AXL
Tyrosine-protein kinase receptor UFO precursor (EC 2.7.10.1) (AXL oncogene) [UFO]
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Acidosis of the tumor microenvironment is a characteristic of solid tumors such as malignant melanoma. Main causes of the extracellular acidification are metabolic alterations in cancer cells. While numerous studies showed that acidosis promotes tumor invasiveness, metastasis, and neoangiogenesis resulting in malignant progression, contrary data reported that acidosis induces cell apoptosis, inhibits cell proliferation, and mediates cell autophagy. Here, we show that low pH (pH 6.7) induces senescent/quiescent phenotype in melanoma cells after long-time treatment defined by induction of SA-ß-galactosidase, upregulation of p21, G /G cell cycle arrest, and reduction of proliferation. Moreover, we revealed that extracellular acidosis triggers the inhibition of eIF2α and subsequently the activation of ATF4 expression, a key component of the integrated stress response (ISR), indicating an acid-mediated translation reprogramming. Interestingly, we also demonstrated that acidosis represses microphthalmia-associated transcription factor (MITF) and activates the expression of the receptor tyrosine kinase AXL. This MITF /AXL phenotype is correlated with drug resistance and therapeutic outcome in melanoma. Our results suggest that acidosis is an important microenvironmental factor triggering phenotypic plasticity and promoting tumor progression.
MeSH Terms
- Acidosis
- Cell Cycle Checkpoints
- Cell Line, Tumor
- Cell Proliferation
- Cellular Senescence
- Drug Resistance, Neoplasm
- Etoposide
- Extracellular Space
- Humans
- Hydrogen-Ion Concentration
- Melanoma
- Phenotype
Keywords
- dormancy
- extracellular acidosis
- melanoma
- senescence
- slow-cycling phenotype
- tumor microenvironment
Hippocampal sclerosis of aging (HS-Aging) is a common cause of dementia in older adults. We tested the variability in cerebrospinal fluid (CSF) proteins associated with previously identified HS-Aging risk single nucleotide polymorphisms (SNPs). Alzheimer's Disease Neuroimaging Initiative cohort (ADNI; n=237) data, combining both multiplexed proteomics CSF and genotype data, were used to assess the association between CSF analytes and risk SNPs in four genes (SNPs): GRN (rs5848), TMEM106B (rs1990622), ABCC9 (rs704180), and KCNMB2 (rs9637454). For controls, non-HS-Aging SNPs in APOE (rs429358/rs7412) and MAPT (rs8070723) were also analyzed against Aβ1-42 and total tau CSF analytes. The GRN risk SNP (rs5848) status correlated with variation in CSF proteins, with the risk allele (T) associated with increased levels of AXL Receptor Tyrosine Kinase (AXL), TNF-Related Apoptosis-Inducing Ligand Receptor 3 (TRAIL-R3), Vascular Cell Adhesion Molecule-1 (VCAM-1) and clusterin (CLU) (all p<0.05 after Bonferroni correction). The TRAIL-R3 correlation was significant in meta-analysis with an additional dataset (p=5.05×10 ). Further, the rs5848 SNP status was associated with increased CSF tau protein - a marker of neurodegeneration (p=0.015). These data are remarkable since this GRN SNP has been found to be a risk factor for multiple types of dementia-related brain pathologies.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Amyloid beta-Peptides
- Biomarkers
- Clusterin
- Databases, Factual
- Dementia
- Female
- GPI-Linked Proteins
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Hippocampus
- Humans
- Intercellular Signaling Peptides and Proteins
- Male
- Polymorphism, Single Nucleotide
- Progranulins
- Receptors, Tumor Necrosis Factor, Member 10c
- Regression Analysis
- Risk Factors
- Sclerosis
- Vascular Cell Adhesion Molecule-1
- tau Proteins
Keywords
- Biomarkers
- Clusterin
- Granulin
- Neuroinflammation
- Progranulin
- Proteomics
The aim of this study was to determine the relationship of the central corneal thickness (CCT) and axial length (AXL) with the central lamina cribrosa thickness (LCT) in healthy human eyes. This was a prospective observational case series. The optic discs of 189 eyes from 100 healthy subjects with a refractive error smaller than -8 diopters were scanned using enhanced-depth imaging spectral-domain optical coherence tomography (Spectralis OCT, Heidelberg Engineering, Heidelberg, Germany). The thickness of the lamina cribrosa (LC) was measured on B-scan images obtained at the center of the optic nerve head. A linear mixed-effects model was used to determine the factors associated with LCT, taking into account clustering of eyes within subjects. The thickness of the central LC was 273.19 ± 34.74 μm (mean ± SD; range, 173.73-367.94 μm). Multivariate analysis revealed a significant influence of older age on increased central LCT (p = 0.001). There was no significant association between central LCT and either CCT or AXL. In this study, the central LCT increased significantly with older age in healthy human eyes. Neither CCT nor AXL was significantly associated with the central LCT in healthy human eyes with a spherical equivalent within the range from -7.0 to 3.0 diopters.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Axial Length, Eye
- Cornea
- Corneal Topography
- Female
- Gonioscopy
- Humans
- Intraocular Pressure
- Male
- Middle Aged
- Optic Disk
- Organ Size
- Prospective Studies
- Tomography, Optical Coherence
- Tonometry, Ocular
- Visual Field Tests
- Visual Fields
- Young Adult