Membrane Transporters in Human Parotid Gland-Targeted Proteomics Approach.
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ABSTRACT:
SUBMITTER: Lapczuk-Romanska J
PROVIDER: S-EPMC6801960 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Salivary gland cancer represents a heterogeneous group of malignant tumors. Due to their low incidence and the existence of multiple morphologically defined subtypes, these tumors are still poorly understood with regard to their molecular pathogenesis and therapeutically relevant genetic alterations.Performing a systematic and comprehensive study covering 13 subtypes of salivary gland cancer, next generation sequencing was done on 84 tissue samples of parotid gland cancer using multiplex PCR for enrichment of cancer related gene loci covering hotspots of 46 cancer genes.Mutations were identified in 22 different genes. The most frequent alterations affected TP53, followed by RAS genes, PIK3CA, SMAD4 and members of the ERB family. HRAS mutations accounted for more than 90% of RAS mutations, occurring especially in epithelial-myoepithelial carcinomas and salivary duct carcinomas. Additional mutations in PIK3CA also affected particularly epithelial-myoepithelial carcinomas and salivary duct carcinomas, occurring simultaneously with HRAS mutations in almost all cases, pointing to an unknown and therapeutically relevant molecular constellation. Interestingly, 14% of tumors revealed mutations in surface growth factor receptor genes including ALK, HER2, ERBB4, FGFR, cMET and RET, which might prove to be targetable by new therapeutic agents. 6% of tumors revealed mutations in SMAD4.In summary, our data provide novel insight into the fundamental molecular heterogeneity of salivary gland cancer, relevant in terms of tumor classification and the establishment of targeted therapeutic concepts.
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Project description:The purpose of this study was to determine the incidence of an anterior extension of the parotid gland, such as an accessory parotid gland (APG) or facial process (FP) and to evaluate its characteristics on computed tomography (CT) scans. We reviewed CT scans of 1,600 parotid glands from 800 patients. An APG on CT was defined as a soft-tissue mass of the same density as the main parotid gland, located at the anterior part of the main parotid gland, and completely separate from the main parotid gland. An FP was defined as a lobe of the parotid gland protruding anteriorly over the anterior edge of the ramus of the mandible on CT and showing continuity with the main gland. The overall incidence rates and characteristics of APGs and FPs were evaluated according to age, sex, and side. The incidence rates of APGs and FPs were 10.2% (163/1,600) and 28.3% (452/1,600), respectively. The mean size of an APG was 15.8 mm × 5.0 mm and the mean distance from the main parotid gland was 10.5 mm. The FP reached anteriorly between the anterior edge of the mandibular ramus and the anterior border of the masseter muscle in 405 (89.6%) cases, while it extended over the anterior border of the masseter muscle in 47 (10.4%) cases. The incidence rates of APGs and FPs decreased and increased, respectively, with increasing age, showing significant linear correlations. However, the incidence of an anterior extension of the parotid gland (either an APG or an FP) was similar across all age groups. The present study showed that CT might be helpful in identifying anterior extensions of the parotid gland including APGs and FPs. The anatomical information gained from this study contributes to a better understanding of APGs and FPs and how their incidence changes with age.
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Project description:BackgroundCurrently, clinical examination, ultrasound scanning (with or without fine needle aspiration cytology), preoperative CT-scan and MRI are available for the differential diagnosis of parotid gland swelling. A preliminary non-invasive salivary diagnostic tool may be helpful in the clinical decision making process. Altered salivary micro-RNA (miRNA) expression levels have been observed in saliva from patients with various cancers. Therefore, we investigated miRNA expression levels in saliva samples from patients with a parotid gland neoplasm using Human miRNA cards in comparison to controls.ResultsIn the discovery phase, eight miRNAs were identified having different expression levels in patients compared to controls. In the validation phase, the differences in miRNA expression levels between patients and controls were confirmed for seven out of eight discovered miRNAs (p < 0.001). A combination of two miRNAs yielded a receiver-operator-characteristics curve with an AUC of 0.94 (95% CI: 0.87-1.00; sensitivity 91%; specificity 86%). Validation of discovered miRNAs in segregated collected parotid saliva revealed that expression of these miRNAs differ between whole saliva and parotid saliva.ConclusionsA two miRNA combination can predict the presence of a parotid gland neoplasm. Furthermore, this study suggested that the identified, patient-specific, salivary miRNAs were not derived from the parotid gland itself.
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Project description:ObjectiveThe present study evaluated differences in gene expression associated with age and gender in the human parotid gland.DesignParotid gland tissue was analysed using the Affymetrix GeneChip HGU133plus2.0 array.ResultsDifferential gene expression, defined as a statistically significant difference with a 1.5-fold or greater change, was detected in 787 gene probe sets; 467 (approximately 59%) showed higher expression in females. Several genes associated with saliva secretion were differentially expressed in male and female parotid glands including vesicle-associated membrane protein 3 VAMP3, synaptosomal-associated protein SNAP23, RAS oncogene family member RAB1A and the syntaxin binding protein STXBP1. Evaluation of gene expression in the youngest and the oldest female subjects revealed that the expression of 228 probe sets were altered during aging; 155 genes were up-regulated in the aged female parotid gland. However, of the genes that were altered during aging, 22 of the 30 probes (73%) classified as being associated with immune responses were down-regulated in the aged parotid gland. A panel of differentially expressed, age- and gender-related genes was selected for validation by quantitative, real-time RT-PCR. Comparable differences in gene expression were detected by both Affymetrix array and quantitative, real-time RT-PCR methods.ConclusionsOur data suggest that salivary gland function may be adversely affected in the aged population due, at least in part, to the altered regulation of several categories of genes. Moreover, the gender specific differences in gene expression identified in the present study correlate with the previously observed sexual dimorphism in salivary gland function.
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Project description: Not available
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Project description:Human ductal saliva contributes over a thousand unique proteins to whole oral fluids. The mechanism by which most of these proteins are secreted by salivary glands remains to be determined. The present study used a mass spectrometry-based, shotgun proteomics approach to explore the possibility that a subset of the proteins found in saliva are derived from exosomes, membrane-bound vesicles of endosomal origin within multivesicular endosomes. Using MudPIT (multidimensional protein identification technology) mass spectrometry, we catalogued 491 proteins in the exosome fraction of human parotid saliva. Many of these proteins were previously observed in ductal saliva from parotid glands (265 proteins). Furthermore, 72 of the proteins in parotid exosomes overlap with those previously identified as urinary exosome proteins, proteins which are also frequently associated with exosomes from other tissues and cell types. Gene Ontology (GO) and KEGG pathway analyses found that cytosolic proteins comprise the largest category of proteins in parotid exosomes (43%), involved in such processes as phosphatidylinositol signaling system, calcium signaling pathway, inositol metabolism, protein export, and signal transduction, among others; whereas the integral plasma membrane proteins and associated/peripheral plasma membrane proteins (26%) were associated with extracellular matrix-receptor interaction, epithelial cell signaling, T-cell and B-cell receptor signaling, cytokine receptor interaction, and antigen processing and presentation, among other biological functions. In addition, these putative saliva exosomal proteins were linked to specific diseases (e.g., neurodegenerative disorders, prion disease, cancers, type I and II diabetes). Consequently, parotid glands secrete exosomes that reflect the metabolic and functional status of the gland and may also carry informative protein markers useful in the diagnosis and treatment of systemic diseases.
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Project description:ObjectiveDiabetes mellitus causes deterioration in the body, including serious damage of the oral cavity related to salivary gland dysfunction, characterised by hyposalivation and xerostomia. Human dental pulp stem cells (hDPSCs) represent a promising therapy source, due to the easy, minimally invasive surgical access to these cells and their high proliferative capacity. It was previously reported that the trophic support mediated by these cells can rescue the functional and structural alterations of damaged salivary glands. However, potential differentiation and paracrine effects of hDPSCs in diabetic-induced parotid gland damage have not been investigated. Our study aimed to investigate the therapeutic effects of intravenous transplantation of hDPSCs on parotid gland injury in a rat model of streptozotocin (STZ)-induced type 1 diabetes.MethodsThirty Sprague-Dawley male rats were randomly categorised into three groups: control, diabetic (STZ), and transplanted (STZ + hDPSCs). The hDPSCs or the vehicles were injected into the rats' tail veins, 7 days after STZ injection. Fasting blood glucose levels were monitored weekly. A glucose tolerance test was performed, and the parotid gland weight, salivary flow rate, oxidative stress indices, parotid gland histology, and caspase-3, vascular endothelial growth factor, proliferating cell nuclear antigen, neuronal nitric oxide synthase, endothelial nitric oxide synthase, and tetrahydrobiopterin biosynthetic enzyme expression levels in parotid tissues were assessed 28 days post-transplantation.ResultsTransplantation of hDPSCs decreased blood glucose, improved parotid gland weight and salivary flow rate, and reduced oxidative stress. The cells migrated to the STZ-injured parotid gland and differentiated into acinar, ductal, and myoepithelial cells. Moreover, hDPSCs downregulated the expression of caspase-3 and upregulated the expression of vascular endothelial growth factor and proliferating cell nuclear antigen, likely exerting pro-angiogenic and anti-apoptotic effects and promoting endogenous regeneration. In addition, the transplanted cells enhanced the parotid nitric oxide-tetrahydrobiopterin pathway.ConclusionsOur results showed that hDPSCs migrated to and survived within the STZ-injured parotid gland, where functional and morphological damage was prevented due to the restoration of normal glucose levels, differentiation into parotid cell populations, and stimulation of paracrine-mediated regeneration. Thus, hDPSCs may have potential in the treatment of diabetes-induced parotid gland injury.
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Project description:The technology to reprogram human somatic cells to pluripotent state allows the generation of patient-specific induced pluripotent stem cells (iPSCs) and holds a great promise for regenerative medicine and autologous transplantation. Here we, for the first time, identified mesenchymal stem cells isolated from parotid gland (hPMSCs) as a suitable candidate for iPSC production. In the present study, hPMSCs were isolated from parotid gland specimens in patients with squamous cell carcinoma of the oral cavity. The mesenchymal stem cell properties of cultured hPMSCs were confirmed by expression of surface markers and induced differentiation into osteogenic, chondrogenic and adipogenic cell lineages. hPMSCs were then reprogrammed to pluripotent cells by episomal vector-mediated transduction of reprogramming factors (OCT3/4, SOX2, KLF4, c-MYC, LIN28 and TP53 shRNA). The resulting hPMSC-iPSCs showed similar characteristics as human embryonic stem cells (ESCs) with regard to morphology, pluripotent markers, global gene expression, and methylation status of pluripotent cell-specific genes OCT4 and NANOG. These hPMSC-iPSCs were able to differentiate into cells of all three germ layers both in vitro and in vivo. Our results indicate that hPMSCs could be an alternative cell source for generation of iPSCs and have the potential to be used in cell-based regenerative medicine.
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