RESUMEN
Macrophages (MΦs) are an abundant component in the multiple myeloma (MM) environment and contribute to MM drug resistance. We previously showed that interleukin-32 (IL-32) is highly expressed in MM patients and induces the immunosuppressive function of MΦs. The present study was designed to explore the role of IL-32 in MΦ-mediated MM drug resistance and the underlying mechanism. Our analysis revealed that IL-32 expression was upregulated in relapsed MM patients and associated with CD206+ M2 MΦ infiltration. Subsequently, we found that the most active isoform, IL-32γ, promoted MΦs to protect MM cells from drug-induced apoptosis both in vitro and in vivo. Furthermore, by evaluating many parameters, including surface markers, cytokines, metabolic enzymes and characteristic molecules, IL-32γ was verified to induce the polarization of M2 MΦs, a function that was partly dependent on increasing the expression of colony-stimulating factor 1 (CSF1). Taken together, the results of our study indicate that IL-32γ promotes MΦ-mediated MM drug resistance and modifies MΦs toward the M2 phenotype, providing a crucial theoretical basis for targeted MΦ immunotherapy.
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Factor Estimulante de Colonias de Macrófagos , Mieloma Múltiple , Humanos , Factor Estimulante de Colonias de Macrófagos/metabolismo , Mieloma Múltiple/metabolismo , Resistencia a Antineoplásicos , Macrófagos/metabolismo , Interleucinas/metabolismoRESUMEN
Background: Multiple myeloma (MM) is a malignant proliferative disease of the blood system, characterized by the abnormal growth of clonal plasma cells in the bone marrow. The bone marrow microenvironment (BMM) is highly critical in the pathological process of MM. Many studies have shown that serum interleukin-17A (IL-17A) plays a key role in various infectious diseases, autoimmune diseases, and cancers. However, more clinical studies need to be performed to further prove the influence of serum IL-17A levels on multiple myeloma patients. Methods: Among a total of 357 participants in our institution's MM cohort, 175 were eligible for the retrospective study. Multivariate regression models adjusted by potential confounding factors, the violin plots, the generalized additive model and smooth curve fittings, receiver operating characteristic (ROC) curve, and Kaplan-Meier (K-M) curve analysis were applied to the research. Results: A total of 175 patients with newly diagnosed MM were enrolled in this study. The multivariate linear regression analysis showed that serum IL-17A level in MM patients correlated with the degree of bone lesions and fracture incidence (fully adjusted model, pbone lesion < 0.0001, pfracture < 0.0001). The violin plot showed that MM patients with higher serum IL-17A levels had more severe bone lesions and higher fracture incidence than those with lower serum IL-17A levels. A total of 171 patients were included in the study of the relationship between serum IL-17A and best overall effect (BOE). We found that serum IL-17A levels were independently related to the best inductive therapeutic efficacy (fully adjusted model, p = 0.037), and the relationship was especially obvious in the light chain group (fully adjusted model, p = 0.009) and IgA group (fully adjusted model, p = 0.0456). It could be deduced from the smooth curve that the higher the serum IL-17A level, the worse the BOE (p = 0.0163). The ROC prediction curve suggested that serum IL-17A could predict the BOE to a certain extent (area under the curve (AUC) = 0.717, p = 0.0327). A total of 148 MM patients were observed in the longitudinal study of the relationship between serum IL-17A and progression-free survival/overall survival (PFS/OS). The K-M curve analysis indicated that serum IL-17A levels in MM patients were not significantly correlated with PFS and OS. However, in the light chain subgroup, MM patients with high serum IL-17A had worse PFS (p = 0.015) and OS (p = 0.0076) compared to those with low serum IL-17A. In the IgA type subgroup, the higher IL-17A level was related to worse OS (p = 0.0061). Conclusion: This retrospective study found that higher levels of serum IL-17A were independently correlated with higher severity of bone disease and fracture incidence in newly diagnosed MM patients. High serum IL-17A level was related to poor best overall efficacy in the light chain type. High serum IL-17A was also associated with poor PFS and OS in the light chain type and OS in the IgA type subgroup.
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Multiple myeloma (MM) is characterized by an accumulation of monoclonal plasma cells within the bone marrow (BM). Macrophages are an abundant component of myeloma BM microenvironment and support survival of the malignant cells and foster myeloma development and progression by suppression of the immune response. In our previous study, we found that MM patients overexpress pro-inflammatory cytokine interleukin-32 (IL-32). The present study aimed to investigate the role of IL-32 in myeloma progression and mechanisms of IL-32 on macrophages functions. We discovered that the expression of IL-32 was associated with the disease stage in myeloma patients. MM-derived exosomes containing IL-32γ promoted the expression of programmed death-ligand 1(PD-L1) by macrophages, thus promoting immune evasion. Mechanistically, myeloma-secreted IL-32γ acted via proteinase 3 (PR3) to enhance 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) dependent glycolysis and subsequent PD-L1 expression. Moreover, the PFKFB3-Janus kinase 1 (JAK1) axis might contribute to the expression of PD-L1 by macrophages. To sum up, we concluded that IL-32 was a critical mediator in myeloma progression, and targeting IL-32 signaling might be used as a potential strategy for treating myeloma.
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Antígeno B7-H1 , Interleucinas , Mieloma Múltiple , Antígeno B7-H1/genética , Humanos , Interleucinas/fisiología , Janus Quinasa 1/metabolismo , Macrófagos/metabolismo , Mieloma Múltiple/metabolismo , Fosfofructoquinasa-2/metabolismo , Microambiente TumoralRESUMEN
RNA demethylase ALKBH5 takes part in the modulation of N6-methyladenosine (m6A) modification and controls various cell processes. ALKBH5-mediated m6A demethylation regulates gene expression by affecting multiple events in RNA metabolism, e.g., pre-mRNA processing, mRNA decay and translation. Mounting evidence shows that ALKBH5 plays critical roles in a variety of human malignancies, mostly via post-transcriptional regulation of oncogenes or tumor suppressors in an m6A-dependent manner. Meanwhile, increasing non-coding RNAs are recognized as functional targets of ALKBH5 in cancers. Here we reviewed up-to-date findings about the pathological roles of ALKBH5 in cancer, the molecular mechanisms by which it exerts its functions, as well as the underlying mechanism of its dysregulation. We also discussed the therapeutic implications of targeting ALKBH5 in cancer and potential ALKBH5-targeting strategies.
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Desmetilasa de ARN, Homólogo 5 de AlkB/metabolismo , Neoplasias/metabolismo , ARN/metabolismo , Adenosina/análogos & derivados , Adenosina/genética , Adenosina/metabolismo , Desmetilasa de ARN, Homólogo 5 de AlkB/química , Desmetilasa de ARN, Homólogo 5 de AlkB/genética , Animales , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Humanos , Modelos Moleculares , Neoplasias/genética , ARN/genética , Procesamiento Postranscripcional del ARNRESUMEN
BACKGROUND: Acute promyelocytic leukemia differentiation syndrome (APL DS) is a common and severe complication seen in patients with APL treated with all-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO). The presenting symptoms of APL DS are diverse, and rare symptoms are easy to be misdiagnosed. Therefore, it is very crucial to identify DS from uncommon signs to avoid delay in treatment. CASE PRESENTATION: Here, we report a patient of APL who developed severe abdominal pain during ATRA and ATO therapy, with increasing leukocyte count. Organic diseases were firstly excluded, and empiric treatment for DS was adopted. The abdominal pain was gradually relieved and the patient eventually achieved complete remission. CONCLUSION: This case history suggests that APL DS may manifest as severe abdominal pain, and the early identification of DS and immediate treatment could improve the prognosis of patients.
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Macrophages are critical mediators of tissue homeostasis, with the function of tissue development and repair, but also in defense against pathogens. Tumor-associated macrophages (TAMs) are considered as the main component in the tumor microenvironment and play an important role in tumor initiation, growth, invasion, and metastasis. Recently, metabolic studies have revealeded specific metabolic pathways in macrophages are tightly associated with their phenotype and function. Generally, pro-inflammatory macrophages (M1) rely mainly on glycolysis and exhibit impairment of the tricarboxylic acid (TCA) cycle and mitochondrial oxidative phosphorylation (OXPHOS), whereas anti-inflammatory macrophages (M2) are more dependent on mitochondrial OXPHOS. However, accumulating evidence suggests that macrophage metabolism is not as simple as previously thought. This review discusses recent advances in immunometabolism and describes how metabolism determines macrophage phenotype and function. In addition, we describe the metabolic characteristics of TAMs as well as their therapeutic implications. Finally, we discuss recent obstacles facing this area as well as promising directions for future study.
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Lung adenocarcinoma (LUAD) is the predominant subtype of lung cancer with a relatively poor prognosis. The dramatic improvements of new immunotherapy strategies have shown promising results in lung cancer patients. This study aimed to elucidate the functions of immune-associated genes in LUAD prognosis and pathogenesis by analyzing public databases. We obtained expression profiles of LUAD patients from The Cancer Genome Atlas (TCGA) database and applied the ESTIMATE algorithm to calculate immune scores and stromal scores. A series of microenvironment-related genes with prognostic value was then identified. Of note, heat shock factor 5 (HSF5) was found to be decreased in LUAD patients and positively correlated with overall survival, which was further confirmed in the Gene Expression Omnibus (GEO) database. Moreover, Gene Ontology (GO) analysis based on the correlated genes of HSF5 demonstrated that HSF5 expression was significantly associated with the immune response and inflammatory activities. Based on the Tumor IMmune Estimation Resource (TIMER) and Gene Expression Profiling Interactive Analysis (GEPIA) datasets, HSF5 expression showed strong correlations with various immune cell infiltration and diverse immune marker sets. These findings suggest that HSF5 can be used as a promising biomarker for determining prognosis and immune infiltration in LUAD patients.
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Adenocarcinoma del Pulmón/genética , Biomarcadores de Tumor/metabolismo , Regulación Neoplásica de la Expresión Génica/inmunología , Factores de Transcripción del Choque Térmico/metabolismo , Neoplasias Pulmonares/genética , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/mortalidad , Adenocarcinoma del Pulmón/patología , Conjuntos de Datos como Asunto , Perfilación de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Pulmón/inmunología , Pulmón/patología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Pronóstico , RNA-Seq , Microambiente Tumoral/genética , Microambiente Tumoral/inmunologíaRESUMEN
Dihydroartemisinin (DHA), an active metabolite and derivative of artemisinin, is the most effective antimalarial drug and has strong antitumor activity in various tumor types. It has recently been reported that DHA can induce autophagy and has significant effects on multiple myeloma (MM), but the mechanisms and the relationship between the autophagy and apoptosis induced by DHA remain to be elucidated. Herein, we demonstrated that DHA significantly induces cell death in a dose- and time-dependent manner via the extrinsic and intrinsic apoptosis pathways. Moreover, DHA-induced autophagy, which plays a prodeath role in MM, can regulate canonical apoptosis and vice versa. Furthermore, the P38/MAPK signaling pathway is responsible for decreased autophagy and increased apoptosis. DHA induces autophagy and apoptosis also through the inhibition of the Wnt/ß-catenin signaling pathway. In addition, DHA shows a strong effect in a xenograft mouse model. Collectively, these findings reveal that DHA, as an artemisinin-based drug, could be an effective and safe therapeutic agent for MM.
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Apoptosis/efectos de los fármacos , Artemisininas/farmacología , Autofagia/efectos de los fármacos , Mieloma Múltiple/patología , Vía de Señalización Wnt , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Ratones Endogámicos NOD , Modelos Biológicos , Vía de Señalización Wnt/efectos de los fármacosRESUMEN
Calcific aortic valve disease (CAVD) is highly prevalent in our aging world and has no effective pharmaceutical treatment. Intense efforts have been made but the underlying molecular mechanisms of CAVD are still unclear.This study was designed to identify the critical genes and pathways in CAVD by bioinformatics analysis. Microarray datasets of GSE12644, GSE51472, and GSE83453 were obtained from Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified and functional and pathway enrichment analysis was performed. Subsequently, the protein-protein interaction network (PPI) was constructed with Search Tool for the Retrieval of Interacting Genes and was visualized with Cytoscape to identify the most significant module. Hub genes were identified by Cytoscape plugin cytoHubba.A total of 179 DEGs, including 101 upregulated genes and 78 downregulated genes, were identified. The enriched functions and pathways of the DEGs include inflammatory and immune response, chemotaxis, extracellular matrix (ECM) organization, complement and coagulation cascades, ECM receptor interaction, and focal adhesion. The most significant module in the PPI network was analyzed and genes among it were mainly enriched in chemotaxis, locomotory behavior, immune response, chemokine signaling pathway, and extracellular space. In addition, DEGs, with degrees ≥ 10 and the top 10 highest Maximal Chique Centrality (MCC) score, were identified as hub genes. CCR1, MMP9, VCAM1, and ITGAX, which were of the highest degree or MCC score, were manually reviewed.The DEGs and hub genes identified in the present study help us understand the molecular mechanisms underlying the pathogenesis of CAVD and might serve as candidate therapeutic targets for CAVD.
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Estenosis de la Válvula Aórtica/genética , Válvula Aórtica/patología , Calcinosis/genética , Genes/genética , Predisposición Genética a la Enfermedad/genética , Estenosis de la Válvula Aórtica/etiología , Calcinosis/etiología , Estudios de Casos y Controles , Biología Computacional , Genes/fisiología , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
E3 ubiquitin ligases primarily determine the substrate specificity of the ubiquitin-proteasome system and play an essential role in the resistance to bortezomib in multiple myeloma (MM). Neural precursor cell-expressed developmentally downregulated gene 4-1 (NEDD4-1, also known as NEDD4) is a founding member of the NEDD4 family of E3 ligases and is involved in the proliferation, migration, invasion and drug sensitivity of cancer cells. In the present study, we investigated the role of NEDD4-1 in MM cells and explored its underlying mechanism. Clinically, low NEDD4-1 expression has been linked to poor prognosis in patients with MM. Functionally, NEDD4-1 knockdown (KD) resulted in bortezomib resistance in MM cells in vitro and in vivo. The overexpression (OE) of NEDD4-1, but not an enzyme-dead NEDD4-1-C867S mutant, had the opposite effect. Furthermore, the overexpression of NEDD4-1 in NEDD4-1 KD cells resensitized the cells to bortezomib in an add-back rescue experiment. Mechanistically, pAkt-Ser473 levels and Akt signaling were elevated and decreased by NEDD4-1 KD and OE, respectively. NEDD4-1 ubiquitinated Akt and targeted pAkt-Ser473 for proteasomal degradation. More importantly, the NEDD4-1 KD-induced upregulation of Akt expression sensitized MM cells to growth inhibition after treatment with an Akt inhibitor. Collectively, our results suggest that high NEDD4-1 levels may be a potential new therapeutic target in MM.
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Bortezomib/farmacología , Resistencia a Antineoplásicos , Mieloma Múltiple/patología , Ubiquitina-Proteína Ligasas Nedd4/metabolismo , Animales , Bortezomib/uso terapéutico , Línea Celular Tumoral , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Ratones , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/mortalidad , Ubiquitina-Proteína Ligasas Nedd4/genética , Cultivo Primario de Células , Pronóstico , Proteolisis , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ubiquitinación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We previously showed that the chemokine CCL2 can recruit macrophages (Mφs) to the bone marrow (BM) in multiple myeloma (MM) and that myeloma-associated Mφs are important in drug resistance. Here, we explore the role of increased CCL2 expression in the BM microenvironment of MM and elucidate the underlying mechanism. Our results show that CCL2 expression is associated with the treatment status of MM patients. Mφs interact with MM cells and further upregulate their expression of CCL2. These increased level of CCL2 polarizes Mφs toward the M2-like phenotype and promotes Mφs to protect MM cells from drug-induced apoptosis. Mechanistically, CCL2 upregulated the expression of the immunosuppressive molecular MCP-1-induced protein (MCPIP1) in Mφs. MCPIP1 mediates Mφs' polarization and protection via dual catalytic activities. Additionally, we found that CCL2 induces MCPIP1 expression via the JAK2-STAT3 signaling pathway. Taken together, our results indicate that increased CCL2 expression in MM patients' BM polarizes Mφs toward the M2-like phenotype and promotes the protective effect of Mφs through MCPIP1, providing novel insight into the mechanism of Mφs-mediated drug resistance in MM.
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Apoptosis/genética , Quimiocina CCL2/genética , Mieloma Múltiple/genética , Ribonucleasas/genética , Factores de Transcripción/genética , Animales , Proliferación Celular/genética , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica , Xenoinjertos , Humanos , Janus Quinasa 2/genética , Activación de Macrófagos/genética , Macrófagos/metabolismo , Ratones , Mieloma Múltiple/patología , Factor de Transcripción STAT3/genética , Transducción de Señal/genética , Microambiente Tumoral/genéticaRESUMEN
Acute myeloid leukemia (AML) is a common and lethal hematopoietic malignancy that is highly dependent on the bone marrow (BM) microenvironment. Infiltrating immune and stromal cells are important components of the BM microenvironment and significantly influence the progression of AML. This study aimed to elucidate the value of immune/stromal cell-associated genes for AML prognosis by integrated bioinformatics analysis. We obtained expression profiles from The Cancer Genome Atlas (TCGA) database and used the ESTIMATE algorithm to calculate immune scores and stromal scores; we then identified differentially expressed genes (DEGs) based on these scores. Overall survival analysis was applied to reveal common DEGs of prognostic value. Subsequently, we conducted a functional enrichment analysis, generated a protein-protein interaction (PPI) network and performed an interrelation analysis of immune system processes, showing that these genes are mainly associated with the immune/inflammatory response. Finally, eight genes (CD163, CYP27A1, KCNA5, PPM1J, FOLR1, IL1R2, MYOF, VSIG2) were verified to be significantly associated with AML prognosis in the Gene Expression Omnibus (GEO) database. In summary, we identified key microenvironment-related genes that affect the outcomes of AML patients and might serve as therapeutic targets.
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Médula Ósea/patología , Inflamación/genética , Leucemia Mieloide Aguda/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biología Computacional , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunidad Celular/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Mapas de Interacción de Proteínas , Análisis de Supervivencia , Microambiente Tumoral , Adulto JovenRESUMEN
Multiple myeloma (MM) is a common hematologic malignancy for which the underlying molecular mechanisms remain largely unclear. This study aimed to elucidate key candidate genes and pathways in MM by integrated bioinformatics analysis. Expression profiles GSE6477 and GSE47552 were obtained from the Gene Expression Omnibus database, and differentially expressed genes (DEGs) with p < .05 and [logFC] > 1 were identified. Functional enrichment, protein-protein interaction network construction and survival analyses were then performed. First, 51 upregulated and 78 downregulated DEGs shared between the two GSE datasets were identified. Second, functional enrichment analysis showed that these DEGs are mainly involved in the B cell receptor signaling pathway, hematopoietic cell lineage, and NF-kappa B pathway. Moreover, interrelation analysis of immune system processes showed enrichment of the downregulated DEGs mainly in B cell differentiation, positive regulation of monocyte chemotaxis and positive regulation of T cell proliferation. Finally, the correlation between DEG expression and survival in MM was evaluated using the PrognoScan database. In conclusion, we identified key candidate genes that affect the outcomes of patients with MM, and these genes might serve as potential therapeutic targets.
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Biología Computacional/métodos , Regulación Neoplásica de la Expresión Génica/genética , Redes Reguladoras de Genes/genética , Mieloma Múltiple/genética , Biomarcadores de Tumor/genética , Análisis por Conglomerados , Bases de Datos Genéticas , Perfilación de la Expresión Génica , Humanos , Mieloma Múltiple/patología , Pronóstico , Mapas de Interacción de Proteínas/genética , Transcriptoma/genéticaRESUMEN
High glucose metabolism provides sufficient energy for cancer cells and is enabled by metabolic enzymes. PFKFB3 (6-phosphofructo-2-kinase) accelerates the synthesis of fructose 2,6-bisphosphate (F2,6P2), which is a powerful allosteric regulatory activator of 6-phosphofructo-1-kinase (PFK-1), a rate-limiting enzyme of glycolysis. The aim of this study was to investigate the anti-myeloma function and underlying mechanism of suppressing PFKFB3 via PFK15 (1-(4-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one). The role of PFK15 in killing multiple myeloma (MM) cells was evaluated by cytotoxicity and apoptosis assays, flow cytometry and Western blotting. The oral hypoglycemic drug metformin (Met) was found to inhibit PFKFB3 protein expression by gene chip and Western blotting techniques in our study. PFK15 also demonstrated a synergistic effect with metformin to eliminate MM cells. Taken together, our findings indicate that PFK15 inhibits MM cell proliferation through the PFKFB3/MAPKs/STAT signaling pathway. The combination therapy of PFK15 and metformin may be a promising anticancer drug regimen for the treatment of MM.
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Inhibidores Enzimáticos/administración & dosificación , Metformina/administración & dosificación , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/metabolismo , Fosfofructoquinasa-2/antagonistas & inhibidores , Piridinas/efectos adversos , Quinolinas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Fructosadifosfatos/metabolismo , Glucosa/metabolismo , Humanos , Hipoglucemiantes/administración & dosificación , Mieloma Múltiple/patología , Fosfofructoquinasa-2/genética , Fosfofructoquinasa-2/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
The interaction of multiple myeloma (MM) cells with macrophages (MΦs) contributes to the pathophysiology of MM. We previously showed that IL-32 is overexpressed in MM patients. The present study was designed to explore the clinical significance of IL-32 in MM and to further elucidate the mechanisms underlying the IL-32-mediated immune function of MΦs. Our results showed that high IL-32 expression in MM patients was associated with more advanced clinical stage. RNA-sequencing revealed that IL-32γ significantly induced the production of the immunosuppressive molecule indoleamine 2,3-dioxygenase (IDO) in MΦs, and this effect was verified by qRT-PCR, western blotting, and immunofluorescence. Furthermore, MM cells with IL-32-knockdown showed a reduced ability to promote IDO expression. As a binding protein for IL-32, proteinase 3 (PR3) was universally expressed on the surfaces of MΦs, and knockdown of PR3 or inhibition of the STAT3 and NF-κB pathways hindered the IL-32γ-mediated stimulation of IDO expression. Finally, IDO-positive IL-32γ-educated MΦs inhibited CD4+ T cell proliferation and IL-2, IFN-γ, and TNF-α production. Taken together, our results indicate that IL-32γ derived from MM cells promotes the immunosuppressive function of MΦs and is a potential target for MM treatment.
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Tolerancia Inmunológica , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Interleucinas/metabolismo , Macrófagos/enzimología , Mieloma Múltiple/metabolismo , Comunicación Paracrina , Adulto , Anciano , Línea Celular Tumoral , Medios de Cultivo Condicionados/metabolismo , Femenino , Humanos , Interleucinas/genética , Macrófagos/inmunología , Masculino , Persona de Mediana Edad , Mieloma Múltiple/genética , Mieloma Múltiple/inmunología , Fenotipo , Transducción de Señal , Microambiente TumoralRESUMEN
BACKGROUND: The guiding effect of prognostic stratification in multiple myeloma (MM) for treatment has been increasingly emphasized in recent years. The stratification of risk factors based on the International Staging System (ISS), Durie-Salmon (DS) staging and related indicators is affected by the renal function of patients, resulting in poor performance. This study assesses the relationship between interleukin-32 (IL-32) and related risk factors in 67 patients with MM and their clinical outcomes. AIM: To investigate the feasibility of IL-32 in evaluating prognosis in patients with MM and the factors influencing prognosis. METHODS: This was a pragmatic, prospective observational study of patients with MM at a single center. According to IL-32 level, patients were divided into two groups. The variables under consideration included age, blood ß2-microglobulin, albumin, C-reactive protein, serum calcium, serum creatinine, lactate dehydrogenase, M protein type, ISS stage, DS stage, and IL-32 levels and minimal residual disease (MRD) after induction treatment. The main outcomes were progression-free survival (PFS) and overall survival (OS). RESULTS: IL-32 was an important factor affecting PFS and OS in patients with MM. Compared with patients with IL-32 levels ≥ 856.4 pg/mL, patients with IL-32 levels < 856.4 pg/mL had longer PFS (P = 0.0387) and OS (P = 0.0379); Univariate analysis showed that IL-32 level and MRD were significantly associated with OS and PFS (P < 0.05). Multivariate analysis showed that IL-32 levels ≥ 856.4 pg/mL and MRD positive were still independent risk factors for OS and PFS (P < 0.05). CONCLUSION: IL-32 is valuable for assessing the prognosis of MM patients. IL-32 level combined with MRD may be a useful routine evaluation index for MM patients after treatment.
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Interleukin-32 (IL-32), a novel proinflammatory cytokine, is highly expressed in various cancer tissues and in established cancer cell lines. IL-32 has been revealed to serve a crucial role in human cancer development, including tumour initiation, proliferation and maintenance. The expression of IL-32 is regulated by numerous factors, including genetic variations, hypoxia and acidosis in the tumour microenvironment. Understanding the underlying mechanisms of IL-32 expression and its function are critical for the discovery of novel therapeutic strategies that target IL-32. This is a review of the current literature on the regulation and function of IL-32 in cancer progression, focusing on the molecular pathways linking IL-32 and tumour development.
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Histone deacetylases are promising therapeutic targets in hematological malignancies. In the work herein, we investigated the effect of chidamide, a new subtype-selective histone deacetylase inhibitor that was independently produced in China, on multiple myeloma and its associated bone diseases using different models. The cytotoxicity of chidamide toward myeloma is due to its induction of cell apoptosis and cell cycle arrest by increasing the levels of caspase family proteins p21 and p27, among others. Furthermore, chidamide exhibited significant cytotoxicity against myeloma cells co-cultured with bone mesenchymal stromal cells and chidamide-pretreated osteoclasts. Importantly, chidamide suppressed osteoclast differentiation and resorption in vitro by dephosphorylating p-ERK, p-p38, p-AKT and p-JNK and inhibiting the expression of Cathepsin K, NFATc1 and c-fos. Finally, chidamide not only prevented tumor-associated bone loss in a disseminated murine model by partially decreasing the tumor burden but also prevented rapid receptor activator of nuclear factor κ-ß ligand (RANKL)-induced bone loss in a non-tumor-bearing mouse model. Based on our results, chidamide exerted dual anti-myeloma and bone-protective effects in vitro and in vivo These findings strongly support the potential clinical use of this drug as a treatment for multiple myeloma in the near future.
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Aminopiridinas/uso terapéutico , Benzamidas/uso terapéutico , Enfermedades Óseas/tratamiento farmacológico , Inhibidores de Histona Desacetilasas/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Aminopiridinas/farmacología , Animales , Apoptosis/efectos de los fármacos , Benzamidas/farmacología , Enfermedades Óseas/etiología , Resorción Ósea/tratamiento farmacológico , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Células Cultivadas , Humanos , Ratones , Mieloma Múltiple/complicaciones , Mieloma Múltiple/patología , Osteoblastos/efectos de los fármacos , Osteoclastos/efectos de los fármacosRESUMEN
Multiple myeloma (MM) is a malignant plasma disease closely associated with inflammation. In MM bone marrow microenvironment, bone marrow stromal cells (BMSCs) are the primary source of interleukin-6 (IL-6) secretion, which promotes the proliferation and progression of MM cells. However, it is still unknown how the microenvironment stimulates BMSCs to secrete IL-6. Interleukin-32 (IL-32) is a newly identified pro-inflammatory factor. It was reported that in solid tumors, IL-32 induces changes in other inflammatory factors including IL-6, IL-10, and TNF-α. The aim of this study was to investigate the expression of IL-32 and the role of IL-32 in the MM bone marrow microenvironment. Our data illustrate that MM patients have higher expression of IL-32 than healthy individuals in both bone marrow and peripheral blood. We used ELISA and qRT-PCR to find that malignant plasma cells are the primary source of IL-32 production in MM bone marrow. ELISA and Western blot analysis revealed that recombinant IL-32α induces production of IL-6 in BMSCs by activating NF-κB and STAT3 signaling pathways, konckdown of IL-32 receptor PR3 inhibit this process. Knockdown of IL-32 by shRNA decreased the proliferation in MM cells that induced by BMSCs. In conclusion, IL-32 secreted from MM cells has paracrine effect to induce production of IL-6 in BMSCs, thus feedback to promote MM cells growth.