RESUMO
Efficient predictive biomarkers are needed for immune checkpoint inhibitor (ICI)-based immunotherapy in non-small cell lung cancer (NSCLC). Testing the predictive value of single nucleotide polymorphisms (SNPs) in programmed cell death 1 (PD-1) or its ligand 1 (PD-L1) has shown contrasting results. Here, we aim to validate the predictive value of PD-L1 SNPs in advanced NSCLC patients treated with ICIs as well as to define the molecular mechanisms underlying the role of the identified SNP candidate. rs822336 efficiently predicted response to anti-PD-1/PD-L1 immunotherapy in advanced non-oncogene addicted NSCLC patients as compared to rs2282055 and rs4143815. rs822336 mapped to the promoter/enhancer region of PD-L1, differentially affecting the induction of PD-L1 expression in human NSCLC cell lines as well as their susceptibility to HLA class I antigen matched PBMCs incubated with anti-PD-1 monoclonal antibody nivolumab. The induction of PD-L1 expression by rs822336 was mediated by a competitive allele-specificity binding of two identified transcription factors: C/EBPß and NFIC. As a result, silencing of C/EBPß and NFIC differentially regulated the induction of PD-L1 expression in human NSCLC cell lines carrying different rs822336 genotypes. Analysis by binding microarray further validated the competitive allele-specificity binding of C/EBPß and NFIC to PD-L1 promoter/enhancer region based on rs822336 genotype in human NSCLC cell lines. These findings have high clinical relevance since identify rs822336 and induction of PD-L1 expression as novel biomarkers for predicting anti-PD-1/PD-L1-based immunotherapy in advanced NSCLC patients.
Assuntos
Antígeno B7-H1 , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Biomarcadores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Fatores de Transcrição NFI/metabolismo , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêuticoRESUMO
OBJECTIVES: BAG3 (Bcl2-associated athanogene3) is able to induce the transformation of cancer-associated fibroblasts to alpha smooth muscle actin (a-SMA) positive (+) myofibroblasts. In systemic sclerosis (SSc), a-SMA+ myofibroblasts also play an important role in the progression of fibrosis in the skin and involved internal organs. The aim of the study was to investigate whether BAG3 is overexpressed in SSc and may be a biomarker of fibrogenesis. METHODS: BAG3 serum levels were measured in 106 patients with SSc, 47 with the limited (lc) and 59 the diffuse (dc) SSc, and in age- and sex-matched healthy controls (HC). BAG3 levels were then compared according to their clinical subset, nailfold video-capillaroscopic (NVC) patterns, interstitial lung disease (ILD, and correlated with modified Rodnan skin score (mRSS) and global disease activity. BAG3 expression was also investigated in skin biopsies of 8 dcSSc patients. RESULTS: BAG3 serum levels were significantly higher in dcSSc (143.3 pg/mL, 95%CI 78-208.5) than in HC (0.68 pg/mL, 95%CI 0.13-1.23), and were significantly higher in patients with late NVC pattern and ILD but did not correlate with disease activity and mRSS. Of note, BAG3 was strongly expressed in the skin biopsies of dcSSc patients. CONCLUSIONS: BAG3 is overexpressed in dcSSc patients and may contribute to skin and organ fibrosis by prompting the transition of fibroblasts into myofibroblasts and increasing their survival. Thus, BAG3 may play an important role in SSc fibrotic pathogenesis and be a potential biomarker of fibrosis. Further research on its role as a therapeutic target is warranted.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Proteínas Reguladoras de Apoptose , Biomarcadores , Pele , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Reguladoras de Apoptose/sangue , Pele/patologia , Pele/metabolismo , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Fibrose , Idoso , Regulação para Cima , Esclerodermia Difusa/sangue , Esclerodermia Limitada/sangue , Esclerodermia Limitada/diagnóstico , Biópsia , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/patologia , Escleroderma Sistêmico/metabolismoRESUMO
Climate change and globalization have raised the risk of vector-borne disease (VBD) introduction and spread in various European nations in recent years. In Italy, viruses carried by tropical vectors have been shown to cause viral encephalitis, one of the symptoms of arboviruses, a spectrum of viral disorders spread by arthropods such as mosquitoes and ticks. Arboviruses are currently causing alarm and attention, and the World Health Organization (WHO) has released recommendations to adopt essential measures, particularly during the hot season, to restrict the spreading of the infectious agents among breeding stocks. In this scenario, rapid analysis systems are required, because they can quickly provide information on potential virus-host interactions, the evolution of the infection, and the onset of disabling clinical symptoms, or serious illnesses. Such systems include bioinformatics approaches integrated with molecular evaluation. Viruses have co-evolved different strategies to transcribe their own genetic material, by changing the host's transcriptional machinery, even in short periods of time. The introduction of genetic alterations, particularly in RNA viruses, results in a continuous adaptive fight against the host's immune system. We propose an in silico pipeline method for performing a comprehensive motif analysis (including motif discovery) on entire genome sequences to uncover viral sequences that may interact with host RNA binding proteins (RBPs) by interrogating the database of known RNA binding proteins, which play important roles in RNA metabolism and biological processes. Indeed, viral RNA sequences, able to bind host RBPs, may compete with cellular RNAs, altering important metabolic processes. Our findings suggest that the proposed in silico approach could be a useful and promising tool to investigate the complex and multiform clinical manifestations of viral encephalitis, and possibly identify altered metabolic pathways as targets of pharmacological treatments and innovative therapeutic protocols.
Assuntos
Arbovírus , Encefalite Viral , Animais , Humanos , Arbovírus/genética , Sequência de Bases , Mosquitos Vetores , RNA Viral/genética , Encefalite Viral/genética , Proteínas de Ligação a RNA/genéticaRESUMO
Hypoxia and angiogenesis in solid tumors are often strictly linked to the development of fibrotic tissues, a detrimental event that compromises the antitumor immunity. As a consequence, tumor aggressiveness and poor patient prognosis relate to higher incidence of tissue fibrosis and stromal stiffness. The molecular pathways through which normal fibroblasts are converted in cancer-associated fibroblasts (CAFs) have a central role in the onset of fibrosis in tumor stroma, thus emerging as a strategic target of novel therapeutic approaches for cancer disease. Several studies addressed the role of BAG3 in sustaining growth and survival of cancer cell and also shed light on the different mechanisms in which the intracellular protein is involved. More recently, new pieces of evidence revealed a pivotal role of extracellular BAG3 in pro-tumor cell signaling in the tumor microenvironment, as well as its involvement in the development of fibrosis in tumor tissues. Here we report further data showing the presence of the BAG3 receptor (Interferon-induced transmembrane protein [IFITM]-2) on the plasma membrane of normal dermal fibroblasts and the activity of BAG3 as a factor able to induce the expression of α-smooth muscle actin and the phosphorylation of AKT and focal adhesion kinase, that sustain CAF functions in tumor microenvironment. Furthermore, in agreement with these findings, bag3 gene expression has been analyzed by high throughput RNA sequencing databases from patients-derived xenografts. A strong correlation between bag3 gene expression and patients' survival was found in several types of fibrotic tumors. The results obtained provide encouraging data that identify BAG3 as a promising therapeutic target to counteract fibrosis in tumors.
Assuntos
Actinas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/farmacologia , Adenocarcinoma/genética , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/farmacologia , Fibroblastos Associados a Câncer/metabolismo , Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Neoplasias Hepáticas/genética , Mesotelioma/genética , Neoplasias Pancreáticas/genética , Transdução de Sinais/efeitos dos fármacos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Fibroblastos Associados a Câncer/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Proteínas de Membrana/metabolismo , Mesotelioma/metabolismo , Mesotelioma/patologia , Camundongos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Fosforilação/efeitos dos fármacos , Prognóstico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Pancreatic ductal adenoma carcinoma (PDAC) is considered one of the deadliest solid cancers as it is usually diagnosed in advanced stages and has a poor response to treatment. The enormous effort made in the last 2 decades in the oncology field has not led to significant progress in improving early diagnosis or therapy for PDAC. The stroma of PDAC plays an active role in tumour initiation and progression and includes immune cells and stromal cells. We previously reported that Bcl2-associated athanogene (BAG3) secreted by PDAC cells activates tumour-associated macrophages to promote tumour growth. The disruption of this tumour-stroma axis by the anti-BAG3 H2L4 therapeutic antibody is sufficient to delay tumour growth and limit metastatic spreading in different PDAC preclinical models. In the present study, we examined the role of BAG3 to activate human fibroblasts (HF) in releasing cytokines capable of supporting tumour progression. Treatment of fibroblasts with recombinant BAG3 induced important changes in the organisation of the cytoskeleton of these cells and stimulated the production of interleukin-6, monocyte chemoattractant protein-1/C-C motif chemokine ligand 2, and hepatocyte growth factor. Specifically, we observed that BAG3 triggered a depolymerisation of microtubules at the periphery of the cell while they were conserved in the perinuclear area. Conversely, the vimentin-based intermediate filaments increased and spread to the edges of the cells. Finally, the conditioned medium (CM) collected from BAG3-treated HF promoted the survival, proliferation, and migration of the PDAC cells. Blocking of the PDAC-fibroblast axis by the H2L4 therapeutic anti-BAG3 antibody, resulted in inhibition of cytokine release and, consequently, the inhibition of the migratory phenotype conferred by the CM to PDAC cells.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/farmacologia , Proteínas Reguladoras de Apoptose/farmacologia , Carcinoma Ductal Pancreático/metabolismo , Movimento Celular/efeitos dos fármacos , Citocinas/metabolismo , Citocinas/farmacologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Neoplasias Pancreáticas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/imunologia , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Humanos , Neoplasias Pancreáticas/patologia , Proteínas Recombinantes/farmacologia , Células Sf9 , SpodopteraRESUMO
Diuron [3-(3,4-dichlorophenyl)-1,1-dimethylurea] is a substituted urea herbicide, carcinogenic for the rat urinary bladder. It has been hypothesized that Diuron cytotoxicity, resulting in regenerative proliferation, leads to urothelial hyperplasia and, finally, to bladder tumors, but molecular mechanisms of carcinogenesis have not still fully investigated. Here, we report the results of a study aimed at verifying the involvement of BAG3, an intracellular protein expressed in several tumors, in the Diuron-induced carcinogenesis. For this purpose, we analyzed the effect of Diuron on human primary urothelial cells and on human dermal fibroblasts. We found that while high concentrations of Diuron have a cytotoxic effect in human primary urothelial cells, in the same cells, noncytotoxic concentrations of the herbicide induce BAG3 expression. These findings show that BAG3 is a molecular target of Diuron and unravel the possible involvement of BAG3 protein in bladder carcinogenesis induced by the herbicide. In addition, these results suggest that BAG3 might be a potential early biomarker of damage induced by chronic exposure to Diuron.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Carcinógenos/toxicidade , Diurona/toxicidade , Herbicidas/toxicidade , Urotélio/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/genética , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/genética , Células Cultivadas , Relação Dose-Resposta a Droga , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Masculino , Regulação para Cima , Urotélio/metabolismo , Urotélio/patologiaRESUMO
BAG3, a member of the BAG family of co-chaperones, is a multidomain protein with a role in several cellular processes, including the control of apoptosis, autophagy and cytoskeletal dynamics. The expression of bag3 is negligible in most cells but can be induced by stress stimuli or malignant transformation. In some tumours, BAG3 has been reported to promote cell survival and resistance to therapy. The expression of BAG3 has been documented in ovarian, endometrial and cervical cancers, and studies have revealed biochemical and functional connections of BAG3 with proteins involved in the survival, invasion and resistance to therapy of these malignancies. BAG3 expression has also been shown to correlate with the grade of dysplasia in squamous intraepithelial lesions of the uterine cervix. Some aspects of BAG3 activity, such as its biochemical and functional interaction with the human papillomavirus proteins, could help in our understanding of the mechanisms of oncogenesis induced by the virus. This review aims to highlight the potential value of BAG3 studies in the field of gynaecological tumours.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Resistencia a Medicamentos Antineoplásicos , Neoplasias dos Genitais Femininos/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Neoplasias dos Genitais Femininos/tratamento farmacológico , Neoplasias dos Genitais Femininos/patologia , Humanos , Gradação de Tumores , Invasividade Neoplásica , Análise de SobrevidaRESUMO
BAG3 is a multifunctional protein that can bind to heat shock proteins (Hsp) 70 through its BAG domain and to other partners through its WW domain, proline-rich (PXXP) repeat and IPV (Ile-Pro-Val) motifs. Its intracellular expression can be induced by stressful stimuli, while is constitutive in skeletal muscle, cardiac myocytes and several tumour types. BAG3 can modulate the levels, localisation or activity of its partner proteins, thereby regulating major cell pathways and functions, including apoptosis, autophagy, mechanotransduction, cytoskeleton organisation, motility. A secreted form of BAG3 has been identified in studies on pancreatic ductal adenocarcinoma (PDAC). Secreted BAG3 can bind to a specific receptor, IFITM2, expressed on macrophages, and induce the release of factors that sustain tumour growth and the metastatic process. BAG3 neutralisation therefore appears to constitute a novel potential strategy in the therapy of PDAC and, possibly, other tumours.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Carcinoma Ductal Pancreático/patologia , Proteínas de Choque Térmico HSP70/metabolismo , Neoplasias Pancreáticas/patologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Apoptose/fisiologia , Proteínas Reguladoras de Apoptose/genética , Autofagia/fisiologia , Biomarcadores Tumorais/sangue , Carcinoma Ductal Pancreático/genética , Humanos , Macrófagos/metabolismo , Mecanotransdução Celular/fisiologia , Proteínas de Membrana/metabolismo , Neoplasias Pancreáticas/genética , Comunicação Parácrina/fisiologia , Domínios Proteicos/fisiologiaRESUMO
INTRODUCTION: Bcl-2-associated athanogene 3 (BAG3) is a protein involved in apoptosis and stress response, which is overexpressed in invasive cervical cancer. However, nothing is known about BAG3 expression in precancerous lesions of the uterine cervix. We aimed to evaluate the expression of BAG3 in cervical intraepithelial neoplasia/squamous intraepithelial lesions (CIN/SIL). MATERIAL AND METHODS: Forty patients (16 CIN1/L-SIL, 11 CIN2/H-SIL and 13 CIN3/H-SIL) were assessed by immunohistochemistry for BAG3. The intensity of BAG3 expression was categorized as null, minimal, weak, moderate or strong. The association of BAG2 intensity of expression with the grade of dysplasia was assessed using Chi-square test (significant P value <0.05). RESULTS: In all normal controls, BAG3 expression was negative. In L-SIL specimens, BAG3 expression was confined to the basal third of the epithelium, with an intensity minimal in nine cases (56.3%), weak in six (37.5%) and strong in one (6.3%). In H-SIL specimens, BAG3 expression involved also the two upper thirds of the epithelium, with an intensity moderate in 13 cases (54.2%; 8 CIN2 and 5 CIN3) and strong in 11 cases (45.8%; 3 CIN2 and 8 CIN3). The distribution of BAG3 expression correlated perfectly with the grade of dysplasia (P = 0.0); a moderate/strong expression of BAG3 was significantly associated with H-SIL (P < 0.0001), with no significant difference between CIN2 and CIN3 (P = 0.1228). CONCLUSIONS: In CIN/SIL, both distribution and intensity of BAG3 expression correlate directly with the grade of dysplasia, supporting the involvement of BAG3 in all phases of cervical carcinogenesis and its possible diagnostic and prognostic role in cervical premalignant lesions.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Lesões Intraepiteliais Escamosas/metabolismo , Displasia do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Gradação de Tumores , Lesões Intraepiteliais Escamosas/patologia , Neoplasias do Colo do Útero/patologia , Displasia do Colo do Útero/patologiaAssuntos
Proteínas Adaptadoras de Transdução de Sinal , Proteínas Reguladoras de Apoptose , Psoríase , Humanos , Psoríase/sangue , Proteínas Adaptadoras de Transdução de Sinal/sangue , Masculino , Feminino , Proteínas Reguladoras de Apoptose/sangue , Proteínas Reguladoras de Apoptose/metabolismo , Pessoa de Meia-Idade , AdultoRESUMO
The Bcl2-associated athanogene-3 (BAG3) protein, a critical regulator of cellular survival, has been identified as a potential therapeutic target in various malignancies. This study investigates the role of BAG3 within stromal fibroblasts and its interaction with B-cell chronic lymphocytic leukemia (B-CLL) cells. Previous research demonstrated that BAG3 maintains the active state of pancreatic stellate cells (PSCs) and aids pancreatic ductal adenocarcinoma (PDAC) spread via cytokine release. To explore BAG3's role in bone marrow-derived stromal fibroblasts, BAG3 was silenced in HS-5 cells using siRNA. In co-culture experiments with PBMCs from B-CLL patients, BAG3 silencing in HS-5 cells increased apoptosis and decreased phosphorylation of BTK, AKT, and ERK in B-CLL cells, thus disrupting their pro-survival key signaling pathways. The observation of fibroblast-activated protein (FAP) positive cells in infiltrated bone marrow specimens co-expressing BAG3 further support the involvement of the protein in fibroblast-mediated tumor survival. Additionally, BAG3 appears to support B-CLL survival by modulating cytokine networks, including IL-10 and CXCL12, which are essential for leukemic cell survival and proliferation. A robust correlation between BAG3 expression and the levels of CXCL12 and IL-10 was observed in both co-cultures and patient specimens. These findings point out the need for a more in-depth comprehension of the intricate network of interactions within the tumor microenvironment and provide valuable insights for the selection of new potential therapeutic targets in the medical treatment of CLL.
RESUMO
Bicuspid Aortic Valve (BAV) is the most common adult congenital heart lesion with an estimated population prevalence of 1%. We hypothesize that early onset complications of BAV (EBAV) are driven by specific impactful genetic variants. We analyzed whole exome sequences (WES) to identify rare coding variants that contribute to BAV disease in 215 EBAV families. Predicted pathogenic variants of causal genes were present in 111 EBAV families (51% of total), including genes that cause BAV (8%) or heritable thoracic aortic disease (HTAD, 17%). After appropriate filtration, we also identified 93 variants in 26 novel genes that are associated with autosomal dominant congenital heart phenotypes, including recurrent deleterious variation of FBN2, MYH6, channelopathy genes, and type 1 and 5 collagen genes. These findings confirm our hypothesis that unique rare genetic variants contribute to early onset complications of BAV disease.
RESUMO
Bicuspid aortic valve (BAV) is the most common congenital heart malformation in adults but can also cause childhood-onset complications. In multicenter study, we found that adults who experience significant complications of BAV disease before age 30 are distinguished from the majority of BAV cases that manifest after age 50 by a relatively severe clinical course, with higher rates of surgical interventions, more frequent second interventions, and a greater burden of congenital heart malformations. These observations highlight the need for prompt recognition, regular lifelong surveillance, and targeted interventions to address the significant health burdens of patients with early onset BAV complications.
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Dendritic cells (DCs) are immunological sentinels of the organism acting as antigen-presenting cells (APC) and are critical for induction of innate and adaptive immunity. Traditionally they are divided in myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs), a rare population of circulating cells that selectively express Toll-like receptors (TLR) 7 and TLR9 and have the capacity to produce large amounts of type I interferons (IFNs) in response to pathogenic agents or danger signals. It has been demonstrated that pDCs can coordinate events during the course of viral infections, allergic and autoimmune diseases and cancer. Through the production of type I IFNs, pDCs initiate protective immunity by activating classical DCs, T cells, natural killer cells and B cells. Upon activation, pDCs also differentiate into mature DCs and may contribute to the contraction of T-cell response. Human pDCs preferentially express immunoglobulin-like transcript 7 (ILT7; LILRA4), which couples with a signaling adapter to activate a prominent immune-receptor tyrosine-based activation motif (ITAM)-mediated signaling pathway. The interaction between ILT7 and bone marrow stromal cell antigen 2 (BST2, CD317) assures an appropriate TLR response by pDCs during viral infections and likely participates in pDCs tumor crosstalk. Moreover these cells seem to play a crucial role in the initiation of the pathological process of autoimmune diseases such as lupus or psoriasis. Despite the fact that their function within a tumor context is still controversial they represent an attractive target for therapeutic manipulation of the immune system to elicit a powerful immune response against tumor antigens in combination with other therapies.
Assuntos
Células Dendríticas/fisiologia , Neoplasias/imunologia , Animais , Ensaios Clínicos como Assunto , Humanos , Neoplasias/terapia , Fenótipo , Receptores Imunológicos/fisiologia , Transdução de Sinais , Receptores Toll-Like/fisiologiaRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly cancers, being the fourth leading cause of cancer-related deaths. Long-term survival reaching 15% is achieved in less than 5% of patients who undergo surgery, and median survival is only 6 months in those with inoperable lesions. A deeper understanding of PDAC biologic characteristics as well as novel prognostic markers are therefore required to improve outcomes. Herein we report that BAG3, a protein with recognized anti-apoptotic activity, was expressed in 346 PDACs analyzed, but was not expressed in the surrounding nonneoplastic tissue. In a cohort of 66 patients who underwent radical resection (R0), survival was significantly shorter in patients with high BAG3 expression (median, 12 months) than in those with low BAG3 expression (median, 23 months) (P = 0.001). Furthermore, we report that BAG3 expression in PDAC-derived cell lines protects from apoptosis and confers resistance to gemcitabine, offering a partial explanation for the survival data. Our results indicate that BAG3 has a relevant role in PDAC biology, and suggest that BAG3 expression level might be a potential marker for prediction of patient outcome.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Apoptose , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Adenocarcinoma/tratamento farmacológico , Idoso , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose , Linhagem Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias Pancreáticas/tratamento farmacológico , Modelos de Riscos Proporcionais , Análise de Sobrevida , GencitabinaRESUMO
BAG3, a member of the BAG family of heat shock protein (HSP) 70 cochaperones, is expressed in response to stressful stimuli in a number of normal cell types and constitutively in a variety of tumors, including pancreas carcinomas, lymphocytic and myeloblastic leukemias, and thyroid carcinomas. Down-regulation of BAG3 results in cell death, but the underlying molecular mechanisms are still elusive. Here, we investigated the molecular mechanism of BAG3-dependent survival in human osteosarcoma (SAOS-2) and melanoma (M14) cells. We show that bag3 overexpression in tumors promotes survival through the NF-kappaB pathway. Indeed, we demonstrate that BAG3 alters the interaction between HSP70 and IKKgamma, increasing availability of IKKgamma and protecting it from proteasome-dependent degradation; this, in turn, results in increased NF-kappaB activity and survival. These results identify bag3 as a potential target for anticancer therapies in those tumors in which this gene is constitutively expressed. As a proof of principle, we show that treatment of a mouse xenograft tumor model with bag3siRNA-adenovirus that down-regulates bag3 results in reduced tumor growth and increased animal survival.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Regulação Neoplásica da Expressão Gênica , Quinase I-kappa B/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose , Proteínas Reguladoras de Apoptose , Linhagem Celular Tumoral , Feminino , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Modelos Biológicos , NF-kappa B/metabolismo , RNA Interferente Pequeno/metabolismoRESUMO
Pancreatic Ductal Adenocarcinoma (PDAC) is a ravaging disease with a poor prognosis, requiring a more detailed understanding of its biology to foster the development of effective therapies. The unsatisfactory results of treatments targeting cell proliferation and its related mechanisms suggest a shift in focus towards the inflammatory tumor microenvironment (TME). Here, we discuss the role of cancer-secreted proteins in the complex TME tumor-stroma crosstalk, shedding lights on druggable molecular targets for the development of innovative, safer and more efficient therapeutic strategies.