ABSTRACT
The role and prognostic value of tetraspanins (TSPANs) in vulvar squamous cell carcinoma (VSCC) remain poorly understood. We sought to primarily determine, at both the molecular and tissue level, the expression profile of the TSPANs CD9, CD63, CD81, and CD82 in archived VSCC samples (n = 117) and further investigate their clinical relevance as prognostic markers. Our studies led us to identify CD63 as the most highly expressed TSPAN, at the gene and protein levels. Multicomparison studies also revealed that the expression of CD9 was associated with tumor size, whereas CD63 upregulation was associated with histological diagnosis and vascular invasion. Moreover, low expression of CD81 and CD82 was associated with worse prognosis. To determine the role of TSPANs in VSCC at the cellular level, we assessed the mRNA levels of CD63 and CD82 in established metastatic (SW962) and non-metastatic (SW954) VSCC human cell lines. CD82 was found to be downregulated in SW962 cells, thus supporting its metastasis suppressor role. However, CD63 was significantly upregulated in both cell lines. Silencing of CD63 by siRNA led to a significant decrease in proliferation of both SW954 and SW962. Furthermore, in SW962 particularly, CD63-siRNA also remarkably inhibited cell migration. Altogether, our data suggest that the differential expression of TSPANs represents an important feature for prognosis of VSCC patients and indicates that CD63 and CD82 are likely potential therapeutic targets in VSCC.
Subject(s)
Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/mortality , Gene Expression Regulation, Neoplastic , Tetraspanins/genetics , Transcriptome , Vulvar Neoplasms/genetics , Vulvar Neoplasms/mortality , Adult , Aged , Carcinoma, Squamous Cell/diagnosis , Disease Susceptibility , Female , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Middle Aged , Models, Biological , Neoplasm Grading , Neoplasm Staging , Prognosis , Risk Factors , Tetraspanins/metabolism , Vulvar Neoplasms/pathologyABSTRACT
The molecular mechanisms that control the biosynthetic trafficking, surface delivery, and degradation of TrkA receptor are essential for proper nerve growth factor (NGF) function, and remain poorly understood. Here, we identify Tetraspanin1 (Tspan1) as a critical regulator of TrkA signaling and neuronal differentiation induced by NGF. Tspan1 is expressed by developing TrkA-positive dorsal root ganglion (DRG) neurons and its downregulation in sensory neurons inhibits NGF-mediated axonal growth. In addition, our data demonstrate that Tspan1 forms a molecular complex with the immature form of TrkA localized in the endoplasmic reticulum (ER). Finally, knockdown of Tspan1 reduces the surface levels of TrkA by promoting its preferential sorting towards the autophagy/lysosomal degradation pathway. Together, these data establish a novel homeostatic role of Tspan1, coordinating the biosynthetic trafficking and degradation of TrkA, regardless the presence of NGF.
Subject(s)
Nerve Growth Factor/metabolism , Neurogenesis , Proteostasis , Receptor, trkA/metabolism , Signal Transduction , Tetraspanins/metabolism , Animals , Female , HEK293 Cells , Humans , Male , PC12 Cells , Rats , Rats, WistarABSTRACT
AIM: This cross-sectional case-control study was designed to determine the association of the salivary concentration of CD9/CD81 exosome-related tetraspanins with the periodontal clinical status. MATERIALS AND METHODS: Saliva samples from 104 periodontitis patients and 45 healthy controls were collected. Periodontal status was assessed based on full-mouth clinico-radiographical data, and salivary concentration of the analytes was calculated by ELISA. The association between the biomarkers with disease status was analysed using multivariate binary logistic regression models. RESULTS: Significantly decreased salivary levels of CD9 and CD81 exosomes were detected in periodontitis patients in comparison with healthy controls. Also, negative significant correlations between salivary concentrations of CD9/CD81 exosomes regarding clinical measurements were observed. Likewise, a significant downward trend of the concentration of these two biomarkers concerning the stage and grade of disease could be identified. Logistic regression analyses revealed a strong/independent association for decreased salivary concentration of CD81 exosomes regarding disease status. Confounding and interaction effects between age and salivary concentration of CD9 exosomes were also noted. CONCLUSION: Reduced salivary concentration of CD9/CD81 exosomes might be of significance in the context of periodontal disease pathogenesis.