Neurotrophin receptor TrkB promotes lung adenocarcinoma metastasis.
Ontology highlight
ABSTRACT:
SUBMITTER: Sinkevicius KW
PROVIDER: S-EPMC4104911 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:A better understanding of the mechanisms underlying neuronal death in cerebral ischemia is required for the development of stroke therapies. Here we analyze the contribution of the tropomyosin-related kinase B (TrkB) neurotrophin receptor to excitotoxicity, a primary pathological mechanism in ischemia, which is induced by overstimulation of glutamate receptors of the N-methyl-D-aspartate type. We demonstrate a significant modification of TrkB expression that is strongly associated with neurodegeneration in models of ischemia and in vitro excitotoxicity. Two mechanisms cooperate for TrkB dysregulation: (1) calpain-processing of full-length TrkB (TrkB-FL), high-affinity receptor for brain-derived neurotrophic factor, which produces a truncated protein lacking the tyrosine-kinase domain and strikingly similar to the inactive TrkB-T1 isoform and (2) reverse regulation of the mRNA of these isoforms. Collectively, excitotoxicity results in a decrease of TrkB-FL, the production of truncated TrkB-FL and the upregulation of TrkB-T1. A similar neuro-specific increase of the TrkB-T1 isoform is also observed in stroke patients. A lentivirus designed for both neuro-specific TrkB-T1 interference and increased TrkB-FL expression allows recovery of the TrkB-FL/TrkB-T1 balance and protects neurons from excitotoxic death. These data implicate a combination of TrkB-FL downregulation and TrkB-T1 upregulation as significant causes of neuronal death in excitotoxicity, and reveal novel targets for the design of stroke therapies.
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Project description:The fibroblast growth factor receptor (FGFR) substrate 2 (FRS2) family proteins function as scaffolding adapters for receptor tyrosine kinases (RTKs). The FRS2? proteins interact with RTKs through the phosphotyrosine-binding (PTB) domain and transfer signals from the activated receptors to downstream effector proteins. Here, we report the nuclear magnetic resonance structure of the FRS2? PTB domain bound to phosphorylated TrkB. The structure reveals that the FRS2?-PTB domain is comprised of two distinct but adjacent pockets for its mutually exclusive interaction with either nonphosphorylated juxtamembrane region of the FGFR, or tyrosine phosphorylated peptides TrkA and TrkB. The new structural insights suggest rational design of selective small molecules through targeting of the two conjunct pockets in the FRS2? PTB domain.
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Project description:Background: Lung adenocarcinoma has a strong tendency to develop into bone metastases, especially spinal metastases (SM). Long noncoding RNAs (lncRNAs) play critical roles in regulating several biological processes in cancer cells. However, the mechanisms underlying the roles of lncRNAs in the development of SM have not been elucidated to date. Methods: Clinical specimens were collected for analysis of differentially expressed lncRNAs. The Kyoto Encyclopedia of Genes and Genomes (KEGG) was used to examine the effects of these genes on pathways. RNA pull-down was utilized to identify the targeting protein of lncRNAs. The effects of lncRNA on its target were detected in A549 and SPCA-1 cells via perturbation of the lncRNA expression. Oncological behavioral changes in transfected cells and phosphorylation of kinases in the relevant pathways, with or without inhibitors, were observed. Further, tumorigenicity was found to occur in experimental nude mice. Results: LINC00852 and the mitogen-activated protein kinase (MAPK) pathway were found to be associated with SM. Moreover, the LINC00852 target S100A9 had a positive regulatory role in the progression, migration, invasion, and metastasis of lung adenocarcinoma cells, both in vitro and in vivo. Furthermore, S100A9 strongly activated the P38 and REK1/2 kinases, and slightly activated the phosphorylation of the JNK kinase in the MAPK pathway in A549 and SPCA-1 cells. Conclusion: LINC00852 targets S100A9 to promote progression and oncogenic ability in lung adenocarcinoma SM through activation of the MAPK pathway. These findings suggest a potential novel target for early intervention against SM in lung cancer.
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Project description:DEAD box RNA helicase 17 (DDX17) has been shown to be an RNA binding protein involved in RNA metabolism and associated with cancer progression. However, the biological role of DDX17 in the pathogenesis of lung adenocarcinoma (LUAD) has not been well characterized. Here, we demonstrated that DDX17 promoted the proliferation, migration and invasion of H1299 and A549 lung adenocarcinoma cells. Analyses of public datasets showed that DDX17 is upregulated in LUAD specimens. Our tumor xenograft models confirmed the in vivo promoting role of DDX17 in the growth and metastasis of LUAD. Mechanistic analyses further revealed that DDX17 protein interacts with the mRNA of MYL9 and MAGEA6 and upregulates their levels. MYL9 could mediate the function of DDX17 to regulate the actin cytoskeleton rearrangement and cell adhesion, particularly by modulating the stress fiber and focal adhesion formation, whereas DDX17 might inhibit the autophagy process through MAGEA6/AMPKα1 axis in LUAD cells. Collectively, our study revealed the oncogenic role and pathways of DDX17 in LUAD.
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Project description:Lymph nodes metastases are common in patients with lung cancer. Additionally, those patients are often at a higher risk for death from lung tumor than those with tumor-free lymph nodes. Somatic DNA alterations are key drivers of cancer, and copy number alterations (CNAs) are major types of DNA alteration that promote lung cancer progression. Here, we performed genome-wide DNA copy number analysis, and identified a novel lung-cancer-metastasis-related gene, EFNA4. The EFNA4 genome locus was significantly amplified, and EFNA4 mRNA expression was significantly up-regulated in lung cancer compared with normal lung tissue, and also in lung cancer with lymph node metastases compared with lung cancer without metastasis. EFNA4 encodes Ephrin A4, which is the ligand for Eph receptors. The function of EFNA4 in human lung cancer remains largely unknown. Through cell line experiments we showed that EFNA4 overexpression contributes to lung tumor cells growth, migration and adhesion. Conversely, EFNA4 knockdown or knockout led to the growth suppression of cells and tumor xenografts in mice. Lung cancer patients with EFNA4 overexpression have poor prognosis. Together, by elucidating a new layer of the role of EFNA4 in tumor proliferation and migration, our study demonstrates a better understanding of the function of the significantly amplified and overexpressed gene EFNA4 in lung tumor metastasis, and suggests EFNA4 as a potential target in metastatic lung cancer therapy.
| S-EPMC9454565 | biostudies-literature
Project description:The forkhead box M1 (FOXM1) transcription factor is one of the key genes inducing tumor invasion and metastasis by an unknown mechanism. In this study, we set out to investigate the effects of FOXM1 overexpression on metastatic human lung adenocarcinoma and the underlying mechanism. FOXM1 expression was analyzed in 78 frozen lung adenocarcinoma tissue samples using an Affymetrix microarray and a 155-paraffin-embedded lung adenocarcinoma tissue microarray with immunohistochemical detection. FOXM1 was found to be overexpressed in lung adenocarcinoma, particularly in metastatic patients, compared to non-metastatic patients. Knockdown of FOXM1 by a specific siRNA significantly suppressed EMT progression, migration and invasion of lung adenocarcinoma cells in vitro, and tumor growth and metastasis in vivo, whereas restored expression of FOXM1 had the opposite effect. FOXM1 binds directly to the SNAIL promoter through two specific binding sites and constitutively transactivates it. Collectively, our findings indicate that FOXM1 may play an important role in advancing lung adenocarcinoma progression. Aberrant FOXM1 expression directly and constitutively activates SNAIL, thereby promoting lung adenocarcinoma metastasis. Inhibition of FOXM1-SNAIL signaling may present an ideal target for future treatment.
| S-EPMC4279094 | biostudies-literature
Project description:The function of protein products generated from intramembraneous cleavage by the ?-secretase complex is not well defined. The ?-secretase complex is responsible for the cleavage of several transmembrane proteins, most notably the amyloid precursor protein that results in A?, a transmembrane (TM) peptide. Another protein that undergoes very similar ?-secretase cleavage is the p75 neurotrophin receptor. However, the fate of the cleaved p75 TM domain is unknown. p75 neurotrophin receptor is highly expressed during early neuronal development and regulates survival and process formation of neurons. Here, we report that the p75 TM can stimulate the phosphorylation of TrkB (tyrosine kinase receptor B). In vitro phosphorylation experiments indicated that a peptide representing p75 TM increases TrkB phosphorylation in a dose- and time-dependent manner. Moreover, mutagenesis analyses revealed that a valine residue at position 264 in the rat p75 neurotrophin receptor is necessary for the ability of p75 TM to induce TrkB phosphorylation. Because this residue is just before the ?-secretase cleavage site, we then investigated whether the p75(??) peptide, which is a product of both ?- and ?-cleavage events, could also induce TrkB phosphorylation. Experiments using TM domains from other receptors, EGFR and FGFR1, failed to stimulate TrkB phosphorylation. Co-immunoprecipitation and biochemical fractionation data suggested that p75 TM stimulates TrkB phosphorylation at the cell membrane. Altogether, our results suggest that TrkB activation by p75(??) peptide may be enhanced in situations where the levels of the p75 receptor are increased, such as during brain injury, Alzheimer's disease, and epilepsy.
| S-EPMC5633122 | biostudies-literature
Project description:Objective: Explore the mechanism of CaSR's involvement in bone metastasis in lung adenocarcinoma. Methods: Immunohistochemistry (IHC) was used to detect the expression of calcium-sensing receptor (CaSR) in 120 cases of lung adenocarcinoma with bone metastasis. Stably transfected cell lines with CaSR overexpression and knockdown based on A549 cells were constructed. The expression of CaSR was verified by western blot and qPCR. The proliferation and migration abilities of A549 cells were tested using cholecystokinin-8 (CCK-8) and Transwell assays, respectively. Western blotting was used to detect the expression of matrix metalloproteinases MMP2, MMP9, CaSR, and NF-?B. The supernatant from each cell culture group was collected as a conditional co-culture solution to study the induction of osteoclast precursor cells and osteoblasts. Western blot and qPCR were used to validate the expression of bone matrix degradation-related enzymes cathepsin K and hormone calcitonin receptor (CTR) and osteoblast-induced osteoclast maturation and differentiation enzyme receptor activator of nuclear factor-?B ligand (RANKL), macrophage colony-stimulating factor (M-CSF), osteoprotegerin (OPG), and PTHrP. Immunofluorescent staining was used to detect F-actin ring formation and osteocalcin expression. Western blot results for NF-?B expression identified a regulatory relationship between NF-?B and CaSR. Results: CaSR expression in lung cancer tissues was significantly higher than that in adjacent and normal lung tissues. The expression of CaSR in lung cancer tissues with bone metastasis was higher than that in non-metastatic lung cancer tissues. The proliferation and migration ability of A549 cells increased significantly with overexpressed CaSR. The co-culture solution directly induced osteoclast precursor cells and the expression of bone matrix degradation-related enzymes significantly increased. Osteoblasts were significantly inhibited and osteoblast-induced osteoclast maturation and differentiation enzymes were significantly downregulated. It was found that the expression of NF-?B and PTHrP increased when CaSR was overexpressed. Osteoclast differentiation factor expression was also significantly increased, which directly induces osteoclast differentiation and maturation. These results were reversed when CaSR was knocked down. Conclusions: CaSR can positively regulate NF-?B and PTHrP expression in A549 cells with a high metastatic potential, thereby promoting osteoclast differentiation and maturation, and facilitating the occurrence and development of bone metastasis in lung adenocarcinoma.
| S-EPMC7109411 | biostudies-literature
Project description:BackgroundDistant metastasis is the major cause of lung adenocarcinoma (LUAD)-associated mortality. However, molecular mechanisms involved in LUAD metastasis remain to be fully understood. While the role of long non-coding RNAs (lncRNAs) in cancer development, progression, and treatment resistance is being increasingly appreciated, the list of dysregulated lncRNAs that contribute to LUAD pathogenesis is also rapidly expanding.MethodsBioinformatics analysis was conducted to interrogate publicly available LUAD datasets. In situ hybridization and qRT-PCR assays were used to test lncRNA expression in human LUAD tissues and cell lines, respectively. Wound healing as well as transwell migration and invasion assays were employed to examine LUAD cell migration and invasion in vitro. LUAD metastasis was examined using mouse models in vivo. RNA pulldown and RNA immunoprecipitation were carried out to test RNA-protein associations. Cycloheximide-chase assays were performed to monitor protein turnover rates and Western blotting was employed to test protein expression.ResultsThe expression of the lncRNA LINC01559 was commonly upregulated in LUADs, in particular, in those with distant metastasis. High LINC01559 expression was associated with poor outcome of LUAD patients and was potentially an independent prognostic factor. Knockdown of LINC01559 diminished the potential of LUAD cell migration and invasion in vitro and reduced the formation of LUAD metastatic lesions in vivo. Mechanistically, LINC01559 binds to vimentin and prevents its ubiquitination and proteasomal degradation, leading to promotion of LUAD cell migration, invasion, and metastasis.ConclusionLINC01559 plays an important role in LUAD metastasis through stabilizing vimentin. The expression of LINC01559 is potentially an independent prognostic factor of LUAD patients, and LINC01559 targeting may represent a novel avenue for the treatment of late-stage LUAD.
| S-EPMC10840222 | biostudies-literature
Project description:Aberrant epidermal growth factor receptor (EGFR) signaling in non-small cell lung cancer (NSCLC) is linked to tumor progression, metastasis and poor survival rates. Here we report the role of Cdc42-interacting protein 4 (CIP4) in the regulation of NSCLC cell invasiveness and tumor metastasis. CIP4 was highly expressed in a panel of NSCLC cell lines and normal lung epithelial cell lines. Stable knockdown (KD) of CIP4 in lung adenocarcinoma H1299 cells, expressing wild-type EGFR, led to increased EGFR levels on the cell surface and defects in sustained activation of Erk kinase in H1299 cells treated with EGF. CIP4 localized to leading edge projections in NSCLC cells, and CIP4 KD cells displayed defects in EGF-induced cell motility and invasion through extracellular matrix. This correlated with reduced expression and activity of matrix metalloproteinase-2 (MMP-2) in CIP4 KD cells compared with control. In xenograft assays, CIP4 silencing had no effect on tumor growth but resulted in significant defects in spontaneous metastases to the lungs from these subcutaneous tumors. This correlated with reduced expression of the Erk target gene Zeb1 and the Zeb1 target gene MMP-2 in CIP4 KD tumors compared with control. CIP4 also enhanced rates of metastasis to the liver and lungs in an intrasplenic experimental metastasis model. In human NSCLC tumor sections, CIP4 expression was elevated greater than or equal to twofold in 43% of adenocarcinomas and 32% of squamous carcinomas compared with adjacent normal lung tissues. Analysis of microarray data for NSCLC patients also revealed that high CIP4 transcript levels correlated with reduced overall survival. Together, these results identify CIP4 as a positive regulator of NSCLC metastasis and a potential poor prognostic biomarker in lung adenocarcinoma.
| S-EPMC4978543 | biostudies-literature