investigated expression and mechanism long noncoding RNA BDNF-AS in human cervical cancer (CC).
METHODS: BDNF-AS expressions were examined by qPCR in CC cell lines and human CC tumors. CC cell lines, SiHa and DoTc2-4510 were transduced with lentivirus to ectopically overexpress BDNF-AS. Possible anti-cancer effects of BDNF overexpression were examined on CC in vitro proliferation and migration, and in vivo transplantation. Human BDNF gene expression was also examined in CC cell lines and tumors. In CC cells with overexpressed BDNF-AS, BDNF was upregulated to examine its direct effect in NDNF-AS-modulated CC proliferation and migration.
RESULTS: BDNF was downregulated in both CC cells and human CC tumors. In CC cells, BDNF-AS overexpression is anti-cancer by inhibiting proliferation and migration in vitro, and transplantation in vivo. BDNF was inversely expressed as BDNF-AS in CC. Upregulation of BDNF in BDNF-AS-overexpressed CC cells reversed the anti-cancer effects of BDNF-AS.
CONCLUSION: BDNF-AS is downregulated in CC. Overexpressing BDNF-AS may inhibit CC, possibly through inverse regulation on BDNF.

Yang M, Li H, Li Y, et al.
Identification of genes and pathways associated with MDR in MCF-7/MDR breast cancer cells by RNA-seq analysis.
Mol Med Rep. 2018; 17(5):6211-6226 [PubMed] Free Access to Full Article Related Publications
Multidrug resistance (MDR) is a major problem in the treatment of breast cancer. In the present study, next-generation sequencing technology was employed to identify differentially expressed genes in MCF‑7/MDR cells and MCF‑7 cells, and aimed to investigate the underlying molecular mechanisms of MDR in breast cancer. Differentially expressed genes between MCF‑7/MDR and MCF‑7 cells were selected using software; a total of 2085 genes were screened as differentially expressed in MCF‑7/MDR cells. Furthermore, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the DAVID database. Finally, a protein‑protein interaction network was constructed and the hub genes in the network were analyzed using the STRING database. GO annotation demonstrated that the differentially expressed genes were enriched in various biological processes, including 'regulation of cell differentiation', 'cell development', 'neuron development', 'movement of cell or subcellular component' and 'cell morphogenesis involved in neuron differentiation'. Cellular component analysis by GO revealed that differentially expressed genes were enriched in 'plasma membrane region' and 'extracellular matrix' terms. Furthermore, KEGG analysis demonstrated that the target genes were enriched in various pathways, including 'cell adhesion molecules (CAMs)', 'calcium signaling pathway', 'tight junction', 'Wnt signaling pathway' and 'pathways in cancer' terms. A protein‑protein interaction network demonstrated that certain hub genes, including cyclin D1, nitric oxide synthase 3 (NOS3), NOTCH3, brain‑derived neurotrophic factor (BDNF), paired box 6, neuropeptide Y, phospholipase C β (PLCB) 4, PLCB2 and actin α cardiac muscle 1, may be associated with MDR in breast cancer. Subsequently, RT‑qPCR confirmed that the expression of these 9 hub genes was higher in MCF‑7/MDR cells compared with MCF‑7 cells, consistent with the RNA‑sequencing analysis. Additionally, a Cell Counting Kit‑8 assay demonstrated that specific inhibitors of NOS3 and BDNF/neurotrophic receptor tyrosine kinase, type 2 signaling reduced the IC50 of MCF‑7/MDR cells in response to various anticancer drugs, including adriamycin, cisplatin and 5‑fluorouracil. The results of the present study provide novel insights into the mechanism underlying MDR in MCF‑7 cells and may identify novel targets for the treatment of breast cancer.

Li C, Zeng X, Liu Z, et al.
BDNF VAL66MET Polymorphism Elevates the Risk of Bladder Cancer via MiRNA-146b in Micro-Vehicles.
Cell Physiol Biochem. 2018; 45(1):366-377 [PubMed] Related Publications
BACKGROUND/AIMS: Emerging studies on brain-derived neurotrophic factor (BDNF) have shown that might be novel biomarkers and therapeutic targets for cancer. We explore the role of BDNF in the tumorigenesis of bladder cancer and the underlying molecular mechanism.
METHODS: 368 patients with diagnosed bladder cancer and 352 healthy controls were enrolled to evaluate the association of BDNF and the miR-146b. Bioinformatics algorithm analysis and luciferase assay were performed to identify the target genes of miR-146b. Real-time PCR and western-blot were carried out to validate the relationship between miR-146b and CRK. MTT assay and FACS were used to evaluated the proliferation and apoptosis of cancer cells. MVs were isolated and transfect into the culture cells to confirm the above observation.
RESULTS: The clinical study shows that BDNF Met/Met was significantly associated with the risk of bladder cancer. In addition, comparing with Val/Val and Val/Met, Met/Met has lower miR-146b level. Luciferase assay shows that BDNF Val/Val is apparently enhanced miR-146b promoter-luciferase, but not BDNF Met/Met. Based on luciferase assay, CRK is a direct target gene of miR-146b. MiR-146b mimics significantly inhibited the expression of CRK and activation of AKT level. The expression of CRK and the activation of AKT (p-AKT) were significantly inhibited by MV-BDNF Val/Val-miR-146b or MV-BDNF Val/Met-miR-146b, but not MV-BDNF Met/Met-miR-146b. MV-BDNF Val/Val-miR-146b or Val/Met-miR-146b obviously inhibited cell proliferation, which eliminated by CRK. Meanwhile, with MV-BDNF Met/Met-miR-146b or Met/Met-miR-146b+CRK did not affect the proliferation. MV-BDNF Val/Val-miR-146b or Val/Met-miR-146b enhanced cell apoptosis, which could be eliminated by CRK. Meanwhile, MV-BDNF Met/Met-miR-146b or Met/Met-miR-146b+CRK did not promote apoptosis.
CONCLUSION: BDNF VAL66MET polymorphism is associated with miR-146b and its target gene CRK. MiR-146b and CRK mediated BDNF VAL66MET polymorphism associated proliferation and apoptosis via activation of AKT. Thus, BDNF Val66Met is associated with the risk of bladder cancer, and the BDNF variant could be used a biomarker for the diagnosis of bladder cancer.

Farah CS, Fox SA, Dalley AJ
Integrated miRNA-mRNA spatial signature for oral squamous cell carcinoma: a prospective profiling study of Narrow Band Imaging guided resection.
Sci Rep. 2018; 8(1):823 [PubMed] Free Access to Full Article Related Publications
Oral squamous cell carcinoma (OSCC) is a common malignancy for which there is poor prognosis and limited therapeutic options. The objective was to identify mRNA targets of dysregulated miRNAs in OSCC using integrated analysis and understand molecular abnormality in surgical margins. We used biopsies along the spatial axis from normal tissue defined by narrow band imaging (NBI) through conventional white light (WL) margins to tumour from 18 patients undergoing surgical resection for OSCC. Overall 119 miRNA and 4794 mRNA were differentially expressed along the adjacent normal tissue to tumour axis. Analysis of miRNA profiles demonstrated the NBI margins were molecularly distinct from both the tumour and WL margin. Integrated analysis identified 193 miRNA-mRNA interactions correlated to the spatial axis of NBI-WL-T. We used cross-validation analysis to derive a spatial interactome signature of OSCC comprising 100 putative miRNA-mRNA interactions between 40 miRNA and 96 mRNA. Bioinformatic analysis suggests that miRNA dysregulation in OSCC may contribute to activation of the oncostatin M, BDNF and TGF-β pathways. Our data demonstrates that surgical margins defined by NBI leave less potentially malignant residual tissue. The miRNA-mRNA interactome provides insight into dysregulated miRNA signalling in OSCC and supports molecular definition of tumour margins.

Gao L, Yan P, Guo FF, et al.
MiR-1-3p inhibits cell proliferation and invasion by regulating BDNF-TrkB signaling pathway in bladder cancer.
Neoplasma. 2018; 65(1):89-96 [PubMed] Related Publications
Recent studies have confirmed the existence of BDNF and tropomyosin-related kinase B (TrkB) in normal and cancerous urothelium. However, the corresponding mechanisms and upstream signal pathways of BDNF/TrkB have not been fully discovered. This study aimed to investigate the effects of miR-1-3p on bladder cancer (BC) by regulating BDNF-TrkB signal pathway. The expression of miR-1-3p and BDNF in BC tissues and cell lines were detected by Cancer Genome Atlas (TCGA) microarray analysis, RT-qPCR and western blot. Cell transfection was done using Lipofectamine 2000. Then cell viability, proliferation, migration and apoptosis were measured by MTT, colony formation assay, Transwell assay and flow cytometry, respectively. The relationship between miR-1-3p and BDNF was confirmed by luciferase reporter gene assay. MiR-1-3p was significantly down-regulated in BC tissues and cell lines, while BDNF was significantly up-regulated compared to normal samples. MiR-1-3p targeted BDNF and suppressed its expression. Transfections of miR-1-3p mimics and BDNF siRNAs can suppress BC cell proliferation, invasion and induce cell apoptosis. In addition, miR-1-3p can inhibit phosphorylation of the TrkB by regulating BDNF.In conclusion, MiR-1-3p has significant effects on viability, proliferation, invasion and apoptosis of BC cells by regulating BDNF-TrkB pathway.

Wang L, Liu Y, Song J
MicroRNA-103 suppresses glioma cell proliferation and invasion by targeting the brain-derived neurotrophic factor.
Mol Med Rep. 2018; 17(3):4083-4089 [PubMed] Related Publications
Glioma is the most common and aggressive of malignant brain tumours. MicroRNAs (miRNAs/miRs) are involved in tumour development of various human cancers, including glioma. Therefore, miRNAs may have potential tumour diagnostic, prognostic and therapeutic values in human glioma. miR‑103 is abnormally expressed in various human cancer types. However, the detailed expression pattern, biological functions and underlying molecular mechanism of miR‑103 in glioma remain unclear. Therefore, the present study aimed to investigate the expression, biological roles and underlying mechanisms of miR‑103 in glioma. Results of the present study demonstrated that miR‑103 was significantly down‑regulated in glioma tissues and cell lines. Functional experiments demonstrated that miR‑103 overexpression inhibited the proliferation and invasion of glioma cells in vitro. Additionally, brain‑derived neurotrophic factor (BDNF) was identified as a direct functional target of miR‑103 in glioma. Furthermore, mRNA and protein expression levels of BDNF were highly upregulated in glioma tissues compared with normal brain tissues. Spearman's correlation analysis indicated a negative association between miR‑103 and BDNF mRNA expression levels in glioma tissues. Furthermore, rescue experiments demonstrated that BDNF up‑regulation reversed the suppressive effects of miR‑103 on glioma cell proliferation and invasion. Therefore, the authors of the present study hypothesized that the interaction between miR‑103 and BDNF serves a role in glioma progression and, in the future, may serve as a therapeutic target for glioma treatment.

Jóźwiak-Bębenista M, Jasińska-Stroschein M, Kowalczyk E
The differential effects of neuroleptic drugs and PACAP on the expression of BDNF mRNA and protein in a human glioblastoma cell line.
Acta Neurobiol Exp (Wars). 2017; 77(3):205-213 [PubMed] Related Publications
Despite numerous studies, the molecular mechanisms underpinning the action of antipsychotic drugs remain not fully understood. It has been suggested that, in addition to the modulation of monoaminergic neurotransmission, antipsychotic drugs can also affect the expression of neurotrophic factors in the brain. The present study examines the effects of a first-generation neuroleptic drug (FGA; haloperidol) and two second-generation neuroleptic drugs (SGAs; olanzapine and amisulpride) on the expression and levels of brain-derived neurotrophic factor (BDNF) in an astrocyte-like T98G glioblastoma cell line. The effects of these drugs were compared to the action of PACAP38, a neuropeptide with well-known BDNF-mediated neuroprotective effects. The tested neuroleptics differentially regulated the mRNA expression and protein level of BDNF depending on concentration and incubation time. Real-time PCR analysis demonstrates that, of the three tested neuroleptics, both haloperidol and olanzapine at a concentration of 5 µM (but not at 20 µM) increased BDNF mRNA expression with similar efficacy after 72-hour incubation. In order to confirm the observed changes in the mRNA expression of BDNF, a protein expression assay was performed. The exposure of cells to 5 μM olanzapine alone for 72 hours increased BDNF concentration in the culture medium by 29%. Additionally, PACAP significantly up-regulated BDNF mRNA expression in T98G cells and the obtained results correlated positively with the increased production of BDNF protein, 22% above control values. Our findings show that olanzapine, similarly to exogenous PACAP38, increased BDNF mRNA expression and protein release, which can contribute to its neuroprotective mechanism of action in the cells of non-neuronal origin. The results of the paper show that olanzapine, similarly to exogenous PACAP38, increased BDNF mRNA expression and protein release, which can contribute to its neuroprotective mechanism of action in the cells of nonneuronal origin. The results of the present paper confirm the findings that BDNF may represent the key target for olanzapine and PACAP.

Rolfo C, Raez L
New targets bring hope in squamous cell lung cancer: neurotrophic tyrosine kinase gene fusions.
Lab Invest. 2017; 97(11):1268-1270 [PubMed] Related Publications
Neurotrophic tyrosine kinase genes encode for the Trk-family proteins TrkA, TrkB, and TrkC, which have an important role in the development of the nervous system; however, they have been identified as oncogenic fusions in solid tumors (NTK-1, NTRK-2, and NTRK-3) and are associated with poor survival in lung cancer. These three new fusions can be detected by fluorescent in situ hybridization or next-generation sequencing in less than 5% of the lung tumors. There are several ongoing clinical trials of NTRK oncogenes in lung cancer and other tumors. The agents entrectinib (RXDX-101), a multi-kinase small molecule inhibitor that selectively inhibits NTRK1, NTRK2, and NTRK3, ROS1 and ALK, and LOXO-101, an ATP-competitive pan-NTRK inhibitor, have shown responses in patients with lung cancer with an acceptable toxicity profile. Although these oncogenic fusions are not very prevalent, the high prevalence of lung cancer makes these findings very relevant and suggests the feasibility of these oncogenes as targets in lung cancer. New data from Ozono and collaborators presented in this issue suggest that BDNF/TrkB signal promotes proliferating migratory and invasive phenotypes and cellular plasticity in squamous cell carcinoma (SCC) of the lung but that it also represents a druggable target that may bring hope to squamous lung cancer patients.

Takada Y, Sakai Y, Matsushita Y, et al.
Sustained endocrine profiles of a girl with WAGR syndrome.
BMC Med Genet. 2017; 18(1):117 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Wilms tumor, aniridia, genitourinary anomalies and mental retardation (WAGR) syndrome is a rare genetic disorder caused by heterozygous deletions of WT1 and PAX6 at chromosome 11p13. Deletion of BDNF is known eto be associated with hyperphagia and obesity in both humans and animal models; however, neuroendocrine and epigenetic profiles of individuals with WAGR syndrome remain to be determined.
CASE PRESENTATION: We report a 5-year-old girl with the typical phenotype of WAGR syndrome. She showed profound delays in physical growth, motor and cognitive development without signs of obesity. Array comparative genome hybridization (CGH) revealed that she carried a 14.4 Mb deletion at 11p14.3p12, encompassing the WT1, PAX6 and BDNF genes. She experienced recurrent hypoglycemic episodes at 5 years of age. Insulin tolerance and hormonal loading tests showed normal hypothalamic responses to the hypoglycemic condition and other stimulations. Methylation analysis for freshly prepared DNA from peripheral lymphocytes using the pyro-sequencing-based system showed normal patterns of methylation at known imprinting control regions.
CONCLUSIONS: Children with WAGR syndrome may manifest profound delay in postnatal growth through unknown mechanisms. Epigenetic factors and growth-associated genes in WAGR syndrome remain to be characterized.

Song D, Diao J, Yang Y, Chen Y
MicroRNA‑382 inhibits cell proliferation and invasion of retinoblastoma by targeting BDNF‑mediated PI3K/AKT signalling pathway.
Mol Med Rep. 2017; 16(5):6428-6436 [PubMed] Related Publications
It has previously been demonstrated that multiple microRNAs (miRNAs or miRs) are aberrantly expressed in retinoblastoma (RB) and contribute to RB initiation and progression. miR‑382 has been revealed to be aberrantly expressed and therefore exhibits a key role in the progression of various types of cancer. However, the expression pattern, functional roles and underlying molecular mechanism of miR‑382 in RB remain unknown. The present study investigated the expression levels of miR‑382 and its effects on RB cells and the underlying regulatory mechanism of its action. It was demonstrated that miR‑382 was downregulated in RB tissues and cell lines. Upregulation of miR‑382 inhibited RB cell proliferation and invasion in vitro. Additionally, brain‑derived neurotrophic factor (BDNF) was identified as a novel target of miR‑382 in RB. BDNF was upregulated in RB tissues and negatively associated with miR‑382 expression levels. Furthermore, BDNF overexpression rescued the tumour‑suppressing effects on RB cells induced by miR‑382. miR‑382 inactivated the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signalling pathway in RB. These findings suggested that miR‑382 serves as a tumour suppressor in RB, in part, by targeting the BDNF‑mediated PI3K/AKT signalling pathway. The results of the present study suggest a potential therapeutic strategy for treating RB patients in the future.

Jahn K, Wieltsch C, Blumer N, et al.
A cell culture model for investigation of synapse influenceability: epigenetics, expression and function of gene targets important for synapse formation and preservation in SH-SY5Y neuroblastoma cells differentiated by retinoic acid.
J Neural Transm (Vienna). 2017; 124(11):1341-1367 [PubMed] Related Publications
SH-SY5Y neuroblastoma cells are frequently used for different neuronal cell culture models. As there is no "gold-standard", miscellaneous protocols exist to differentiate these cells into a neuronal cell type. Here, the aim was to find a differentiation condition making cells suitable for investigation of influenceability of synapses by environmental conditions in pharmacologic experiments. For this purpose, effects on synapse molecules should be somehow rateable and cells should be usable for functional analysis like calcium imaging. A system like this is desirable for example in basic research concerning schizophrenia, depression, autism or neurodegeneration as synaptic plasticity and neuronal maturation are known to have a significant impact in these diseases. Cells grown on laminin-coated glass cover slips and treated with 50 µM retinoic acid (RA) turned out to show most convincing morphological signs of neuronal differentiation and attached strongly to the ground, thereby also fulfilling preconditions for functional analysis. Systematic characterisation of this differentiation condition in comparison to non-treated controls revealed lower methylation rates and higher expression of most candidate molecules relevant for formation, preservation and function of synapses as well as differential function. In conclusion, this combination of differentiation strategy and markers seems to be a suitable system to estimate synapse modifications in basic research as it could help to identify possible dedifferentiating effects. To our knowledge, differentiation of SH-SY5Y has not been described as systematic before regarding comprehensiveness of the set of investigated synapse molecules and coverage of applied methods spanning from epigenetics to protein function. Furthermore, this is the first time that SH-SY5Y cells were differentiated on glass cover slips to an extent making them suitable for investigation of synapse molecules as part of stable intercellular connections in downstream functional analyses.

Boltaev U, Meyer Y, Tolibzoda F, et al.
Multiplex quantitative assays indicate a need for reevaluating reported small-molecule TrkB agonists.
Sci Signal. 2017; 10(493) [PubMed] Related Publications
Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), have emerged as key regulators of brain plasticity and represent disease-modifying targets for several brain disorders, including Alzheimer's disease and major depressive disorder. Because of poor pharmacokinetic properties of BDNF, the interest in small-molecule TrkB agonists and modulators is high. Several compounds have been reported to act as TrkB agonists, and their increasing use in various nervous system disorder models creates the perception that these are reliable probes. To examine key pharmacological parameters of these compounds in detail, we have developed and optimized a series of complementary quantitative assays that measure TrkB receptor activation, TrkB-dependent downstream signaling, and gene expression in different cellular contexts. Although BDNF and other neurotrophic factors elicited robust and dose-dependent receptor activation and downstream signaling, we were unable to reproduce these activities using the reported small-molecule TrkB agonists. Our findings indicate that experimental results obtained with these compounds must be carefully interpreted and highlight the challenge of developing reliable pharmacological activators of this key molecular target.

Chiu JH, Chen FP, Tsai YF, et al.
Effects of Chinese medicinal herbs on expression of brain-derived Neurotrophic factor (BDNF) and its interaction with human breast cancer MDA-MB-231 cells and endothelial HUVECs.
BMC Complement Altern Med. 2017; 17(1):401 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Our previous study demonstrated that an up-regulation of the Brain-Derived Neurotrophic Factor (BDNF) signaling pathway is involved the mechanism causing the recurrence of triple negative breast cancer. The aim of this study is to investigate the effects of commonly used Chinese medicinal herbs on MDA-MB-231 and HUVEC cells and how they interact with BDNF.
METHODS: Human TNBC MDA-MB-231 cells and human endothelial HUVEC cells were used to explore the effect of commonly used Chinese herbal medicines on cancer cells alone, on endothelial cells alone and on cancer cell/endothelial cell interactions; this was done via functional studies, including migration and invasion assays. Furthermore, Western blot analysis and real-time PCR investigations were also used to investigate migration signal transduction, invasion signal transduction, and angiogenic signal transduction in these systems. Finally, the effect of the Chinese medicinal herbs on cancer cell/endothelial cell interactions was assessed using co-culture and ELISA.
RESULTS: In terms of autoregulation, BDNF up-regulated TrkB gene expression in both MDA-MB-231 and HUVEC cells. Furthermore, BDNF enhanced migration by MDA-MB-231 cells via Rac, Cdc42 and MMP, while also increasing the migration of HUVEC cells via MMP and COX-2 expression. As measured by ELISA, the Chinese herbal medicinal herbs A. membranaceus, P. lactiflora, L. chuanxiong, P. suffruticosa and L. lucidum increased BDNF secretion by MDA-MB-231 cells. Similarly, using a co-culture system with MDA-MB-231 cells, A. membranaceus and L. lucidum modulated BDNF-TrkB signaling by HUVEC cells.
CONCLUSION: We conclude that BDNF plays an important role in the metastatic interaction between MDA-MB-231 and HUVEC cells. Some Chinese medicinal herbs are able to enhance the BDNF-related metastatic potential of the interaction between cancer cells and endothelial cells. These findings provide important information that should help with the development of integrated medical therapies for breast cancer patients.

Xu AJ, Fu LN, Wu HX, et al.
MicroRNA‑744 inhibits tumor cell proliferation and invasion of gastric cancer via targeting brain‑derived neurotrophic factor.
Mol Med Rep. 2017; 16(4):5055-5061 [PubMed] Related Publications
Gastric cancer is the fourth most common malignancy and the third leading cause of cancer‑associated deaths worldwide. It has previously been demonstrated that microRNAs (miRNAs) are actively involved in the pathogenesis of gastric cancer. Therefore, miRNAs have been proposed as promising therapeutic targets in gastric cancer patients. MiR‑744 is aberrantly expressed in different types of human cancer. However, the expression pattern and biological roles of miR‑744 in gastric cancer remain unknown. The present study demonstrated that miR‑744 expression was low in gastric cancer tissues and cell lines. Low expression levels of miR‑744 was significantly correlated with lymph node metastasis, invasive depth and TNM staging in gastric cancer patients. The restoration of miR‑744 expression inhibited cell proliferation and invasion in vitro. Bioinformatic prediction, luciferase reporter assay, reverse transcription‑quantitative polymerase chain reaction and western blot analysis verified that brain‑derived neurotrophic factor (BDNF) is a direct target of miR‑744 in gastric cancer cells. Furthermore, BDNF was upregulated in gastric cancer tissues and inversely correlated with miR‑744 expression. Furthermore, enforced BDNF expression reversed the tumor‑suppressing effects of miR‑744 on the proliferation and invasion of gastric cancer cells, indicating that BDNF is a functional mediator of miR‑744 in gastric cancer. The present study suggests that miR‑744 is a potential prognostic biomarker and treatment target in gastric cancer patients.

Makondi PT, Chu CM, Wei PL, Chang YJ
Prediction of novel target genes and pathways involved in irinotecan-resistant colorectal cancer.
PLoS One. 2017; 12(7):e0180616 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Acquired drug resistance to the chemotherapeutic drug irinotecan (the active metabolite of which is SN-38) is one of the significant obstacles in the treatment of advanced colorectal cancer (CRC). The molecular mechanism or targets mediating irinotecan resistance are still unclear. It is urgent to find the irinotecan response biomarkers to improve CRC patients' therapy.
METHODS: Genetic Omnibus Database GSE42387 which contained the gene expression profiles of parental and irinotecan-resistant HCT-116 cell lines was used. Differentially expressed genes (DEGs) between parental and irinotecan-resistant cells, protein-protein interactions (PPIs), gene ontologies (GOs) and pathway analysis were performed to identify the overall biological changes. The most common DEGs in the PPIs, GOs and pathways were identified and were validated clinically by their ability to predict overall survival and disease free survival. The gene-gene expression correlation and gene-resistance correlation was also evaluated in CRC patients using The Cancer Genomic Atlas data (TCGA).
RESULTS: The 135 DEGs were identified of which 36 were upregulated and 99 were down regulated. After mapping the PPI networks, the GOs and the pathways, nine genes (GNAS, PRKACB, MECOM, PLA2G4C, BMP6, BDNF, DLG4, FGF2 and FGF9) were found to be commonly enriched. Signal transduction was the most significant GO and MAPK pathway was the most significant pathway. The five genes (FGF2, FGF9, PRKACB, MECOM and PLA2G4C) in the MAPK pathway were all contained in the signal transduction and the levels of those genes were upregulated. The FGF2, FGF9 and MECOM expression were highly associated with CRC patients' survival rate but not PRKACB and PLA2G4C. In addition, FGF9 was also associated with irinotecan resistance and poor disease free survival. FGF2, FGF9 and PRKACB were positively correlated with each other while MECOM correlated positively with FGF9 and PLA2G4C, and correlated negatively with FGF2 and PRKACB after doing gene-gene expression correlation.
CONCLUSION: Targeting the MAPK signal transduction pathway through the targeting of the FGF2, FGF9, MECOM, PLA2G4C and PRKACB might increase tumor responsiveness to irinotecan treatment.

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