ABSTRACT
Small cell lung cancer (SCLC) continues to cause poor clinical outcomes due to limited advances in sustained treatments for rapid cancer cell proliferation and progression. The transcriptional factor Forkhead Box M1 (FOXM1) regulates cell proliferation, tumor initiation, and progression in multiple cancer types. However, its biological function and clinical significance in SCLC remain unestablished. Analysis of the Cancer Cell Line Encyclopedia and SCLC datasets in the present study disclosed significant upregulation of FOXM1 mRNA in SCLC cell lines and tissues. Gene set enrichment analysis (GSEA) revealed that FOXM1 is positively correlated with pathways regulating cell proliferation and DNA damage repair, as evident from sensitization of FOXM1-depleted SCLC cells to chemotherapy. Furthermore, Foxm1 knockout inhibited SCLC formation in the Rb1fl/flTrp53fl/flMycLSL/LSL (RPM) mouse model associated with increased levels of neuroendocrine markers, Ascl1 and Cgrp, and decrease in Yap1. Consistently, FOXM1 depletion in NCI-H1688 SCLC cells reduced migration and enhanced apoptosis and sensitivity to cisplatin and etoposide. SCLC with high FOXM1 expression (N = 30, 57.7%) was significantly correlated with advanced clinical stage, extrathoracic metastases, and decrease in overall survival (OS), compared with the low-FOXM1 group (7.90 vs. 12.46 months). Moreover, the high-FOXM1 group showed shorter progression-free survival after standard chemotherapy, compared with the low-FOXM1 group (3.90 vs. 8.69 months). Our collective findings support the utility of FOXM1 as a prognostic biomarker and potential molecular target for SCLC.
Subject(s)
Biomarkers, Tumor , Forkhead Box Protein M1/genetics , Lung Neoplasms/etiology , Lung Neoplasms/mortality , Small Cell Lung Carcinoma/etiology , Small Cell Lung Carcinoma/mortality , Adult , Aged , Aged, 80 and over , Animals , Cell Line, Tumor , Cell Proliferation , Disease Models, Animal , Female , Forkhead Box Protein M1/metabolism , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Lung Neoplasms/diagnosis , Male , Mice , Mice, Transgenic , Middle Aged , Neoplasm Grading , Neoplasm Staging , Prognosis , Small Cell Lung Carcinoma/diagnosis , X-Ray Microtomography , Xenograft Model Antitumor AssaysABSTRACT
Aspartate-serine-serine (DSS) repeats are abundant in naturally occurring proteins that are critical for tooth formation. In this study, we reported a possible role of triplet repeats of aspartate-serine-serine (3DSS) peptides in promoting mineral deposition onto human enamel from free ions. Human enamel specimens were acid demineralized, exposed briefly to 3DSS peptide solution, and then immersed in artificial saliva. At various stages of treatments, nanomechanical behaviors, surface morphology, surface roughness and the sorts of deposited minerals were characterized by nanoindentation, scanning electron microscopy (SEM), atomic force microscopy (AFM) and X-ray diffraction (XRD), respectively. The results indicated that treatment with 3DSS peptide promoted the uniform deposition of apatites with small crystalline size, in terms of prohibiting deformation, which resulted in a smaller average surface roughness and higher average values of nanohardness and elastic modulus of demineralized enamel treated with 33.3 µM 3DSS peptide and immersed in artificial saliva compared to that without peptide treatment.
Subject(s)
Dental Enamel/drug effects , Dental Enamel/metabolism , Minerals/metabolism , Peptides/chemistry , Peptides/pharmacology , Repetitive Sequences, Amino Acid , Saliva, Artificial , Adult , Biomimetics , Elastic Modulus , Hardness , Humans , Microtechnology , Nanotechnology , Surface PropertiesABSTRACT
This study evaluates the influences of 8DSS peptide and ionic concentrations of simulated body fluid on remineralization behaviors. The polished enamel specimens were acid-demineralized, exposed briefly to 8DSS peptide solution, and then immersed into simulated body fluid (SBF) that favors mineral deposition. At various stages of treatment, nanohardness and elastic modulus were determined by nanoindentation. The results show that the nanomechanical properties of the acid-demineralized enamel were greatly improved as increasing the ionic concentrations of SBF due to the acceleration of mineral deposition. Additionally, the demineralized enamel, treated with 8DSS peptide and immersed into SBF×2 solution, possesses the highest values of nanohardness and elastic modulus resulting from the combinative effects of surface roughness, morphology, microstructure and crystallinity of the newly formed nanocomposite of calcium phosphate carbonate and hydroxyapatite. The formation of pores in the subsurface induced a reduction in the nanomechanical properties for the enamel subjected into SBF×3 solution.
Subject(s)
Calcification, Physiologic , Dental Enamel/physiology , Mechanical Phenomena , Nanotechnology , Adult , Biomechanical Phenomena , Biomimetic Materials/chemistry , Dental Enamel/metabolism , Elastic Modulus , Hardness , Humans , Microscopy, Atomic Force , Microscopy, Electron, Transmission , X-Ray DiffractionABSTRACT
Dental remineralization may be achieved by mediating the interactions between tooth surfaces with free ions and biomimetic peptides. We recently developed octuplet repeats of aspartate-serine-serine (DSS-8) peptide, which occurs in high abundance in naturally occurring proteins that are critical for tooth remineralization. In this paper, we evaluated the possible role of DSS-8 in enamel remineralization. Human enamel specimens were demineralized, exposed briefly to DSS-8 solution, and then exposed to concentrated ionic solutions that favor remineralization. Enamel nano-mechanical behaviors, hardness and elastic modulus, at various stages of treatment were determined by nanoindentation. The phase, microstructure and morphology of the resultant surfaces were characterized using the grazing incidence X-ray diffraction (GIXD), variable pressure scanning electron microscopy (VPSEM), and atomic force microscopy (AFM), respectively. Nanoindentation results show that the DSS-8 remineralization effectively improves the mechanical and elastic properties for demineralized enamel.
