RESUMEN
OBJECTIVE: This study was designed to investigate the expression of syndecan-1 (Sdc-1), protein kinase C (PKC) and vascular endothelial growth factor (VEGF) in rats with acute kidney injury, as well as the association between Sdc-1 and indicators [such as serum creatinine (Scr) and blood urea nitrogen (BUN)] related to renal function. MATERIALS AND METHODS: A total of 120 clean grade 2-week-old SD rats were selected and randomized into experimental group and control group (n=60). At 12 h (T1), 24 h (T2), 36 h (T3), 48 h (T4) after the model was established, 3 mL blood from abdominal aorta was taken, and Sdc-1, PKC, VEGF, serum creatinine (Scr), urea nitrogen (BUN) and other indicators were detected by Enzyme-Linked Immunosorbent Assay (ELISA). RESULTS: The expression levels of Sdc-1, PKC and VEGF in the experimental group were increasing from T1 to T4, with statistically significant difference between every two time points (p<0.05); the expression levels of Scr and BUN in the experimental group was increasing from T1 to T4, with statistically significant difference between every two time points (p<0.05). The level of Sdc-1 in the serum of rats in the experimental group was positively correlated with Scr (r=0.668, p<0.001), negatively correlated with BUN (r=0.722, p<0.001), and positively correlated with BUN (r=0.722, p<0.001); PKC level was positively correlated with Scr (r=0.589, p<0.001), BUN (r=0.788, p<0.001), and VEGF level was positively correlated with Scr (r=0.666, p<0.001), BUN (r=0.784, p<0.001). CONCLUSIONS: As the concentration of syndecan-1 increases gradually, renal dysfunction aggravates accordingly, so syndecan-1 can be used as a marker of acute kidney injury and can be used to judge the degree of kidney injury at an early stage.
Asunto(s)
Lesión Renal Aguda/metabolismo , Riñón/metabolismo , Proteína Quinasa C/biosíntesis , Sindecano-1/biosíntesis , Factor A de Crecimiento Endotelial Vascular/biosíntesis , Lesión Renal Aguda/patología , Animales , Modelos Animales de Enfermedad , Riñón/patología , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVE: Long non-coding RNA (lncRNA) is closely associated with cancer occurrence and tumor development. However, the biological function of lncRNA ZNFX1-AS1 has not yet been reported in bladder cancer. The present study aimed to study the function of ZNFX1-AS1 in bladder cancer cells and the mechanism involved. PATIENTS AND METHODS: The expression of ZNFX1-AS1 in bladder cancer tumor tissues and cell lines was examined by qRT-PCR. The effects of ZNFX1-AS1 knockdown on cell proliferation, cell cycle, cell migration, and invasion were assessed by Cell Counting Kit-8, flow cytometry (FCM), and transwell assays. Bioinformatics analyses and Luciferase reporter assays were performed to explore the mechanism by which ZNFX1-AS1 exerted its oncogenesis role in bladder cancer. The anti-tumor effect of ZNFX1-AS1 silencing on bladder cancer in vivo was also evaluated. RESULTS: ZNFX1-AS1 was over-expressed in bladder cancer tumor tissues and cell lines. ZNFX1-AS1 expression was found to be associated with tumor size and advanced clinical stage in patients with bladder cancer. Downregulation of ZNFX1-AS1 inhibited cell proliferation, cell clone formation, migration, and invasion of bladder cancer cells. ZNFX1-AS1 was found to interact with miR-193a-3p/Syndecan 1 (SDC1). ZNFX1-AS1 expression was negatively correlated with miR-193a-3p expression, but positively correlated with SDC1 expression in bladder cancer samples. ZNFX1-AS1 knockdown also effectively suppressed tumor growth in an in vivo xenograft model. CONCLUSIONS: ZNFX1-AS1 regulated bladder cancer progression by targeting the miR-193a-3p/SDC1 axis. Our study may provide novel insights for bladder cancer prognosis and therapy.
Asunto(s)
Antígenos de Neoplasias/biosíntesis , Movimiento Celular/fisiología , Proliferación Celular/fisiología , MicroARNs/biosíntesis , Sindecano-1/biosíntesis , Neoplasias de la Vejiga Urinaria/metabolismo , Animales , Línea Celular Tumoral , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica/patología , Neoplasias de la Vejiga Urinaria/patología , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
Syndecan-1 (CD138) is a transmembrane proteoglycan expressed in normal and malignant tissues. It is of interest because of a possible prognostic effect in tumors and as a target for Indatuximab, a monoclonal antibody coupled to a cytotoxic agent. To assess the prognostic role of CD138 expression in breast cancer (BCa), a tissue microarray containing 1535 BCa specimens was analyzed by immunohistochemistry. Cytoplasmic, membranous, and stromal CD138 staining was separately analyzed. In normal breast tissue, CD138 staining was limited to epithelial cell membranes. In cancers, membranous staining tended to become weaker or even disappeared (38.3% of cancers with absence of membranous staining) but cytoplasmic and stromal staining newly appeared in 29.7% and 58.1% of cancers. Loss of membranous epithelial CD138 staining as well as presence of cytoplasmic and stromal CD138 positivity were-to a variable degree-associated with high pT, high grade, nodal metastasis, estrogen receptor-negative, progesterone receptor-negative, human epidermal growth factor receptor 2+, and poor overall patient survival. A combined analysis of epithelial and stromal CD138 expression revealed a link to overall patient survival (P < .0001) with best prognosis for patients with stromal positivity and absence of cytoplasmic staining, the worst prognosis for cancers with cytoplasmic staining and stromal negativity and intermediate prognosis for patients having either cytoplasmic staining or stromal negativity. In multivariate analyses, CD138 was not independent of established prognostic features. In summary, these data reveal a compartment depending prognostic effect of CD138 expression in BCa with cytoplasmic positivity being linked to aggressive cancer and stromal CD138 being linked to a more favorable prognosis.
Asunto(s)
Biomarcadores de Tumor/biosíntesis , Neoplasias de la Mama/metabolismo , Membrana Celular/metabolismo , Citoplasma/metabolismo , Células del Estroma/metabolismo , Sindecano-1/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Células Epiteliales/metabolismo , Femenino , Humanos , Inmunoconjugados/uso terapéutico , Inmunohistoquímica , Maitansina/análogos & derivados , Maitansina/uso terapéutico , Persona de Mediana Edad , Terapia Molecular Dirigida , Pronóstico , Análisis de Supervivencia , Sindecano-1/antagonistas & inhibidores , Análisis de Matrices Tisulares/métodos , Adulto JovenRESUMEN
BACKGROUND: The endothelial glycocalyx, located at the interface of vascular lumen, is a carbohydrate-rich complex that controls vascular functions such as solute permeation and mechanotransduction. It anchors to the cell membrane through core proteins, e.g. syndecan-1, which couple to the actin cytoskeleton. Membrane tension plays an important role in the reorganisation of membrane-bound proteins, however, little is known on the effect of the membrane tension on the various components of the glycocalyx. METHODS: Hypo-osmotic stress is used to investigate the effect of the membrane tension on syndecan-1 expression. RESULTS: Following 20â¯min exposure to hypo-osmotic medium, the expression of syndecan-1 in the endothelial glycocalyx layer is reduced to 84.7⯱â¯3.6% (255â¯mOsm) and 64.7⯱â¯2.1% (167â¯mOsm). This reduction, however, is transient and partial recovery is observed at the end of 2â¯h exposure to the hypo-osmotic medium. The transient reduction of syndecan-1 is associated with depolymerisation of the actin cytoskeleton. Further examination of the effect of actin manipulation reveals that actin depolymerisation by cytochalasin D results in sustained syndecan-1 reduction. In contrast, stabilising actin using jasplakinolide abolishes the transient reduction of syndecan-1completely. CONCLUSIONS: We demonstrate, for the first time, that membrane tension plays an important role in the regulation of syndecan-1 expression and this effect is mediated by the reorganisation of the actin cytoskeleton. GENERAL SIGNIFICANCE: Findings in this study suggest a new venue of research on the protective role of the glycocalyx in vascular pathophysiology and diseases.
Asunto(s)
Citoesqueleto de Actina/metabolismo , Actinas/metabolismo , Membrana Celular/metabolismo , Regulación de la Expresión Génica , Presión Osmótica , Sindecano-1/biosíntesis , Glicocálix/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Tensión SuperficialAsunto(s)
Regulación Neoplásica de la Expresión Génica , Mieloma Múltiple/metabolismo , Proteínas de Neoplasias/biosíntesis , Sindecano-1/biosíntesis , Transcriptoma , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/patología , Mieloma Múltiple/terapiaRESUMEN
INTRODUCTION: Syndecan-1 is heparan sulfate proteoglycans (HSPGs) that is used as coreceptors for signaling of growth factors. The comprehensive effect of syndecan-1 is to augment receptor stimulation at little ligand concentrations. THE GOAL OF THIS RESEARCH: is to study syndecan-1 expression in breast carcinoma and its value in predicting the prognosis in comparison to other clinicopathological parameters. MATERIAL &METHODS: immunohistochemistry study for syndecan-1 is done on 103 cases of invasive breast carcinoma. Its expression is assessed and correlated to other clinicopathological parameters and prognosis. RESULTS: overexpression was significantly related to high histologic grade (p = 0.001), large tumor size (p = 0.043), HER2-positive status (p = 0.001), and ER&PR-negative status (p = 0.001). It was also have a negative impact on the overall survival (p=0.012) and disease free survival (p = 0.009). Syndecan-1 expression showed weak positive correlation with Her 2 expression (Correlation Coefficient (co): 0.332, p = 0.001). CONCLUSION: syndecan-1 is a good predictor of poor overall survival and recurrence/ metastasis free survival. It is associated with aggressive phenotype as HER2 enriched and Triple negative rather than luminal subtypes of breast carcinoma. So it can be added to the hormonal receptors and HER 2 assay in the routine management of invasive breast cancer after confirmation on a more larger study.
Asunto(s)
Biomarcadores de Tumor/análisis , Neoplasias de la Mama/patología , Carcinoma/patología , Sindecano-1/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/mortalidad , Carcinoma/mortalidad , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Pronóstico , Receptor ErbB-2/análisis , Receptor ErbB-2/biosíntesis , Receptores de Estrógenos/análisis , Receptores de Estrógenos/biosíntesis , Receptores de Progesterona/análisis , Receptores de Progesterona/biosíntesis , Estudios Retrospectivos , Sindecano-1/análisisRESUMEN
Objective: The aim of this study was to evaluate the relation between the rate of fluorine-18 (18F) fludeoxyglucose (FDG) uptake and CD38 and CD138 expression in myeloma cells in bone marrow and other clinical parameters in patients with multiple myeloma (MM). Materials and Methods: Patients with the diagnosis of MM who underwent 18F-FDG positron emission tomography/computed tomography (PET/CT) for initial staging were evaluated retrospectively. We analyzed a total of 42 patients (43-83 years old, mean: 64.4±9.9). Hematological and biochemical tests including hemoglobin, hematocrit, C-reactive protein, ß2-microglobulin, creatinine, albumin, calcium, lactate dehydrogenase, and erythrocyte sedimentation rate were recorded. In bone marrow samples, plasma cell ratio and CD38 and CD138 immunohistochemical staining were evaluated. On PET/CT images, mean standardized uptake values (SUVmean) of the right anterior and posterior iliac crest and right proximal femora were calculated. The correlations between the average SUVmean of bone marrow and CD38- and CD138-expressing myeloma cells and other parameters were analyzed by Spearman's correlation test. Values of p<0.05 were considered statistically significant. Results: Types of MM were IgGK (45%), IgGL (21%), IgAK (7%), IgAL (10%), and others (17%). Thirty-two (76%) patients were at stage III according to the Salmon-Durie staging system. There was a statistically significant positive correlation between bone marrow FDG uptake and percentage of plasma cells in bone marrow and CD38 and CD138 expression in plasma cells (r=0.403, r=0.339, and r=0.409) and ß2-microglobulin and C-reactive protein levels (r=0.676, r=0.541). There was a negative correlation between bone marrow FDG uptake and hemoglobin and hematocrit values (r=-0.377 and r=-0.368). Other hematological parameters were not correlated with FDG uptake in bone marrow. Conclusion: Increased FDG uptake is correlated with the percentage of CD38 and CD138 expression in plasma cells in bone marrow. In addition to initial staging, 18F-FDG PET/CT is useful in treatment planning and prognostic evaluation in MM patients.
Asunto(s)
ADP-Ribosil Ciclasa 1/biosíntesis , Fluorodesoxiglucosa F18/farmacocinética , Glicoproteínas de Membrana/biosíntesis , Mieloma Múltiple/diagnóstico por imagen , Mieloma Múltiple/metabolismo , Sindecano-1/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Médula Ósea/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/patología , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radiofármacos/farmacocinética , Estudios RetrospectivosRESUMEN
INTRODUCTION: Therapeutic options for multiple myeloma (MM) are growing, yet clinical outcomes remain heterogeneous. Cytogenetic analysis and disease staging are mainstays of risk stratification, but data suggest a complex interplay between numerous abnormalities. Myeloma cell proliferation is a metric shown to predict outcomes, but available methods are not feasible in clinical practice. PATIENTS AND METHODS: Multiplex immunohistochemistry (mIHC), using multiple immunostains simultaneously, is universally available for clinical use. We tested mIHC as a method to calculate a plasma cell proliferation index (PCPI). By mIHC, marrow trephine core biopsy samples were costained for CD138, a plasma cell-specific marker, and Ki-67. Myeloma cells (CD138+) were counted as proliferating if coexpressing Ki-67. Retrospective analysis was performed on 151 newly diagnosed, treatment-naive patients divided into 2 groups on the basis of myeloma cell proliferation: low (PCPI ≤ 5%, n = 87), and high (PCPI > 5%, n = 64). RESULTS: Median overall survival (OS) was not reached versus 78.9 months (P = .0434) for the low versus high PCPI groups. Multivariate analysis showed that only high-risk cytogenetics (hazard ratio [HR] = 2.02; P = .023), International Staging System (ISS) stage > I (HR = 2.30; P = .014), and PCPI > 5% (HR = 1.70; P = .041) had independent effects on OS. Twenty-three (36%) of the 64 patients with low-risk disease (ISS stage 1, without high-risk cytogenetics) were uniquely reidentified as high risk by PCPI. CONCLUSION: PCPI is a practical method that predicts OS in newly diagnosed myeloma and facilitates broader use of MM cell proliferation for risk stratification.
Asunto(s)
Proliferación Celular , Inmunohistoquímica/métodos , Mieloma Múltiple/patología , Células Plasmáticas/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/biosíntesis , Femenino , Humanos , Estimación de Kaplan-Meier , Antígeno Ki-67/biosíntesis , Masculino , Persona de Mediana Edad , Índice Mitótico , Mieloma Múltiple/metabolismo , Células Plasmáticas/metabolismo , Estudios Retrospectivos , Factores de Riesgo , Sindecano-1/biosíntesisRESUMEN
An up-regulated CXCR3 pathway and affluent plasma cell infiltration are characteristic features of Hunner type interstitial cystitis (HIC). We further examined these two features using bladder biopsy samples taken from 27 patients with HIC and 15 patients with non-IC cystitis as a control. The number of CD3-positive T lymphocytes, CD20-positive B lymphocytes, CD138-positive plasma cells, and CXCR3-positive cells was quantified by digital image analysis. Double-immunofluorescence for CXCR3 and CD138 was used to detect CXCR3 expression in plasma cells. Correlations between CXCR3 positivity and lymphocytic and plasma cell numbers and clinical parameters were explored. The density of CXCR3-positive cells showed no significant differences between HIC and non-IC cystitis specimens. However, distribution of CXCR3-positivity in plasma cells indicated co-localization of CXCR3 with CD138 in HIC specimens, but not in non-IC cystitis specimens. The number of CXCR3-positive cells correlated with plasma cells in HIC specimens alone. Infiltration of CXCR3-positive cells was unrelated to clinical parameters of patients with HIC. These results suggest that infiltration of CXCR3-positive plasma cells is a characteristic feature of HIC. The CXCR3 pathway and specific immune responses may be involved in accumulation/retention of plasma cells and pathophysiology of the HIC bladder.
Asunto(s)
Cistitis Intersticial/metabolismo , Cistitis/metabolismo , Células Plasmáticas/metabolismo , Receptores CXCR3/biosíntesis , Anciano , Anciano de 80 o más Años , Cistitis/diagnóstico , Cistitis Intersticial/diagnóstico , Femenino , Técnica del Anticuerpo Fluorescente/métodos , Humanos , Linfocitos/metabolismo , Masculino , Persona de Mediana Edad , Sindecano-1/biosíntesis , Vejiga Urinaria/metabolismo , Vejiga Urinaria/patologíaRESUMEN
CD138 (syndecan-1) immunoexpression has been reported to be specific for the plasmacytoid variant of urothelial carcinomas (UCs). The aim of this study was to examine the utility of CD138 immunohistochemistry for diagnosing the plasmacytoid variant of UCs. The extent and intensity of CD138 immunostaining were evaluated in 22 infiltrating UCs, 2 other infiltrating carcinomas, 15 noninvasive urothelial lesions, 3 other benign lesions, and perilesional normal tissues. CD138 immunostaining of the normal urothelial epithelium was universally diffuse and strong. In addition, all 42 cases of urinary tract lesions exhibited positive CD138 immunostaining; however, 1 of 3 plasmacytoid variants exhibited focal CD138 expression. The frequency of CD138 positivity in plasmacytoid variants may be relatively low, compared with that observed in the conventional types and other variants; thus, it is not appropriate to assume that CD138 expression in UCs is specific for plasmacytoid variants.
Asunto(s)
Biomarcadores de Tumor/análisis , Carcinoma de Células Transicionales/diagnóstico , Sindecano-1/biosíntesis , Neoplasias de la Vejiga Urinaria/diagnóstico , Carcinoma de Células Transicionales/patología , Humanos , Inmunohistoquímica , Sindecano-1/análisis , Neoplasias de la Vejiga Urinaria/patología , Urotelio/metabolismo , Urotelio/patologíaRESUMEN
AIMS: Pathogenic mechanisms involved in early submerged implant failure are poorly understood. In this study we immunohistochemically analyse differences in proliferation, apoptosis and inflammation in edentulous ridge oral mucosa (ERM) of successful and early failed submerged implants. MATERIALS AND METHODS: 30 samples of ERM covering successful and early failed submerged implants were obtained at the end of osseointegration period along with control samples of healthy ERM. Sections were stained with Ki-67 (proliferation), caspase-3 (apoptosis) and syndecan-1 (epithelial marker). Percentage of positive cells was analysed by Kruskal-Wallis test and Dunn's post hoc test. Co-localization of Ki-67 and caspase-3 with α-SMA, CD68 and TGF-ß was done by double immunofluorescence. RESULTS: There was no significant difference in number of Ki-67 positive cells within surface epithelium (SE) in all groups. Proliferation was significantly higher in underlying connective tissue (UCT) of ERM of early failed submerged implants (26%) compared to ERM of successful submerged implants (3%) and controls (4%). More apoptotic cells appeared in UCT of early failed submerged implants (8%) compared to UCT of successful submerged implants (4%) and UCT of control ERM (3%). Co-localization of Ki-67 and α-SMA in ERM of early failed submerged implants disclosed proliferating fibroblasts and pericytes of blood vessels. Macrophages and cells expressing TGF-ß appeared in UCT of failed implants. Expression of syndecan-1 was significantly weaker in SE of early failed submerged implants. CONCLUSIONS: Imbalance between proliferation and apoptosis, changes in syndecan-1 expression and inflammation are histopathological features of ERM of early failed submerged implants.
Asunto(s)
Actinas/biosíntesis , Implantes Dentales/efectos adversos , Fracaso de la Restauración Dental , Mucosa Bucal/metabolismo , Boca Edéntula/metabolismo , Sindecano-1/biosíntesis , Actinas/fisiología , Anciano , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Apoptosis/fisiología , Caspasa 3/metabolismo , Proliferación Celular/fisiología , Implantación Dental Endoósea , Femenino , Humanos , Macrófagos/metabolismo , Masculino , Persona de Mediana Edad , Mucosa Bucal/irrigación sanguínea , Mucosa Bucal/patología , Boca Edéntula/patología , Oseointegración , Sindecano-1/fisiología , Factor de Crecimiento Transformador beta/análisis , Factor de Crecimiento Transformador beta/biosíntesis , Factor de Crecimiento Transformador beta/fisiologíaRESUMEN
The proteoglycan syndecan-1 and the endoglucuronidases heparanase-1 and heparanase-2 are involved in molecular pathways that deregulate cell adhesion during carcinogenesis. Few studies have examined the expression of syndecan-1, heparanase-1 and mainly heparanase-2 proteins in non-neoplastic and neoplastic human colorectal adenoma tissues. The aim of this study was to analyze the correlation among the heparanase isoforms and the syndecan-1 proteins through immunohistochemical expression in the tissue of colorectal adenomas. Primary anti-human polyclonal anti-HPSE and anti-HPSE2 antibodies and primary anti-human monoclonal anti-SDC1 antibody were used in the immunohistochemical study. The expressions of heparanase-1 and heparanase-2 proteins were determined in tissue samples from 65 colorectal adenomas; the expression of syndecan-1 protein was obtained from 39 (60%) patients. The histological type of adenoma was tubular in 44 (67.7%) patients and tubular-villous in 21 (32.3%); there were no villous adenomas. The polyps were <1.0 cm in size in 54 (83.1%) patients and ≥1.0 cm in 11 (16.9%). The images were quantified by digital counter with a computer program for this purpose. The expression index represented the relationship between the intensity expression and the percentage of positively stained cells. The results showed that the average of heparanase-1, heparanase-2 and syndecan-1 expression index was 73.29 o.u./µm², 93.34 o.u./µm², and 55.29 o.u./µm², respectively. The correlation between the heparanase-1 and syndecan-1 expression index was positive (R=0.034) and significant (P=0.035). There was a negative (R= -0.384) and significant (P=0.016) correlation between the expression index of heparanase-1 and heparanase-2. A negative (R= -0.421) and significant (P=0.008) correlation between the expression index of heparanase-2 and syndecan-1 was found. We concluded that in colorectal adenomas, the heparanase-1 does not participate in syndecan-1 degradation; the heparanase-2 does not stimulate syndecan-1 degradation by the action of heparanase-1, and the heparanase-2 may be involved in the modulation of the heparanase-1 activity.
Asunto(s)
Adenoma/metabolismo , Neoplasias Colorrectales/metabolismo , Liasa de Heparina/biosíntesis , Proteínas de Neoplasias/biosíntesis , Sindecano-1/biosíntesis , Adenoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/patología , Femenino , Humanos , Isoenzimas/biosíntesis , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
This study aims to investigate the immunohistochemical expression of mammary serine protease inhibitor (maspin) and CD138 in primary ovarian high-grade serous carcinomas (HGSC) as compared to low-grade serous carcinomas (LGSC) and clear cell carcinomas and investigate if the studied markers have a correlation to International Federation of Gynaecology and Obstetrics (FIGO) stage, Ki67 proliferation index, and to each other. Maspin cellular location varied significantly between studied groups with only nuclear expression seen in 46.7 % of LGSC group, mixed nuclear and cytoplasmic in 13.3, 28.6, and 20 % of LGSC, HGSC, and clear cell carcinoma, respectively, and was only cytoplasmic in 26.7, 71.4, and 80 % of LGSC, HGSC, and clear cell carcinoma, respectively. Mean maspin and CD138 counts were significantly higher in HGSC and clear cell carcinoma compared to LGSC. Both maspin and CD138 scores varied significantly between studied groups and were positively correlated with adverse prognostic factors in studied carcinomas including FIGO stage and Ki67 proliferation index. Besides, both maspin and CD138 had significant correlation to each other. These findings suggest that epithelial cytoplasmic expression of maspin and CD138 may have a significant role in tumorigenesis in ovarian high-grade serous carcinomas and clear cell carcinomas; these markers may regulate tumor cell proliferation, and their significant correlation to each other may suggest that CD138 probably induces maspin expression to protect tumor growth factors from being lysed by proteolytic enzymes.
Asunto(s)
Carcinoma/genética , Cistadenocarcinoma Seroso/genética , Neoplasias Ováricas/genética , Serpinas/biosíntesis , Sindecano-1/biosíntesis , Adulto , Anciano , Biomarcadores de Tumor/biosíntesis , Carcinoma/patología , Cistadenocarcinoma Seroso/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Antígeno Ki-67/genética , Persona de Mediana Edad , Clasificación del Tumor , Neoplasias Ováricas/patología , Serpinas/genética , Sindecano-1/genéticaRESUMEN
The aim of the present study is to delineate the role of human chorionic gonadotropin (hCG) in trophoblast fusion. In this direction, using shRNA lentiviral particles, α- and ß-hCG silenced 'BeWo' cell lines were generated. Treatment of both α- and ß-hCG silenced BeWo cells with either forskolin or exogenous hCG showed a significant reduction in cell fusion as compared with control shRNA treated cells. Studies by qRT-PCR, Western blotting and immunofluorescence revealed down-regulation of fusion-associated proteins such as syncytin-1 and syndecan-1 in the α- and ß-hCG silenced cells. Delineation of downstream signaling pathways revealed that phosphorylation of PKA and CREB were compromised in the silenced cells whereas, no significant changes in p38MAPK and ERK1/2 phosphorylation were observed. Moreover, ß-catenin activation was unaffected by either α- or ß-hCG silencing. Further, inhibition of PKA by H89 inhibitor led to a significant decrease in BeWo cell fusion but had no effect on ß-catenin activation suggesting the absence of non-canonical ß-catenin stabilization via PKA. Interestingly, canonical activation of ß-catenin was associated with the up-regulation of Wnt 10b expression. In summary, this study establishes the significance of hCG in the fusion of trophoblastic BeWo cells, but there may be additional factors involved in this process.
Asunto(s)
Gonadotropina Coriónica Humana de Subunidad beta/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Hormonas Glicoproteicas de Subunidad alfa/genética , Trofoblastos/fisiología , Fusión Celular , Colforsina/farmacología , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Regulación hacia Abajo , Activación Enzimática/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Productos del Gen env/biosíntesis , Humanos , Isoquinolinas/farmacología , Fosforilación/genética , Proteínas Gestacionales/biosíntesis , Inhibidores de Proteínas Quinasas/farmacología , Interferencia de ARN , ARN Interferente Pequeño/genética , Sulfonamidas/farmacología , Sindecano-1/biosíntesis , beta Catenina/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
The heparan sulfate proteoglycan syndecan-1 is proteolytically shed from the surface of multiple myeloma cells and is abundant in the bone marrow microenvironment where it promotes tumor growth, angiogenesis, and metastasis. In this study, we demonstrate for the first time that shed syndecan-1 present in the medium conditioned by tumor cells is taken up by bone marrow-derived stromal cells and transported to the nucleus. Translocation of shed syndecan-1 (sSDC1) to the nucleus was blocked by addition of exogenous heparin or heparan sulfate, pretreatment of conditioned medium with heparinase III, or growth of cells in sodium chlorate, indicating that sulfated heparan sulfate chains are required for nuclear translocation. Interestingly, cargo bound to sSDC1 heparan sulfate chains (i.e. hepatocyte growth factor) was transported to the nucleus along with sSDC1, and removal of heparan sulfate-bound cargo from sSDC1 abolished its translocation to the nucleus. Once in the nucleus, sSDC1 binds to the histone acetyltransferase enzyme p300, and histone acetyltransferase activity and histone acetylation are diminished. These findings reveal a novel function for shed syndecan-1 in mediating tumor-host cross-talk by shuttling growth factors to the nucleus and by altering histone acetylation in host cells. In addition, this work has broad implications beyond myeloma because shed syndecan-1 is present in high levels in many tumor types as well as in other disease states.
Asunto(s)
Carcinogénesis/genética , Histonas/metabolismo , Mieloma Múltiple/genética , Sindecano-1/metabolismo , Factores de Transcripción p300-CBP/metabolismo , Acetilación , Médula Ósea/metabolismo , Médula Ósea/patología , Línea Celular Tumoral , Núcleo Celular/genética , Núcleo Celular/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Células del Estroma/metabolismo , Sindecano-1/biosíntesis , Microambiente Tumoral/genética , Factores de Transcripción p300-CBP/genéticaRESUMEN
There are lines of evidence demonstrating that NEDD9 (Cas-L, HEF-1) plays a key role in the development, progression, and metastasis of breast cancer cells. We previously reported that NEDD9 plays a critical role for promoting migration and growth of MDA-MB-231. In order to further characterize the mechanisms of NEDD9-mediated cancer migration and growth, stable cells overexpressing NEDD9 were generated using HCC38 as a parental cell line which expresses low level of endogenous NEDD9. Microarray studies demonstrated that core proteins of CD44 and Serglycin were markedly upregulated in HCC38(NEDD9) cells compared to HCC38(Vector) cells, while those of Syndecan-1, Syndecan-2, and Versican were downregulated in HCC38(NEDD9). Importantly, enzymes generating chondroitin sulfate glycosaminoglycans (CS) such as CHST11, CHST15, and CSGALNACT1 were upregulated in HCC38(NEDD9) compared to HCC38(Vector). Immunofluorescence studies using specific antibody, GD3G7, confirmed the enhanced expression of CS-E subunit in HCC38(NEDD9). Immunoprecipitation and western blotting analysis demonstrated that CS-E was attached to CD44 core protein. We demonstrated that removing CS by chondroitinase ABC significantly inhibited anchorage-independent colony formation of HCC38(NEDD9) in methylcellulose. Importantly, the fact that GD3G7 significantly inhibited colony formation of HCC38(NEDD9) cells suggests that CS-E subunit plays a key role in this process. Furthermore, treatment of HCC38(NEDD9) cells with chondroitinase ABC or GD3G7 significantly inhibited mammosphere formation. Exogenous addition of CS-E enhanced colony formation and mammosphere formation of HCC38 parental and HCC38(Vector) cells. These results suggest that NEDD9 regulates the synthesis and expression of tumor associated glycocalyx structures including CS-E, which plays a key role in promoting and regulating breast cancer progression and metastasis and possibly stem cell phenotypes.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Neoplasias de la Mama/patología , Sulfatos de Condroitina/biosíntesis , Fosfoproteínas/metabolismo , Esferoides Celulares/patología , Proteínas Adaptadoras Transductoras de Señales/biosíntesis , Anticuerpos Monoclonales/inmunología , Antígenos/biosíntesis , Antígenos/metabolismo , Movimiento Celular , Proliferación Celular , Condroitina ABC Liasa/metabolismo , Condroitina ABC Liasa/farmacología , Regulación hacia Abajo , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Receptores de Hialuranos/biosíntesis , Glicoproteínas de Membrana/biosíntesis , N-Acetilgalactosaminiltransferasas/biosíntesis , Metástasis de la Neoplasia/patología , Fosfoproteínas/biosíntesis , Proteoglicanos/biosíntesis , Proteoglicanos/metabolismo , Sulfotransferasas/biosíntesis , Sindecano-1/biosíntesis , Sindecano-2/biosíntesis , Células Tumorales Cultivadas , Regulación hacia Arriba , Versicanos/biosíntesis , Proteínas de Transporte Vesicular/biosíntesisRESUMEN
Deregulation of c-myc by translocation onto immunoglobulin (Ig) loci can promote B cell malignant proliferations with phenotypes as diverse as acute lymphoid leukemia, Burkitt lymphoma, diffuse large B cell lymphoma, myeloma... The B cell receptor (BCR) normally providing tonic signals for cell survival and mitogenic responses to antigens, can also contribute to lymphomagenesis upon sustained ligand binding or activating mutations. BCR signaling varies among cell compartments and BCR classes. For unknown reasons, some malignancies associate with expression of either IgM or class-switched Ig. We explored whether an IgA BCR, with strong tonic signaling, would affect lymphomagenesis in c-myc IgH 3'RR transgenic mice prone to lymphoproliferations. Breeding c-myc transgenics in a background where IgM expression was replaced with IgA delayed lymphomagenesis. By comparison to single c-myc transgenics, lymphomas from double mutant animals were more differentiated and less aggressive, with an altered transcriptional program. Larger tumor cells more often expressed CD43 and CD138, which culminated in a plasma cell phenotype in 10% of cases. BCR class-specific signals thus appear to modulate lymphomagenesis and may partly explain the observed association of specific Ig classes with human B cell malignancies of differential phenotype, progression and prognosis.
Asunto(s)
Inmunoglobulina A/genética , Inmunoglobulina M/genética , Linfoma/genética , Proteínas Proto-Oncogénicas c-myc/genética , Receptores de Antígenos de Linfocitos B/genética , Animales , Linfocitos B/patología , Supervivencia Celular/genética , Transformación Celular Neoplásica/genética , Humanos , Inmunoglobulina A/inmunología , Cadenas Pesadas de Inmunoglobulina/genética , Inmunoglobulina M/inmunología , Leucosialina/biosíntesis , Linfoma/patología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores de Antígenos de Linfocitos B/biosíntesis , Receptores de Antígenos de Linfocitos B/inmunología , Sindecano-1/biosíntesisRESUMEN
BACKGROUND: Fibroblast growth factor-2 (FGF-2) supports tumor progression in breast cancer. FGF-2 signaling is modulated by heparan sulfate proteoglycans, such as syndecan-1 (CD138). The exact role of CD138 in ductal carcinoma in situ of the breast (DCIS) is still uncertain. Differential expression depending on grading could suggest a role for syndecan-1 during growth and tumor progression. MATERIALS AND METHODS: Samples of 127 cases of breast DCIS associated with follow-up data were included. CD138 staining intensity, number of positive cells, intracellular and tissue localization were examined. RESULTS: Median follow-up was 45.4 months and median recurrence-free survival (RFS) 86 months. Age, menopausal status and previous hormone replacement therapy had no significant influence on RFS. Smoking significantly influenced RFS (p=0.008). Endocrine therapy or radiotherapy did not improve RFS. Grading was not correlated with CD138 staining intensity, but was significantly associated with the percentage of CD138-positive cells (low-vs. high-grade, p=0.043). Estrogen receptor (ER) expression did not influence staining intensity of CD138 (p=0.247), but negatively correlated with the proportion of CD138-positive cells (p=0.032). Progesterone receptor (PR) expression significantly influenced the intensity of staining (p=0.010) and the percentage of CD138-positive cells (p=0.004); both were increased in PR-negative cases. CD138 staining intensity and percentage of positive cells did not correlate with RFS. Nuclear grade and syndecan-1 staining localization were significantly associated (p=0.001). ER-positive, and PR-positive DCIS more often exhibited membrane-bound syndecan-1 than ER- or PR-negative cases (p=0.001). Nuclear grade and tissue localization of CD138 correlated significantly (p=0.005). PR influenced CD138 tissue distribution, while ER did not. Syndecan-1 localization did not statistically impact RFS. CONCLUSION: In DCIS of different nuclear grades, tissue localization of syndecan-1 is significantly divergent, suggesting a specific effect on biology and progression of DCIS.
Asunto(s)
Neoplasias de la Mama/metabolismo , Carcinoma in Situ/metabolismo , Carcinoma Ductal de Mama/metabolismo , Sindecano-1/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/terapia , Carcinoma in Situ/terapia , Carcinoma Ductal de Mama/terapia , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Adhesión en ParafinaRESUMEN
Despite recent advances in the treatment of multiple myeloma (MM), it remains an incurable disease potentially due to the presence of resistant myeloma cancer stem cells (MM-CSC). Although the presence of clonogenic cells in MM was described three decades ago, the phenotype of MM-CSC is still controversial, especially with respect to the expression of syndecan-1 (CD138). Here, we demonstrate the presence of two subpopulations--CD138++ (95-99%) and CD138low (1-5%)--in eight MM cell lines. To find out possible stem-cell-like features, we have phenotypically, genomic and functionally characterized the two subpopulations. Our results show that the minor CD138low subpopulation is morphologically identical to the CD138++ fraction and does not represent a more immature B-cell compartment (with lack of CD19, CD20 and CD27 expression). Moreover, both subpopulations have similar gene expression and genomic profiles. Importantly, both CD138++ and CD138low subpopulations have similar sensitivity to bortezomib, melphalan and doxorubicin. Finally, serial engraftment in CB17-SCID mice shows that CD138++ as well as CD138low cells have self-renewal potential and they are phenotypically interconvertible. Overall, our results differ from previously published data in MM cell lines which attribute a B-cell phenotype to MM-CSC. Future characterization of clonal plasma cell subpopulations in MM patients' samples will guarantee the discovery of more reliable markers able to discriminate true clonogenic myeloma cells.
Asunto(s)
Mieloma Múltiple/fisiopatología , Sindecano-1/genética , Sindecano-1/fisiología , Animales , Ácidos Borónicos/farmacología , Bortezomib , Línea Celular Tumoral , Variaciones en el Número de Copia de ADN , Doxorrubicina/farmacología , Xenoinjertos , Humanos , Inmunofenotipificación , Melfalán/farmacología , Ratones SCID , Mieloma Múltiple/inmunología , Células Madre Neoplásicas , Fenotipo , Células Plasmáticas/inmunología , Células Precursoras de Linfocitos B , Pirazinas/farmacología , Sindecano-1/biosíntesisRESUMEN
BACKGROUND: To determine the diagnostic and prognostic capability of urinary and tumoral syndecan-1 (SDC-1) levels in patients with cancer of the urinary bladder. METHODS: SDC-1 levels were quantitated by enzyme-linked immunosorbent assay (ELISA) in 308 subjects (102 cancer subjects and 206 non-cancer subjects) to assess its diagnostic capabilities in voided urine. The performance of SDC-1 was evaluated using the area under the curve of a receiver operating characteristic curve. In addition, immunohistochemical (IHC) staining assessed SDC-1 protein expression in 193 bladder specimens (185 cancer subjects and 8 non-cancer subjects). Outcomes were correlated to SDC-1 levels. RESULTS: Mean urinary levels of SDC-1 did not differ between the cancer subjects and the non-cancer subjects, however, the mean urinary levels of SDC-1 were reduced in high-grade compared to low-grade disease (p < 0.0001), and in muscle invasive bladder cancer (MIBC) compared to non-muscle invasive bladder cancer (NMIBC) (p = 0.005). Correspondingly, preliminary data note a shift from a membranous cellular localization of SDC-1 in normal tissue, low-grade tumors and NMIBC, to a distinctly cytoplasmic localization in high-grade tumors and MIBC was observed in tissue specimens. CONCLUSION: Alone urinary SDC-1 may not be a diagnostic biomarker for bladder cancer, but its urinary levels and cellular localization were associated with the differentiation status of patients with bladder tumors. Further studies are warranted to define the potential role for SDC-1 in bladder cancer progression.