RESUMO
Cadherin-mediated cell-cell contacts regulated by intracellular binders play critical roles in tissue homeostasis and tumorigenesis. Here, we screened mutational profiles of 312 annotated genes involved in cadherin binding in human squamous cell carcinomas and found MB21D2 to carry a unique recurrent Q311E mutation. MB21D2 overexpression was also frequently found in head and neck cancer (HNSCC) and was associated with poor clinical outcomes. Cell-based characterizations revealed pro-oncogenic roles for MB21D2 wild-type (WT) and its Q311E mutant (Q311E) in cell proliferation, colony formation, sphere growth, and migration/invasion by promoting epithelial-mesenchymal transition. Conversely, MB21D2 knockdown in MB21D2-overexpressing cells resulted in cell growth arrest and apoptosis. Xenograft tumor models with Q311E-expressing cells formed larger and more aggressive lesions, compared to models with WT-MB21D2-expressing cells or an empty vector. Transcriptome and protein interactome analyses revealed enrichment of KRAS signaling by MB21D2 expression. Immunoblotting confirmed RAS elevation, along with upregulation/phosphorylation of PI3K, AKT, and CREB. Blocking RAS signaling in MB21D2-expressing cells by manumycin significantly reduced cell growth and survival. Our study thus defined RAS signaling-dependent pro-oncogenic roles for MB21D2 overexpression and Q311E MB21D2 expression in HNSCC development.
Assuntos
Carcinogênese/genética , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Mutação/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Animais , Apoptose/genética , Caderinas/metabolismo , Carcinogênese/patologia , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos Nus , Proteínas Mutantes/metabolismo , Proteínas de Neoplasias/metabolismo , Fenótipo , Ligação Proteica , Transdução de Sinais , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia , Ensaio Tumoral de Célula-Tronco , Regulação para Cima/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
CONTEXT: The study investigated the medicinal properties of Spathiphyllum cannifolium (Dryand. ex Sims) Schott as a possible source of antimicrobial compounds. MATERIALS AND METHODS: The phytochemical constituents were screened using qualitative methods and the antibacterial and antifungal activities were determined using agar well diffusion method. STATISTICAL ANALYSIS: One-way analysis of variance and Fisher's least significant difference test were used. RESULTS: The phytochemical screening showed the presence of sterols, flavonoids, alkaloids, saponins, glycosides, and tannins in both ethanol and chloroform leaf extracts, but triterpenes were detected only in the ethanol leaf extract. The antimicrobial assay revealed that the chloroform leaf extract inhibited Candida albicans, Escherichia coli, Staphylococcus aureus, Bacillus subtilis, and Pseudomonas aeruginosa, whereas the ethanol leaf extract inhibited E. coli, S. aureus, and B. subtilis only. The ethanol and chloroform leaf extracts exhibited the highest zone of inhibition against B. subtilis. The antifungal assay showed that both the leaf extracts have no bioactivity against Aspergillus niger and C. albicans. CONCLUSIONS: Results suggest that chloroform is the better solvent for the extraction of antimicrobial compounds against the test organisms used in this study. Findings of this research will add new knowledge in advancing drug discovery and development in the Philippines.
