ABSTRACT
Lysyl oxidase-like 2 (LOXL2) is a matrix-remodeling enzyme that has recently been identified as an important regulator of tumor progression and metastasis. This study discovered that LOXL2 expression in oral squamous cell carcinoma (OSCC) tissues was significantly associated with tumor clinical stage, lymph node metastasis and patients' overall survival time. LOXL2-overexpressing human buccal SCC TW2.6 (TW2.6/LOXL2) and hypopharyngeal SCC FaDu (FaDu/LOXL2) cells exhibited enhanced migration, invasion, epithelial-mesenchymal transition (EMT), and cancer stem cell (CSC) phenotypes, independently of its enzymatic activity. Moreover, TW2.6/LOXL2 significantly increased tumor-initiating frequency in SCID mice. We further demonstrated that LOXL2 increased the levels of interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) and IFIT3 in TW2.6/LOXL2 and FaDu/LOXL2 cells. We also identified IFIT1 and IFIT3 as key downstream components of LOXL2 action in migration, invasion, EMT, and CSC phenotypes in TW2.6 and FaDu cells. Furthermore, a significant positive correlation between LOXL2 expression and IFIT1 and IFIT3 overexpression in human OSCC tissues was observed. In addition, TW2.6/LOXL2 and FaDu/LOXL2 cells were 3.3- to 3.6-fold more susceptible to the epidermal growth factor receptor (EGFR) inhibitor gefitinib than were their respective control cells. The antitumor effect of gefitinib on orthotopic TW2.6/LOXL2 xenograft tumor was fourfold higher than that on controls. Our results indicate that LOXL2 expression is a strong prognostic factor for OSCC and may be used as a marker to identify patients most likely to respond to EGFR-targeted therapy.
Subject(s)
Carcinoma, Squamous Cell , Head and Neck Neoplasms , Mouth Neoplasms , Animals , Mice , Humans , Gefitinib/pharmacology , Carcinoma, Squamous Cell/pathology , Protein-Lysine 6-Oxidase , Mice, SCID , Head and Neck Neoplasms/drug therapy , Squamous Cell Carcinoma of Head and Neck/drug therapy , RNA-Binding Proteins/genetics , ErbB Receptors , Gene Expression Regulation, Neoplastic , Epithelial-Mesenchymal Transition , Cell Line, Tumor , Intracellular Signaling Peptides and ProteinsABSTRACT
BACKGROUND: There are 200-600 million betel quid (BQ) chewers in the world. BQ increases oral cancer risk. Matrix metalloproteinase-9 (MMP-9) is responsible for matrix degradation, cancer invasion and metastasis. Whether areca nut extract (ANE), a BQ component, stimulates MMP-9 secretion, and the related signaling pathways awaits investigation. RESULTS: ANE (but not arecoline) stimulated MMP-9 production of gingival keratinocytes and SAS cancer epithelial cells. ANE stimulated TGF-ß1, p-Smad2, and p-TAK1 protein expression. ANE-induced MMP-9 production/expression in SAS cells can be attenuated by SB431542 (ALK5/Smad2 inhibitor), 5Z-7-Oxozeaenol (TAK1 inhibitor), catalase, PD153035 (EGFR tyrosine kinase inhibitor), AG490 (JAK inhibitor), U0126 (MEK/ERK inhibitor), LY294002 (PI3K/Akt inhibitor), betel leaf (PBL) extract, and hydroxychavicol (HC, a PBL component), and melatonin, but not by aspirin. CONCLUSIONS: AN components contribute to oral carcinogenesis by stimulating MMP-9 secretion, thus enhancing tumor invasion/metastasis. These events are related to reactive oxygen species, TGF-ß1, Smad2-dependent and -independent signaling, but not COX. These signaling molecules can be biomarkers of BQ carcinogenesis. PBL, HC and melatonin and other targeting therapy can be used for oral cancer treatment. METHODS: ANE-induced MMP-9 expression/secretion of oral epithelial cells and related TGF-ß1, Smad-dependent and -independent signaling were studied by MTT assay, RT-PCR, western blotting, immunofluorescent staining, and ELISA.
Subject(s)
Areca , Epithelial Cells/drug effects , Matrix Metalloproteinase 9/metabolism , Plant Extracts/pharmacology , Smad2 Protein/metabolism , Transforming Growth Factor beta/metabolism , Arecoline/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Epithelial Cells/metabolism , Eugenol/analogs & derivatives , Eugenol/pharmacology , Gene Expression Regulation/drug effects , Humans , Matrix Metalloproteinase 9/genetics , Melatonin/pharmacology , Plant Extracts/chemistry , Plant Leaves/chemistry , Smad2 Protein/genetics , Transforming Growth Factor beta/geneticsABSTRACT
STATEMENT OF PROBLEM: The esthetic appearance of anatomic-contour zirconia restorations is influenced by the shade of the coloring liquid and the optical properties of the luting cements. However, few studies are available on the effects of surface-finishing methods and luting cements on colored anatomic-contour zirconia restorations. PURPOSE: The purpose of this in vitro study was to investigate the effects of surface finishing methods on the color distribution of colored anatomic-contour zirconia crowns before and after being cemented onto abutments. MATERIAL AND METHODS: Implant-supported anatomic-contour zirconia premolar crowns were fabricated and immersed in A3-coloring liquid for 30 seconds. The colored zirconia crowns were separated into 3 groups according to the method of surface treatment: no treatment (N), polishing (P), and glazing (G). The zirconia crowns without coloring liquid application served as the control group. CIELab color coordinates were obtained, and color differences (ΔE) between shaded crowns were calculated with a spectrophotometer. The color stability of the crown before and after cement application was also investigated. RESULTS: Before cement application, the mean color difference between groups N and P was 2.85 ΔE units, whereas the mean ΔE value between groups N and G was 3.27. Mean ΔE values with and without cement application among groups ranged from 2.75 to 3.45 ΔE units. CONCLUSIONS: The color appearance of the colored zirconia crowns was strongly influenced by the surface-finishing methods and luting cement application.
Subject(s)
Crowns , Dental Cements , Dental Polishing , Prosthesis Coloring , Dental Prosthesis Design , Dental Prosthesis, Implant-Supported , Humans , Surface Properties , ZirconiumABSTRACT
A novel biodegradable amphiphilic brush-coil block copolymer consisting of poly(epsilon-caprolactone) and PEGylated polyphosphoester was synthesized by ring opening polymerization. The composition and structure of the copolymer were characterized by 1H NMR, 13C NMR, and FT-IR, and the molecular weight and molecular weight distribution were analyzed by gel permeation chromatograph (GPC) measurements to confirm the diblock structure. These amphiphilic copolymers formed micellar structures in water, and the critical micelle concentrations (CMCs) were around 10(-3) mg/mL, which was determined using pyrene as a fluorescence probe. Transmission electron microscopy (TEM) images showed that the micelles took an approximately spherical shape with core-shell structure, which was further demonstrated by laser light scattering (LLS) technique. The degradation behavior of the polymeric micelle was also investigated in the presence of Pseudomonas lipase and characterized by GPC measurement. Such polymer micelles from brush-coil block copolymers are expected to have wide utility in the field of drug delivery.
