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1.
Int J Mol Sci ; 22(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34445387

RESUMO

Prostate cancer (PCa) is the leading cause of cancer-associated mortality in men, and new biomarkers are still needed. The expression pattern and protein tissue localization of proteoglycans of the syndecan family (SDC 1-4) and syntenin-1 (SDCBP) were determined in normal and prostatic tumor tissue from two genetically engineered mouse models and human prostate tumors. Studies were validated using SDC 1-4 and SDCBP mRNA levels and patient survival data from The Cancer Genome Atlas and CamCAP databases. RNAseq showed increased expression of Sdc1 in Pb-Cre4/Ptenf/f mouse Pca and upregulation of Sdc3 expression and downregulation of Sdc2 and Sdc4 when compared to the normal prostatic tissue in Pb-Cre4/Trp53f/f-;Rb1f/f mouse tumors. These changes were confirmed by immunohistochemistry. In human PCa, SDC 1-4 and SDCBP immunostaining showed variable localization. Furthermore, Kaplan-Meier analysis showed that patients expressing SDC3 had shorter prostate-specific survival than those without SDC3 expression (log-rank test, p = 0.0047). Analysis of the MSKCC-derived expression showed that SDC1 and SDC3 overexpression is predictive of decreased biochemical recurrence-free survival (p = 0.0099 and p = 0.045, respectively), and SDC4 overexpression is predictive of increased biochemical recurrence-free survival (p = 0.035). SDC4 overexpression was associated with a better prognosis, while SDC1 and SDC3 were associated with more aggressive tumors and a worse prognosis.


Assuntos
Perfilação da Expressão Gênica/métodos , Neoplasias da Próstata/patologia , Sindecana-1/genética , Sindecana-3/genética , Sindecana-4/genética , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Transplante de Neoplasias , Prognóstico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Análise Serial de Proteínas , Análise de Sequência de RNA , Análise de Sobrevida , Sindecana-1/metabolismo , Sindecana-3/metabolismo , Sindecana-4/metabolismo , Sinteninas/genética , Sinteninas/metabolismo
2.
Adv Clin Exp Med ; 30(7): 655-660, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34286513

RESUMO

BACKGROUND: Syndecan-1 (Sdc1) is a heparin sulfate proteoglycan expressed in intestinal epithelium, which plays a crucial role in inflammation and epithelial repair. Sdc1-knockout mice have a deteriorated course of dextran sulfate sodium-induced colitis as compared to controls. Syndecan-1 is also shed into the serum during inflammation of the epithelium. We hypothesized that an increased serum level of soluble Sdc1 is a biomarker of intestinal inflammation in ulcerative colitis (UC). OBJECTIVES: To evaluate serum soluble Sdc1 as a biomarker of intestinal inflammation in UC. MATERIAL AND METHODS: This is a proof-of-concept study. Patients were recruited by the University Hospital Münster and HELIOS Albert Schweitzer Klinik Northeim (Germany). Blood samples were collected from UC patients actively suffering from this condition and those in remission. The levels of Sdc1 were measured with Diaclone CD 138 ELISA kit (Diaclone Research, Besançon, France) and routine clinical data were collected (C-reactive protein (CRP) levels, calprotectin in stool samples). Data were analyzed using SPSS software. RESULTS: Soluble Sdc1 levels were significantly elevated in the active UC group as compared to the inactive UC group (94.5 ±68.1 ng/mL compared to 28.3 ±12.6 ng/mL, p = 0.0020). The levels of Sdc1 also significantly correlated with the severity of UC as measured with the Mayo score (p = 0.0248). Receiver operating characteristic (ROC) analysis showed a good correlation of Sdc1 with an endoscopic Mayo score ≥2, with a value of 0.7747 (95% confidence interval (95% CI) = 0.5775-0.9718). A cutoff value of 37.1 ng/mL of Sdc1 showed a sensitivity of 78% and a specificity of 77%. A panel of biomarkers including CRP, hemoglobin, hematocrit, and Sdc1 was able to precisely predict active UC with an area under the curve (AUC) = 0.9395 (95% CI = 0.8509-1.0000). CONCLUSIONS: Serum soluble Sdc1 correlates significantly with mucosa inflammation and Mayo score in UC. Clinical trials No. NCT02333526.


Assuntos
Colite Ulcerativa , Animais , Biomarcadores , Colite Ulcerativa/diagnóstico , Fezes , Alemanha , Humanos , Inflamação , Mucosa Intestinal , Complexo Antígeno L1 Leucocitário , Camundongos , Índice de Gravidade de Doença , Sindecana-1/metabolismo
3.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070901

RESUMO

Glycosaminoglycans (GAGs) and proteoglycans (PGs) are major components of the glycocalyx. The secreted GAG and CD44 ligand hyaluronic acid (HA), and the cell surface PG syndecan-1 (Sdc-1) modulate the expression and activity of cytokines, chemokines, growth factors, and adhesion molecules, acting as critical regulators of tumor cell behavior. Here, we studied the effect of Sdc-1 siRNA depletion and HA treatment on hallmark processes of cancer in breast cancer cell lines of different levels of aggressiveness. We analyzed HA synthesis, and parameters relevant to tumor progression, including the stem cell phenotype, Wnt signaling constituents, cell cycle progression and apoptosis, and angiogenic markers in luminal MCF-7 and triple-negative MDA-MB-231 cells. Sdc-1 knockdown enhanced HAS-2 synthesis and HA binding in MCF-7, but not in MDA-MB-231 cells. Sdc-1-depleted MDA-MB-231 cells showed a reduced CD24-/CD44+ population. Furthermore, Sdc-1 depletion was associated with survival signals in both cell lines, affecting cell cycle progression and apoptosis evasion. These changes were linked to the altered expression of KLF4, MSI2, and miR-10b and differential changes in Erk, Akt, and PTEN signaling. We conclude that Sdc-1 knockdown differentially affects HA metabolism in luminal and triple-negative breast cancer model cell lines and impacts the stem phenotype, cell survival, and angiogenic factors.


Assuntos
Regulação Neoplásica da Expressão Gênica , Glicocálix/metabolismo , Ácido Hialurônico/metabolismo , Sindecana-1/genética , Neoplasias de Mama Triplo Negativas/genética , Via de Sinalização Wnt/genética , Apoptose/efeitos dos fármacos , Apoptose/genética , Antígeno CD24/genética , Antígeno CD24/metabolismo , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Bases de Dados Factuais , Feminino , Glicocálix/química , Glicocálix/efeitos dos fármacos , Humanos , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Hialuronan Sintases/genética , Hialuronan Sintases/metabolismo , Ácido Hialurônico/farmacologia , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Células MCF-7 , MicroRNAs/genética , MicroRNAs/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Análise de Sobrevida , Sindecana-1/antagonistas & inibidores , Sindecana-1/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia
4.
Emerg Microbes Infect ; 10(1): 1065-1076, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34013835

RESUMO

A main clinical parameter of COVID-19 pathophysiology is hypoxia. Here we show that hypoxia decreases the attachment of the receptor-binding domain (RBD) and the S1 subunit (S1) of the spike protein of SARS-CoV-2 to epithelial cells. In Vero E6 cells, hypoxia reduces the protein levels of ACE2 and neuropilin-1 (NRP1), which might in part explain the observed reduction of the infection rate. In addition, hypoxia inhibits the binding of the spike to NCI-H460 human lung epithelial cells by decreasing the cell surface levels of heparan sulfate (HS), a known attachment receptor of SARS-CoV-2. This interaction is also reduced by lactoferrin, a glycoprotein that blocks HS moieties on the cell surface. The expression of syndecan-1, an HS-containing proteoglycan expressed in lung, is inhibited by hypoxia on a HIF-1α-dependent manner. Hypoxia or deletion of syndecan-1 results in reduced binding of the RBD to host cells. Our study indicates that hypoxia acts to prevent SARS-CoV-2 infection, suggesting that the hypoxia signalling pathway might offer therapeutic opportunities for the treatment of COVID-19.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Hipóxia Celular/fisiologia , Heparitina Sulfato/metabolismo , Neuropilina-1/metabolismo , Glicoproteína da Espícula de Coronavírus/fisiologia , Sindecana-1/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Animais , Chlorocebus aethiops , Regulação da Expressão Gênica/efeitos dos fármacos , Heparitina Sulfato/genética , Humanos , Neuropilina-1/genética , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/química , Sindecana-1/genética , Células Vero , Ligação Viral/efeitos dos fármacos
5.
Int J Mol Sci ; 22(8)2021 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-33921767

RESUMO

Cell surface proteoglycans are known to be important regulators of many aspects of cell behavior. The principal family of transmembrane proteoglycans is the syndecans, of which there are four in mammals. Syndecan-1 is mostly restricted to epithelia, and bears heparan sulfate chains that are capable of interacting with a large array of polypeptides, including extracellular matrix components and potent mediators of proliferation, adhesion and migration. For this reason, it has been studied extensively with respect to carcinomas and tumor progression. Frequently, but not always, syndecan-1 levels decrease as tumor grade, stage and invasiveness and dedifferentiation increase. This parallels experiments that show depletion of syndecan-1 can be accompanied by loss of cadherin-mediated adhesion. However, in some tumors, levels of syndecan-1 increase, but the characterization of its distribution is relevant. There can be loss of membrane staining, but acquisition of cytoplasmic and/or nuclear staining that is abnormal. Moreover, the appearance of syndecan-1 in the tumor stroma, either associated with its cellular component or the collagenous matrix, is nearly always a sign of poor prognosis. Given its relevance to myeloma progression, syndecan-1-directed antibody-toxin conjugates are being tested in clinical and preclinical trials, and may have future relevance to some carcinomas.


Assuntos
Carcinoma/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Sindecana-1/metabolismo , Animais , Glicosaminoglicanos/metabolismo , Heparitina Sulfato/metabolismo , Humanos , Proteoglicanas/metabolismo
6.
Cancer Sci ; 112(6): 2314-2324, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33792119

RESUMO

Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin's lymphoma, which is characterized by overexpression of cyclin D1. Although novel drugs, such as ibrutinib, show promising clinical outcomes, relapsed MCL often acquires drug resistance. Therefore, alternative approaches for refractory and relapsed MCL are needed. Here, we examined whether a novel inhibitor of enhancer of zeste homologs 1 and 2 (EZH1/2), OR-S1 (a close analog of the clinical-stage compound valemetostat), had an antitumor effect on MCL cells. In an ibrutinib-resistant MCL patient-derived xenograft (PDX) mouse model, OR-S1 treatment by oral administration significantly inhibited MCL tumor growth, whereas ibrutinib did not. In vitro growth assays showed that compared with an established EZH2-specific inhibitor GSK126, OR-S1 had a marked antitumor effect on MCL cell lines. Furthermore, comprehensive gene expression analysis was performed using OR-S1-sensitive or insensitive MCL cell lines and showed that OR-S1 treatment modulated B-cell activation, differentiation, and cell cycle. In addition, we identified Cyclin Dependent Kinase Inhibitor 1C (CDKN1C, also known as p57, KIP2), which contributes to cell cycle arrest, as a direct target of EZH1/2 and showed that its expression influenced MCL cell proliferation. These results suggest that EZH1/2 may be a potential novel target for the treatment of aggressive ibrutinib-resistant MCL via CDKN1C-mediated cell cycle arrest.


Assuntos
Adenina/análogos & derivados , Antineoplásicos/farmacologia , Inibidor de Quinase Dependente de Ciclina p57/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Linfoma de Célula do Manto/tratamento farmacológico , Piperidinas/farmacologia , Complexo Repressor Polycomb 2/antagonistas & inibidores , Adenina/farmacologia , Adenina/uso terapêutico , Animais , Antineoplásicos/uso terapêutico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Inibidor de Quinase Dependente de Ciclina p57/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Camundongos , Piperidinas/uso terapêutico , Sindecana-1/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Lab Invest ; 101(5): 600-611, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33692439

RESUMO

Cartilage degeneration has been reported to deteriorate osteoarthritis (OA), a prevalent joint disease caused by intrinsic and epigenetic factors. This study aimed to examine the molecular mechanism of enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2)/microRNA-138 (miR-138)/syndecan 1 (SDC1) and its epigenetic regulation in cartilage degeneration in OA. An OA cell model was induced by stimulating chondrocytes with interleukin (IL)-1ß at a final concentration of 10 ng/mL, followed by alterations in EZH2 and miR-138 expression. Afterwards, cell apoptosis was analyzed using flow cytometry. The expression patterns of cartilage catabolism-related factors (MMP-13, ADAMTS-4, and ADAMTS-5) were determined using RT-qPCR and western blot analyses. The EZH2 and H3K27me3 enrichment at the miR-138 promoter region were determined using ChIP-qPCR. Finally, an OA mouse model was constructed to verify the function of EZH2 in vivo. EZH2 was expressed at high levels in OA models. EZH2 depletion ameliorated OA, as evidenced by reduced cell apoptosis in IL-1ß-treated chondrocytes and decreased levels of cartilage catabolism-related factors. Moreover, EZH2 promoted histone methylation at the miR-138 promoter to suppress miR-138 expression, thereby upregulating the expression of SDC1, a target gene of miR-138. Changes in this pathway increased the expression of cartilage catabolism-related factors in vitro while promoting cartilage degeneration in vivo. Our data provided evidence that EZH2 inhibits miR-138 expression by promoting the histone methylation of its promoter, which induces cartilage degeneration in OA models by upregulating SDC1 expression, suggesting a novel mechanistic strategy for OA treatment.


Assuntos
Cartilagem Articular/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , MicroRNAs/metabolismo , Osteoartrite/metabolismo , Sindecana-1/metabolismo , Adulto , Animais , Artrite Experimental/metabolismo , Biomarcadores/metabolismo , Cartilagem Articular/fisiopatologia , Feminino , Histona Metiltransferases/metabolismo , Humanos , Masculino , Camundongos , MicroRNAs/genética , Pessoa de Meia-Idade , Osteoartrite/fisiopatologia , Cultura Primária de Células
8.
J Am Soc Nephrol ; 32(6): 1371-1388, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33758009

RESUMO

BACKGROUND: Dyslipidemia is an important risk factor in CKD. The liver clears triglyceride-rich lipoproteins (TRL) via LDL receptor (LDLR), LDLR-related protein-1 (LRP-1), and heparan sulfate proteoglycans (HSPGs), mostly syndecan-1. HSPGs also facilitate LDLR degradation by proprotein convertase subtilisin/kexin type 9 (PCSK9). Progressive renal failure affects the structure and activity of hepatic lipoprotein receptors, PCSK9, and plasma cholesterol. METHODS: Uninephrectomy- and aging-induced CKD in normotensive Wistar rats and hypertensive Munich-Wistar-Frömter (MWF) rats. RESULTS: Compared with 22-week-old sex- and strain-matched rats, 48-week-old uninephrectomized Wistar-CKD and MWF-CKD rats showed proteinuria, increased plasma creatinine, and hypercholesterolemia (all P<0.05), which were most apparent in hypertensive MWF-CKD rats. Hepatic PCSK9 expression increased in both CKD groups (P<0.05), with unusual sinusoidal localization, which was not seen in 22-week-old rats. Heparan sulfate (HS) disaccharide analysis, staining with anti-HS mAbs, and mRNA expression of HS polymerase exostosin-1 (Ext-1), revealed elongated HS chains in both CKD groups. Solid-phase competition assays showed that the PCSK9 interaction with heparin-albumin (HS-proteoglycan analogue) was critically dependent on polysaccharide chain length. VLDL binding to HS from CKD livers was reduced (P<0.05). Proteinuria and plasma creatinine strongly associated with plasma cholesterol, PCSK9, and HS changes. CONCLUSIONS: Progressive CKD induces hepatic HS elongation, leading to increased interaction with PCSK9. This might reduce hepatic lipoprotein uptake and thereby induce dyslipidemia in CKD. Therefore, PCSK9/HS may be a novel target to control dyslipidemia.


Assuntos
Envelhecimento , Proteoglicanas de Heparan Sulfato/metabolismo , Hipercolesterolemia/metabolismo , Fígado/metabolismo , Pró-Proteína Convertase 9/metabolismo , Insuficiência Renal Crônica/metabolismo , Animais , Colesterol/sangue , Creatinina/sangue , Dissacarídeos/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Proteoglicanas de Heparan Sulfato/análogos & derivados , Hipercolesterolemia/complicações , Hipertensão/complicações , Hipertensão/metabolismo , Lipoproteínas VLDL/metabolismo , Masculino , N-Acetilglucosaminiltransferases/genética , Nefrectomia , Pró-Proteína Convertase 9/genética , Ratos Wistar , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/fisiopatologia , Sindecana-1/genética , Sindecana-1/metabolismo
9.
Chem Commun (Camb) ; 57(27): 3407-3410, 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33687395

RESUMO

A new convergent chemoenzymatic synthesis strategy, integrating enzymatic synthesis of heparan sulfate, sortase A ligation, copper(i)-catalyzed alkyne-azide cycloaddition, and solid phase peptide synthesis, has been established to efficiently synthesize a mimetic of heparan sulfate proteoglycan syndecan-1 glyco-polypeptide at a milligram scale. The mimic was able to bind with αvß3 integrin faster and exhibit stronger inhibition of breast cancer cell migration compared to the glycan or the polypeptide alone. This novel approach could serve as a general approach for heparan sulfate proteoglycan mimetic synthesis.


Assuntos
Heparitina Sulfato/farmacologia , Proteoglicanas/farmacologia , Sindecana-1/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Feminino , Heparitina Sulfato/química , Humanos , Integrina alfaVbeta3/antagonistas & inibidores , Integrina alfaVbeta3/metabolismo , Conformação Molecular , Proteoglicanas/química , Sindecana-1/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
10.
Sci Rep ; 11(1): 1511, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33452350

RESUMO

This study aimed to compare the effects of volatile anesthesia and total intravenous anesthesia (TIVA) on syndecan-1 shedding in patients with gastric cancer undergoing minimally invasive gastrectomy. Patients were randomly assigned to either the Volatile (n = 68) or the TIVA (n = 68) group. Anesthesia was maintained with sevoflurane/remifentanil or propofol/remifentanil in the Volatile and TIVA groups, respectively. Serum syndecan-1 was evaluated at pre-operation, end of operation, and postoperative day (POD) 1. Inflammatory markers including white blood cell (WBC) count, neutrophil-to-lymphocyte ratio (NLR), and C-reactive protein (CRP), were also measured at pre-operation, end of operation, and POD 1, 2, 3, and 5. The TIVA group showed significantly lower levels of syndecan-1 at the end of the operation compared to the Volatile group; however, no difference was seen between the groups at POD 1. The WBC count and NLR were significantly lower in the TIVA group at the end of the operation than the Volatile group, but there were no differences between the groups at POD 1, 2, 3, and 5. CRP levels were similar between the groups at all time points. In conclusion, despite TIVA being superior to volatile anesthesia in protecting endothelial glycocalyx during the operation, both did not prevent postoperative syndecan-1 shedding after gastrectomy.Clinical trial registration number: NCT04183296 (ClinicalTrial.gov, 03/12/2019).


Assuntos
Anestesia por Inalação/métodos , Anestesia Intravenosa/métodos , Sindecana-1/metabolismo , Idoso , Período de Recuperação da Anestesia , Anestesia Geral/métodos , Anestésicos Inalatórios/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Propofol/farmacologia , Remifentanil/farmacologia , Sevoflurano/farmacologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/cirurgia , Sindecana-1/análise , Sindecana-1/sangue
11.
Blood ; 137(13): 1713-1718, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33512430

RESUMO

Plasma cells no longer express a B-cell antigen receptor and are hence deprived of signals crucial for survival throughout B-cell development. Instead, normal plasma cells, as well as their malignant myeloma counterparts, heavily rely on communication with the bone marrow (BM) microenvironment for survival. The plasma cell heparan sulfate proteoglycan (HSPG) syndecan-1 (CD138) and HSPGs in the BM microenvironment act as master regulators of this communication by co-opting specific growth and survival factors from the BM niche. This designates syndecan-1/HSPGs and their synthesis machinery as potential treatment targets in multiple myeloma.


Assuntos
Heparitina Sulfato/metabolismo , Mieloma Múltiplo/patologia , Plasmócitos/patologia , Proteoglicanas/metabolismo , Sindecana-1/metabolismo , Animais , Medula Óssea/metabolismo , Medula Óssea/patologia , Humanos , Mieloma Múltiplo/metabolismo , Plasmócitos/metabolismo , Microambiente Tumoral
12.
Acta Haematol ; 144(3): 302-307, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32906140

RESUMO

Hypercalcemia is a significant feature of patients with active multiple myeloma (MM) with extensive bone disease. Among the causes of non-neoplastic hypercalcemia, primary hyperparathyroidism (PHPT) is one of the most common, leading to osteoporosis and bone fractures. Interestingly, some preclinical data indicate that high secretion of parathyroid hormone (PTH) may have a negative impact on bone disease and MM progression. However, concomitant diagnosis of MM and PHPT has rarely been described. Here, we present 4 cases of patients with active MM and hypercalcemia with high or inappropriately normal PTH levels. Interestingly, CD138+ cells from these 4 MM patients lack PTH receptor 1 and PTH-related peptide expressions, indicating that PTH could have a paracrine rather than a direct pro-tumoral effect. Moreover, these cases suggest that the concomitant diagnosis of MM and PHTP may not be so rare and should be considered for the clinical management of MM patients with hypercalcemia.


Assuntos
Hiperparatireoidismo Primário/diagnóstico , Mieloma Múltiplo/diagnóstico , Idoso , Antineoplásicos/uso terapêutico , Feminino , Humanos , Hiperparatireoidismo Primário/complicações , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Mieloma Múltiplo/tratamento farmacológico , Hormônio Paratireóideo/sangue , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo , Sindecana-1/metabolismo
13.
FEBS J ; 288(2): 486-506, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32367652

RESUMO

In colon cancer, downregulation of the transmembrane heparan sulfate proteoglycan syndecan-1 (Sdc-1) is associated with increased invasiveness, metastasis, and dedifferentiation. As Sdc-1 modulates signaling pathways relevant to stem cell function, we tested the hypothesis that it may regulate a tumor-initiating cell phenotype. Sdc-1 small-interfering RNA knockdown in the human colon cancer cell lines Caco2 and HT-29 resulted in an increased side population (SP), enhanced aldehyde dehydrogenase 1 activity, and higher expression of CD133, LGR5, EPCAM, NANOG, SRY (sex-determining region Y)-box 2, KLF2, and TCF4/TCF7L2. Sdc-1 knockdown enhanced sphere formation, cell viability, Matrigel invasiveness, and epithelial-to-mesenchymal transition-related gene expression. Sdc-1-depleted HT-29 xenograft growth was increased compared to controls. Decreased Sdc-1 expression was associated with an increased activation of ß1-integrins, focal adhesion kinase (FAK), and wingless-type (Wnt) signaling. Pharmacological FAK and Wnt inhibition blocked the enhanced stem cell phenotype and invasive growth. Sequential flow cytometric SP enrichment substantially enhanced the stem cell phenotype of Sdc-1-depleted cells, which showed increased resistance to doxorubicin chemotherapy and irradiation. In conclusion, Sdc-1 depletion cooperatively enhances activation of integrins and FAK, which then generates signals for increased invasiveness and cancer stem cell properties. Our findings may provide a novel concept to target a stemness-associated signaling axis as a therapeutic strategy to reduce metastatic spread and cancer recurrence. DATABASES: The GEO accession number of the Affymetrix transcriptomic screening is GSE58751.


Assuntos
Neoplasias do Colo/genética , Quinase 1 de Adesão Focal/genética , Regulação Neoplásica da Expressão Gênica , Células-Tronco Neoplásicas/metabolismo , Sindecana-1/genética , Via de Sinalização Wnt/efeitos dos fármacos , Antígeno AC133/genética , Antígeno AC133/metabolismo , Família Aldeído Desidrogenase 1/genética , Família Aldeído Desidrogenase 1/metabolismo , Animais , Benzotiazóis/farmacologia , Células CACO-2 , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Molécula de Adesão da Célula Epitelial/genética , Molécula de Adesão da Célula Epitelial/metabolismo , Quinase 1 de Adesão Focal/antagonistas & inibidores , Quinase 1 de Adesão Focal/metabolismo , Células HT29 , Humanos , Indóis/farmacologia , Integrina beta1/genética , Integrina beta1/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Camundongos , Proteína Homeobox Nanog/genética , Proteína Homeobox Nanog/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Oligopeptídeos/farmacologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Proteína da Região Y Determinante do Sexo/genética , Proteína da Região Y Determinante do Sexo/metabolismo , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia , Sulfonamidas/farmacologia , Sindecana-1/antagonistas & inibidores , Sindecana-1/metabolismo , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Leukemia ; 35(4): 1100-1107, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33262528

RESUMO

POEMS syndrome is a rare plasma cell dyscrasia. Little is known about its pathogenesis and genetic features. We analyzed the mutational features of purified bone marrow plasma cells from 42 patients newly diagnosed with POEMS syndrome using a two-step strategy. Whole exome sequencing of ten patients showed a total of 170 somatic mutations in exonic regions and splicing sites, with paired peripheral blood mononuclear cells as a control. Three significantly mutated genes-LILRB1 (10%), HEATR9 (20%), and FMNL2 (10%)-and eight mutated known driver genes (MYD88, NFKB2, CHD4, SH2B3, POLE, STAT3, CHD3, and CUX1) were identified. Target region sequencing of 77 genes were then analyzed to validate the mutations in an additional 32 patients. A total of 32 mutated genes were identified, and genes recurrently mutated in more than three patients included CUX1 (19%), DNAH5 (16%), USH2A (16%), KMT2D (16%), and RYR1 (12%). Driver genes of multiple myeloma (BIRC3, LRP1B, KDM6A, and ATM) and eleven genes reported in light-chain amyloidosis were also identified in target region sequencing. Notably, VEGFA mutations were detected in one patient. Our study revealed heterogeneous genomic profiles of bone marrow plasma cells in POEMS syndrome, which might share some similarity to that of other plasma cell diseases.


Assuntos
Biomarcadores , Estudos de Associação Genética , Heterogeneidade Genética , Predisposição Genética para Doença , Mutação , Síndrome POEMS/diagnóstico , Síndrome POEMS/genética , Adulto , Idoso , Alelos , Medula Óssea/patologia , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Biologia Computacional/métodos , Feminino , Ontologia Genética , Estudos de Associação Genética/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome POEMS/terapia , Polimorfismo de Nucleotídeo Único , Sindecana-1/genética , Sindecana-1/metabolismo , Sequenciamento Completo do Exoma
15.
J Hematol Oncol ; 13(1): 145, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-33138841

RESUMO

BACKGROUND: Drug-loaded nanoparticles have established their benefits in the fight against multiple myeloma; however, ligand-targeted nanomedicine has yet to successfully translate to the clinic due to insufficient efficacies reported in preclinical studies. METHODS: In this study, liposomal nanoparticles targeting multiple myeloma via CD38 or CD138 receptors are prepared from pre-synthesized, purified constituents to ensure increased consistency over standard synthetic methods. These nanoparticles are then tested both in vitro for uptake to cancer cells and in vivo for accumulation at the tumor site and uptake to tumor cells. Finally, drug-loaded nanoparticles are tested for long-term efficacy in a month-long in vivo study by tracking tumor size and mouse health. RESULTS: The targeted nanoparticles are first optimized in vitro and show increased uptake and cytotoxicity over nontargeted nanoparticles, with CD138-targeting showing superior enhancement over CD38-targeted nanoparticles. However, biodistribution and tumor suppression studies established CD38-targeted nanoparticles to have significantly increased in vivo tumor accumulation, tumor cell uptake, and tumor suppression over both nontargeted and CD138-targeted nanoparticles due to the latter's poor selectivity. CONCLUSION: These results both highlight a promising cancer treatment option in CD38-targeted nanoparticles and emphasize that targeting success in vitro does not necessarily translate to success in vivo.


Assuntos
ADP-Ribosil Ciclase 1/metabolismo , Antibióticos Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos , Lipossomos/metabolismo , Mieloma Múltiplo/tratamento farmacológico , Sindecana-1/metabolismo , ADP-Ribosil Ciclase 1/química , Animais , Antibióticos Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Doxorrubicina/farmacocinética , Humanos , Lipossomos/química , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Simulação de Acoplamento Molecular , Mieloma Múltiplo/metabolismo , Peptídeos/química , Peptídeos/metabolismo , Sindecana-1/química , Distribuição Tecidual
16.
Sci Rep ; 10(1): 20510, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33239699

RESUMO

The heparan sulfate proteoglycan Syndecan-1, a mediator of signals between the extracellular matrix and cells involved is able to interact with OPG, one of the major regulators of osteoclastogenesis. The potential of osteoblasts to induce osteoclastogenesis is characterized by a switch of OPG (low osteoclastogenic potential) towards RANKL production (high osteoclastogenic potential). In the present study, we investigated the influence of endogenous Syndecan-1 on local bone-cell-communication via the RANKL/OPG-axis in murine osteoblasts and osteoclasts in wild type and Syndecan-1 lacking cells. Syndecan-1 expression and secretion was increased in osteoblasts with high osteoclastogenic potential. Syndecan-1 deficiency led to increased OPG release by osteoblasts that decreased the availability of RANKL. In co-cultures of Syndecan-1 deficient osteoblasts with osteoclast these increased OPG in supernatant caused decreased development of osteoclasts. Syndecan-1 and RANKL level were increased in serum of aged WT mice, whereas Syndecan-1 deficient mice showed high serum OPG concentration. However, bone structure of Syndecan-1 deficient mice was not different compared to wild type. In conclusion, Syndecan-1 could be regarded as a new modulator of bone-cell-communication via RANKL/OPG axis. This might be of high impact during bone regeneration or bone diseases like cancer where Syndecan-1 expression is known to be even more prevalent.


Assuntos
Osso e Ossos/citologia , Comunicação Celular , Osteoprotegerina/metabolismo , Ligante RANK/metabolismo , Sindecana-1/metabolismo , Envelhecimento/sangue , Animais , Animais Recém-Nascidos , Desenvolvimento Ósseo , Diferenciação Celular , Camundongos Endogâmicos C57BL , Modelos Biológicos , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteogênese , Osteoprotegerina/sangue , Sindecana-1/sangue , Sindecana-1/deficiência
17.
Nat Commun ; 11(1): 5998, 2020 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-33243988

RESUMO

Intratumoral heterogeneity is a common feature of many myeloid leukemias and a significant reason for treatment failure and relapse. Thus, identifying the cells responsible for residual disease and leukemia re-growth is critical to better understanding how they are regulated. Here, we show that a knock-in reporter mouse for the stem cell gene Musashi 2 (Msi2) allows identification of leukemia stem cells in aggressive myeloid malignancies, and provides a strategy for defining their core dependencies. Specifically, we carry out a high throughput screen using Msi2-reporter blast crisis chronic myeloid leukemia (bcCML) and identify several adhesion molecules that are preferentially expressed in therapy resistant bcCML cells and play a key role in bcCML. In particular, we focus on syndecan-1, whose deletion triggers defects in bcCML growth and propagation and markedly improves survival of transplanted mice. Further, live imaging reveals that the spatiotemporal dynamics of leukemia cells are critically dependent on syndecan signaling, as loss of this signal impairs their localization, migration and dissemination to distant sites. Finally, at a molecular level, syndecan loss directly impairs integrin ß7 function, suggesting that syndecan exerts its influence, at least in part, by coordinating integrin activity in bcCML. These data present a platform for delineating the biological underpinnings of leukemia stem cell function, and highlight the Sdc1-Itgß7 signaling axis as a key regulatory control point for bcCML growth and dissemination.


Assuntos
Crise Blástica/terapia , Leucemia Mieloide Aguda/terapia , Células-Tronco Neoplásicas/patologia , Proteínas de Ligação a RNA/genética , Sindecana-1/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Crise Blástica/genética , Crise Blástica/patologia , Quimiorradioterapia/métodos , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Técnicas de Introdução de Genes , Técnicas de Inativação de Genes , Genes Reporter/genética , Proteínas de Fluorescência Verde/química , Proteínas de Fluorescência Verde/genética , Ensaios de Triagem em Larga Escala , Humanos , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Cadeias beta de Integrinas/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Camundongos Transgênicos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/efeitos da radiação , RNA-Seq , Transdução de Sinais/efeitos dos fármacos , Sindecana-1/genética , Sindecana-1/metabolismo
18.
Biomed Res Int ; 2020: 5845374, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33195694

RESUMO

Syndecan-1 (CD138) is a transmembrane proteoglycan expressed in various normal and malignant tissues. It is of interest due to a possible prognostic effect in tumors and its role as a target for the antibody-drug conjugate indatuximab ravtansine. Here, we analyzed 17,747 prostate cancers by immunohistochemistry. Membranous and cytoplasmic CD138 staining was separately recorded. In normal prostate glands, CD138 staining was limited to basal cells. In cancers, membranous CD138 positivity was seen in 19.6% and cytoplasmic CD138 staining in 11.2% of 12,851 interpretable cases. A comparison with clinico-pathological features showed that cytoplasmic CD138 staining was more linked to unfavorable tumor features than membranous staining. Cytoplasmic CD138 immunostaining was associated with high tumor stage (p < 0.0001), high Gleason grade (p < 0.0001), nodal metastases (p < 0.0001), positive surgical margin (p < 0.0001), and biochemical recurrence (p < 0.0001). This also holds true for both V-ets avian erythroblastosis virus E26 oncogene homolog (ERG) fusion positive and ERG fusion negative tumors although the cytoplasmic CD138 expression was markedly more frequent in ERG positive than in ERG negative tumors (p < 0.0001). Comparison with 11 previously analyzed chromosomal deletions identified a conspicuous association between cytoplasmic CD138 expression and 8p deletions (p < 0.0001) suggesting a possible functional interaction of CD138 with one or several 8p genes. Multivariate analysis revealed the cytoplasmic CD138 expression as an independent prognostic parameter in all cancers and in the ERG positive subgroup. In summary, our study indicates the cytoplasmic CD138 expression as a strong and independent predictor of poor prognosis in prostate cancer. Immunohistochemical measurement of CD138 protein may thus-perhaps in combination with other parameters-become clinically useful in the future.


Assuntos
Citoplasma/metabolismo , Recidiva Local de Neoplasia/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Sindecana-1/metabolismo , Idoso , Membrana Celular/metabolismo , Proliferação de Células/genética , Deleção de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Proteínas de Fusão Oncogênica/metabolismo , Fenótipo , Modelos de Riscos Proporcionais , Próstata/metabolismo , Próstata/patologia
19.
Aging (Albany NY) ; 12(22): 23067-23081, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-33197893

RESUMO

Multiple myeloma (MM) is a disease in which abnormal plasma cells proliferate and secrete monoclonal immunoglobulin in the bone marrow. The main characteristic of plasma cells is the expression of the cell surface antigen syndecan-1 (CD138). However, the expression of CD138 is limited to terminally differentiated plasma cells during B cell development. A small subpopulation (2~5%) of human MM cells that lack CD138 expression has been shown to possess enormous proliferation potential in vitro experiment and in animal models, and they also can differentiate into CD138+ plasma cells. Thus, this small subset of MM cells was regarded as myeloma cancer stem cell (MCSC). However, its characteristics associated with the pathogenesis of MM remain unclear. In this study, we analyzed the gene expression data of CD138 cell lines downloaded from Gene Expression Omnibus (GEO) database. Limma package in RStudio was used to identify differentially expressed genes (DEGs). Genes enrichment and protein-protein interaction (PPI) network analysis were performed on DAVID and STRING databases. Furthermore, overall survival (OS) analysis in MM patient was utilized to screen out the hub-genes closely associate with the MM pathogenesis process. Hub-genes expression validation and receiver operating characteristic curve (ROC) analysis was performed in different stages of plasma cell disorder diseases. Finally, we verified these findings in MM patient samples. Through integrated bioinformatics analysis of MM CD138- and CD138+ cell lines, we found that CDC7, CDK1, and CHK1 are highly expressed in CD138- MM cells. These genes are crucial in the G2/M phase of the cell cycle pathway, which is closely related to the malignant proliferation in various tumor cells. Of note, we found that patients with high expression of CDC7, CDK1, and CHK1 had shorter overall survival time. The expression of CHK1 was significantly increased in MM cells compared with normal plasma cell (NPC) and MGUS. More importantly, we further clarified that the expression of CHK1 in release/refraction MM (R/R MM) has obviously increased compared with new diagnosed MM (ND MM).


Assuntos
Quinase 1 do Ponto de Checagem/metabolismo , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/mortalidade , Sindecana-1/metabolismo , Adulto , Idoso , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mapas de Interação de Proteínas , Sensibilidade e Especificidade
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