[Show abstract][Hide abstract] ABSTRACT: High expression of immunoglobulin G (IgG) in many non-B cell malignancies and its non-conventional roles in promoting proliferation and survival of cancer cells have been demonstrated. However, the precise function of non-B IgG remains incompletely understood. Here we define the antigen specificity of RP215, a monoclonal antibody that specifically recognizes the IgG in cancer cells. Using RP215, our study shows that IgG is overexpressed in cancer cells of epithelial lineage, especially cells with cancer stem/progenitor cell-like features. The RP215-recognized IgG is primarily localized on the cell surface, particularly lamellipodia-like structures. Cells with high IgG display higher migration, increased invasiveness and metastasis, and enhanced self-renewal and tumorgenecity ability in vitro and in vivo. Importantly, depletion of IgG in breast cancer leads to reduced adhesion, invasion and self-renewal and increased apoptosis of cancer cells. We conclude that high expression of IgG is a novel biomarker of tumor progression, metastasis and cancer stem cell maintenance and demonstrate the potential therapeutic benefits of RP215-recognized IgG targeted strategy.
[Show abstract][Hide abstract] ABSTRACT: Cancer cell-derived IgG (cancer-IgG) has been found to be involved in the pathogenesis and progression of many cancers, including lung cancer. The aim of the present study was to investigate the relationship between cancer-IgG expression in lung adenocarcinoma (ADC) and clinicopathological characteristics and clinical outcome.
Immunohistochemical analysis was performed using an RP215 monoclonal antibody to determine cancer-IgG expression in 140 lung ADC patients. Cell migration and invasion were analyzed in A549 cell line after siRNA knockdown of IgG and cell sorting by flow cytometry. Our results show that RP215 immunostaining score is significantly correlated with local invasion (P < 0.05) and tumor differentiation (P < 0.05) in ADC. Moreover, RP215 staining was significantly higher in metastatic tumors than in primary tumors (P < 0.0001). The knockdown of IgG resulted in a reduction of cell migration and invasion. In contrast, RP215(+) cells displayed greater migration and invasion ability than RP215(-) cells. Additionally, a higher RP215 immunostaining score was significantly associated with poor prognosis.
RP215 staining is strongly correlated with differentiation, local invasion, metastasis, and clinical outcome of patients with lung ADC. Our results suggest that RP215 can serve as a biomarker for prognosis of lung ADC. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: The innate immune system of the skin is thought to depend largely on a multi-layered mechanical barrier supplemented by epidermis-derived antimicrobial peptides. To date, there are no reports of antimicrobial antibody secretion by the epidermis. In this study, we report the expression of functional immunoglobulin G (IgG) and immunoglobulin A (IgA), previously thought to be only produced by B cells, in normal human epidermal cells and the human keratinocyte line HaCaT. While B cells express a fully diverse Ig, epidermal cell-expressed IgG or IgA showed one or two conservative VHDJH rearrangements in each individual. These unique VDJ rearrangements in epidermal cells were found neither in the B cell-derived Ig VDJ databases published by others nor in our positive controls. IgG and IgA from epidermal cells of the same individual had different VDJ rearrangement patterns. IgG was found primarily in prickle cells, and IgA was mainly detected in basal cells. Both epidermal cell-derived IgG and IgA showed potential antibody activity by binding pathogens like Staphylococcus aureus, the most common pathogenic skin bacteria, but the microbial-binding profile was different. Our data indicates that normal human epidermal cells spontaneously express IgG and IgA, and we speculate that these Igs participate in skin innate immunity.
Full-text · Article · Feb 2015 · International Journal of Molecular Sciences
[Show abstract][Hide abstract] ABSTRACT: Non-B cell immunoglobulins (Igs) are widely expressed in epithelial cancer cells. The past 20 years of research have demonstrated that non-B cell Igs are associated with cancer cell proliferation, the cellular cytoskeleton and cancer stem cells. In this study we explored the transcriptional mechanism of IgM production in non-B cells.
The promoter region of a V-segment of the heavy mu chain gene (VH6-1) was cloned from a colon cancer cell line HT-29. Next, the promoter activities in non-B cells and B-cells were detected using the dual-luciferase reporter assay. Then the transcription factor binding to the promoter regions was evaluated by electrophoretic mobility shift assays (EMSAs) and gel supershift experiments.
Our data showed that the sequence 1200 bp upstream of VH6-1 exhibited promoter activity in both B and non-B cells. No new regulatory elements were identified within the region 1200 bp to 300 bp upstream of VH6-1. In addition, Oct-1 was found to bind to the octamer element of the Ig gene promoter in cancer cells, in contrast to B cells, which utilize the transcriptional factor Oct-2.
The regulatory mechanisms among different cell types controlling the production of IgM heavy chains are worth discussing.
Preview · Article · Dec 2014 · Cancer Cell International
[Show abstract][Hide abstract] ABSTRACT: CCDC134 is a poorly characterized secreted protein that may act as an immune cytokine. Here we show that CCDC134 is differentially expressed on resting and activated immune cells and that it promotes CD8+ T cell activation, proliferation and cytotoxicity by augmenting expression of the T cell effector molecules IFN-γ, TNF-α, granzyme B and perforin. CCDC134 facilitated infiltration of CD8+ T cells with enhanced cytolytic activity into tumors, demonstrating strong antitumor effects in a CD8+ T cell-dependent manner. Mechanistically, in CD8+ T cells exposure to CCDC134 promoted cell proliferation through the JAK3-STAT5 pathway, a classic feature of many cytokines of the common γ-chain (γc) cytokine receptor family. Overall, our results provide evidence that CCDC134 may serve as a member of the γc cytokine family, and they show illustrate its potent antitumor effects by augmenting CD8+ T cell-mediated immunity.
[Show abstract][Hide abstract] ABSTRACT: Immunoglobulin (Ig), a characteristic marker of B cells, has been reported to be expressed in epithelial cells, with a suggested role in their growth and survival. We have previously reported that IgG heavy chain is expressed in acute myeloid leukemia (AML), but not in the monocytes or neutrophils from patients with non-hematopoietic neoplasms or healthy controls. In the present study, we assessed IgM heavy chain expression and repertoire in human myeloid cells. We detected VHμDJHμ rearrangement and expression in 7/7 AML cell lines, 7/14 primary myeloblasts from AML patients, and interestingly, 8/20 monocytes and 3/20 neutrophils from patients with non-hematopoietic neoplasms and healthy individuals. We also found evidence of somatic hypermutation of the variable (V) gene segments in AML-derived IgM gene rearrangements but not in IgM from monocytes or neutrophils from patients with non-hematopoietic neoplasms and healthy individuals. Furthermore, IgM VHμDJHμ gene rearrangements in AML cell lines, primary myeloblasts, and monocytes and neutrophils from patients with non-hematopoietic neoplasms showed a restricted V usage and repertoire, whereas the VHμDJHμ gene rearrangements in monocytes and neutrophils from healthy individuals displayed more diversity. Anti-human IgM inhibited cell proliferation, but did not induce apoptosis in AML cell lines. Our findings suggest that AML-derived IgM might be a novel AML-related molecule that is involved in leukemogenesis and AML progression and might serve as a useful molecular marker for designing targeted therapy and monitoring minimal residual disease.Cellular & Molecular Immunology advance online publication, 21 October 2013; doi:10.1038/cmi.2013.45.
[Show abstract][Hide abstract] ABSTRACT: It is well known that B-1 B cells are the main cell type that is responsible for the production of natural immunoglobulin M (IgM) and can respond to infection by increasing IgM secretion. However, we unexpectedly found that some epithelial cells also can express rearranged IgM transcript that has natural IgM characteristics, such as germline-encoded and restricted rearrangement patterns. Here we studied IgM expression in human non-B cells and found that IgM was frequently expressed by many human epithelial cancer cells as well as non-cancer epithelial cells. Moreover, CD79A and CD79B, two molecules that are physically linked to membranous IgM on the surface of B cells to form the B cell antigen receptor complex, were also expressed on the cell surface of epithelial cancer cells and co-located with IgM. Like the natural IgM, the epithelial cancer cell-derived IgM recognized a series of microbial antigens, such as single-stranded DNA, double-stranded DNA, lipopolysaccharide, and the HEp-2 cell antigen. More important, stimulation of the toll-like receptor 9 (TLR9), which mimics bacterial infection, substantially increased the secretion of IgM in human epithelial cancer cells. These findings indicate that human epithelial cancer cells as well as non-cancer epithelial cells can spontaneously produce IgM with natural antibody activity.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to synthesize, characterize and tailor the surface properties of magnetic nanoparticles with biocompatible copolymer coatings and to evaluate the efficiency of the resulting nanoconjugates as magnetic resonance imaging (MRI) contrast agents for liver imaging. Magnetic nanoparticles with core diameters of 10 and 30 nm were synthesized by pyrolysis and were subsequently coated with a copolymer containing either carboxyl (SHP) or methoxy groups as termini. All four formulas, and ferumoxides (Feridex I.V.(®)), were individually injected intravenously into separate, normal Balb/C mice (at 2.5, 1.0 and 0.56 mg Fe kg(-1)), and the animals underwent T(2)-weighted MRI at multiple time points post injection (p.i.) to evaluate the hepatic uptake and clearance. Furthermore, we compared the abilities of the new formulas and Feridex to detect tumors in an orthotropic Huh7 tumor model. Transmission electron microscopy (TEM) revealed a narrow size distribution of both the 10 and 30 nm nanoparticles, in contrast to a wide size distribution of Feridex. MTT, apoptosis and cyclin/DNA flow cytometry assays showed that the polymer coated nanoparticles had no adverse effect on cell growth. Among all the tested formulas, including Feridex, SHP-30 showed the highest macrophage uptake at the in vitro level. In vivo MRI studies on normal mice confirmed the superiority of SHP-30 in inducing hypointensities in the liver tissue, especially at clinical dose (0.56 mg Fe kg(-1)) and 3 T field. SHP-30 showed better contrast-to-noise ratio than Feridex on the orthotropic Huh7 tumor model. SHP-30 was found to be an efficient contrast agent for liver MR imaging. The success of this study suggests that, by improving the synthetic approach and by tuning the surface properties of IONPs, one can arrive at better formulas than Feridex for clinical practice.
No preview · Article · Jul 2012 · Contrast Media & Molecular Imaging
[Show abstract][Hide abstract] ABSTRACT: Human transcriptional adaptor hADA2a is an important component of the general control nonderepressible 5 (GCN5) histone acetyltransferase complex. Here, we report that coiled-coil domain containing 134 (CCDC134), a novel nuclear protein, binds to hADA2a and enhances the stability of the hADA2a protein in unstressed conditions. Furthermore, CCDC134 was found to participate in the p300/CBP-associated factor (PCAF) complex via hADA2a and affect the histone acetyltransferase activity of the complex. We also found that CCDC134 increased the PCAF-dependent K320 acetylation of p53 and p53 protein stability in the presence of hADA2a overexpression. Moreover, we demonstrated the biological significance of the interaction between CCDC134 and hADA2a. CCDC134 showed obvious nuclear accumulation after ultraviolet (UV) irradiation, and the knockdown of endogenous CCDC134 suppressed hADA2a-induced cell apoptosis activity and G1/S cell cycle arrest. Together, our findings indicate that CCDC134 might act as a novel regulator of hADA2a, and plays roles in the PCAF complex via hADA2a to affect its acetyltransferase activity and UV-induced DNA damage repair.
[Show abstract][Hide abstract] ABSTRACT: The tumor suppressor protein p53 is a well-known transcription factor that functions as a critical component of the genotoxic
stress response via regulating the expression of effector proteins that control cellular fate following DNA damage. The human p300/CBP-associated
factor (PCAF)-containing histone acetyltransferase (HAT) complex is important for the stability and activity of p53 via its acetylation. The human homolog of yeast alteration/deficiency in activation 2a (ADA2a) is a stable component of the human
PCAF-containing HAT complex. In this study, we demonstrated that p53 and hADA2a physically interact with each other in human
HEK 293T cells. Using overexpression and small interfering RNA-mediated knockdown, we demonstrated that hADA2a stabilizes
p53 via promoting its acetylation at lysine 320 — a PCAF-dependent acetylation site. Furthermore, hADA2a can potentiate the transcriptional
activity of p53 at the BAX and p21 promoters to induce cell apoptosis and cell cycle arrest. Overall, our results establish that hADA2a, a component of the
PCAF-containing histone acetyltransferase co-activator complex, is a mediator of acetylation-dependent stabilization and activation
of p53 in mammalian cells.
Full-text · Article · Feb 2011 · Chinese Science Bulletin
[Show abstract][Hide abstract] ABSTRACT: The effect of nanoparticle size (30-120 nm) on magnetic resonance imaging (MRI) of hepatic lesions in vivo has been systematically examined using polyvinylpyrrolidone (PVP)-coated iron oxide nanoparticles (PVP-IOs). Such biocompatible PVP-IOs with different sizes were synthesized by a simple one-pot pyrolysis method. These PVP-IOs exhibited good crystallinity and high T(2) relaxivities, and the relaxivity increased with the size of the magnetic nanoparticles. It was found that cellular uptake changed with both size and surface physiochemical properties, and that PVP-IO-37 with a core size of 37 nm and hydrodynamic particle size of 100 nm exhibited higher cellular uptake rate and greater distribution than other PVP-IOs and Feridex. We systematically investigated the effect of nanoparticle size on MRI of normal liver and hepatic lesions in vivo. The physical and chemical properties of the nanoparticles influenced their pharmacokinetic behavior, which ultimately determined their ability to accumulate in the liver. The contrast enhancement of PVP-IOs within the liver was highly dependent on the overall size of the nanoparticles, and the 100 nm PVP-IO-37 nanoparticles exhibited the greatest enhancement. These results will have implications in designing engineered nanoparticles that are optimized as MR contrast agents or for use in therapeutics.
[Show abstract][Hide abstract] ABSTRACT: Hollow nanospheres of Sn–Sb–Cu alloy composites have been successfully synthesized via co-reduction of metal chlorides in aqueous alkaline solution without using any surfactants or solid templates. A bubble assisted growth mechanism is proposed to account for the formation of the hollow nanostructures. The concentration of the reactants kinetically controls the nucleation rate of the alloy nuclei, making for the formation of the hollow nanospheres. Compared with the alloy nanoparticles, the hollow spheres exhibit relatively high electrochemical capacity and good cyclic retention when used as anode materials for lithium-ion batteries. The bubble assisted synthesis method can be readily explored for fabricating hollow nanostructure of other alloy system for functional material applications.
No preview · Article · Oct 2010 · Journal of Power Sources
[Show abstract][Hide abstract] ABSTRACT: We report in this Communication a facile, two-step surface modification strategy to achieve manganese oxide nanoparticles with prominent MRI T1 contrast. In a U87MG glioblastoma xenograft model, we confirmed that the particles can accumulate efficiently in tumor area to induce effective T1 signal alteration.
Full-text · Article · Sep 2010 · Chemical Communications
[Show abstract][Hide abstract] ABSTRACT: The restriction of immunoglobulin (Ig) expression to B lymphocytes is well established. However, several reports have confirmed that the Ig gene can be expressed in many non-B cancer cells and/or some normal cells. Our aim is to determine whether the Ig gene promoter can be activated in non-B cancer cells and to identify the regulatory mechanism for Ig gene expression. Our results show that the Ig promoter of VH4-59 was activated in several non-B cancer cell lines. Moreover, two novel positive regulatory elements, an enhancer-like element at -800 to -610 bp and a copromoter-like element at -610 to -300 bp, were identified in two epithelial cancer cell lines, HeLa S3 and HT-29. The octamer element (5'-ATGCAAAT-3') located in the Ig promoter, a crucial element for B-cell-derived Ig gene transcription, was also very important for non-B-cell-derived Ig gene transcription. More importantly, we confirmed that octamer-related protein-1 (Oct-1), but not Oct-2, was a crucial transcriptional factor for Ig gene transcription due to its ability to bind to the octamer element of the Ig promoter in epithelial cancer cells. These results suggested the presence of a distinct regulatory mechanism for Ig gene expression in non-B cancer cells.
[Show abstract][Hide abstract] ABSTRACT: Engineered nanoparticles with theranostic functions have attracted a lot of attention for their potential role in the dawning era of personalized medicine. Iron oxide nanoparticles (IONPs), with their advantages of being non-toxic, biodegradable and inexpensive, are candidate platforms for the buildup of theranostic nanostructures; however, progress in using them has been limited largely due to inefficient drug loading and delivery. In the current study, we utilized dopamine to modify the surface of IONPs, yielding nanoconjugates that can be easily encapsulated into human serum albumin (HSA) matrices (clinically utilized drug carriers). This nanosystem is well-suited for dual encapsulation of IONPs and drug molecules, because the encapsulation is achieved in a way that is similar to common drug loading. To assess the biophysical characteristics of this novel nanosystem, the HSA coated IONPs (HSA-IONPs) were dually labeled with (64)Cu-DOTA and Cy5.5, and tested in a subcutaneous U87MG xenograft mouse model. In vivo positron emission tomography (PET)/near-infrared fluorescence (NIRF)/magnetic resonance imaging (MRI) tri-modality imaging, and ex vivo analyses and histological examinations were carefully conducted to investigate the in vivo behavior of the nanostructures. With the compact HSA coating, the HSA-IONPs manifested a prolonged circulation half-life; more impressively, they showed massive accumulation in lesions, high extravasation rate, and low uptake of the particles by macrophages at the tumor area.
[Show abstract][Hide abstract] ABSTRACT: Co/Co9S8/ZnO core-shell nanoshperes were successfully prepared via a thermal decomposition in the water and oxygen-free environmert. The lattice-match between Co9S8 and ZnO played a significant role on the layer-by-layer self-assembly of the core-shell nanospheres. The as-synthesized nanospheres were characterized by XRD, TEM, SQUID and Photoluminescence Spectra. By controlling the reaction parameters, the core-shell nanostructure with uniform size of about 60 nm and shell thickness of 13.6nm was obtained. The effects on the shape control of the product were further investigated, and a proper formation mechanism of the Co/Co9S8/ZnO core-shell nanostructures was presumed. The results show that the favorable procedure to obtain the core-shell nanostructure shape is as follows, the reactants of OLA as solution and TOPO as surfactant, and the optimal temperature and quantity for precursor Zn(acac)2 is 70°C and 1mmol, respectively. In additon, the sulfidation reaction time for Co is 5 min. The products show ferromagnetism at room temperature with a coercive force of 18.7kA/m. In the photoluminescence measurement, the strongest peak at 460nm which is attributed to oxygen defects can be obtained, while the band edge transitions of ZnO between 380nm and 390nm can hardly be observed.
No preview · Article · Mar 2010 · Journal of Inorganic Materials
[Show abstract][Hide abstract] ABSTRACT: It has been believed that the immunoglobulin (Ig) found abundantly in the colostrum of lactating mammalian is derived from serum or secreted by plasma cells present in the mammary gland. The recent finding of Ig gene rearrangements in breast cancer cells and benign hyperplastic breast epithelial cells suggests that it is likely that hyperplastic mammary gland epithelial cells during lactation can also produce Ig. In this study, we have demonstrated the presence of abundant amounts of Ig heavy and light chain transcripts in sorted cytokeratin 18-positive mammary gland epithelial cells of lactating mice. Interestingly, we found two specific Igkappa variable region sequences (V(CW9)J(kappa1) and V(BV9)J(kappa1)) that were dominantly expressed in different strains of mice. Our data demonstrate that IgG is expressed by mammary gland epithelial cells of lactating mice, and suggest that the IgG found in murine colostrum is at least partially produced by the mammary gland epithelial cells.
No preview · Article · Mar 2010 · Cellular and Molecular Life Sciences CMLS
[Show abstract][Hide abstract] ABSTRACT: A novel dopamine-plus-HSA (human serum albumin) approach was developed to functionalize iron oxide nanoparticles (IONPs), yielding nanoconjugates that are highly efficient in labeling various types of cell lines, which was demonstrated by in vivo MR imaging on xenograft and focal cerebral ischemia models.
Full-text · Article · Jan 2010 · Chemical Communications
[Show abstract][Hide abstract] ABSTRACT: One-dimensional (1D) chainlike arrays of hollow magnetic Fe3O4 spheres have been prepared by simply aging magnetically preassembled Fe nanoparticles in aqueous solution at room temperature. The diameter of the 1D nanomaterials is about 100−200 nm, and the length is up to 1−3 μm, observed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The structure and magnetic properties of the Fe3O4 hollow chains were characterized by X-ray powder diffraction (XRD) and via a superconducting quantum interference device (SQUID) magnetometer. Mechanism investigations on the time dependent process reveal these hollow nanostructures were formed based on the nanoscale Kirkendall effect. Besides the aqueous microenvironment, the partial pressure of oxygen is of great importance in the formation of 1D chainlike Fe3O4 hollow nanostructures.
Full-text · Article · Jul 2009 · The Journal of Physical Chemistry C