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BACKGROUND: Breast cancer is the most common cancer in women diagnosed in the U.S. and worldwide. Obesity increases breast cancer risk without clear underlying molecular mechanisms. Our studies demonstrate that circulating adipose fatty acid binding protein (A-FABP, or FABP4) links obesity-induced dysregulated lipid metabolism and breast cancer risk, thus potentially offering a new target for breast cancer treatment. METHODS: We immunized FABP4 knockout mice with recombinant human FABP4 and screened hybridoma clones with specific binding to FABP4. The potential effects of antibodies on breast cancer cells in vitro were evaluated using migration, invasion, and limiting dilution assays. Tumor progression in vivo was evaluated in various types of tumorigenesis models including C57BL/6 mice, Balb/c mice, and SCID mice. The phenotype and function of immune cells in tumor microenvironment were characterized with multi-color flow cytometry. Tumor stemness was detected by ALDH assays. To characterize antigen-antibody binding capacity, we determined the dissociation constant of selected anti-FABP4 antibodies via surface plasmon resonance. Further analyses in tumor tissue were performed using 10X Genomics Visium spatial single cell technology. RESULTS: Herein, we report the generation of humanized monoclonal antibodies blocking FABP4 activity for breast cancer treatment in mouse models. One clone, named 12G2, which significantly reduced circulating levels of FABP4 and inhibited mammary tumor growth, was selected for further characterization. After confirming the therapeutic efficacy of the chimeric 12G2 monoclonal antibody consisting of mouse variable regions and human IgG1 constant regions, 16 humanized 12G2 monoclonal antibody variants were generated by grafting its complementary determining regions to selected human germline sequences. Humanized V9 monoclonal antibody showed consistent results in inhibiting mammary tumor growth and metastasis by affecting tumor cell mitochondrial metabolism. CONCLUSIONS: Our current evidence suggests that targeting FABP4 with humanized monoclonal antibodies may represent a novel strategy for the treatment of breast cancer and possibly other obesity- associated diseases.
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Neoplasias da Mama , Proteínas de Ligação a Ácido Graxo , Animais , Proteínas de Ligação a Ácido Graxo/antagonistas & inibidores , Proteínas de Ligação a Ácido Graxo/metabolismo , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/imunologia , Humanos , Feminino , Camundongos , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Camundongos Knockout , Ensaios Antitumorais Modelo de Xenoenxerto , Microambiente Tumoral/imunologia , Modelos Animais de Doenças , Camundongos SCIDRESUMO
A high density of tumor-associated macrophages (TAMs) is associated with poorer prognosis and survival in breast cancer patients. Recent studies have shown that lipid accumulation in TAMs can promote tumor growth and metastasis in various models. However, the specific molecular mechanisms that drive lipid accumulation and tumor progression in TAMs remain largely unknown. Herein, we demonstrated that unsaturated fatty acids (FAs), unlike saturated ones, are more likely to form lipid droplets in macrophages. Specifically, unsaturated FAs, including linoleic acids (LA), activate the FABP4/CEBPα pathway, leading to triglyceride synthesis and lipid droplet formation. Furthermore, FABP4 enhances lipolysis and FA utilization by breast cancer cells, which promotes cancer cell migration in vitro and metastasis in vivo . Notably, a deficiency of FABP4 in macrophages significantly reduces LA-induced lipid metabolism. Therefore, our findings suggest FABP4 as a crucial lipid messenger that facilitates unsaturated FA-mediated lipid accumulation and lipolysis in TAMs, thus contributing to the metastasis of breast cancer. Highlights: Unlike saturated fatty acids, unsaturated fatty acids preferentially promote lipid droplet formation in macrophages.Unsaturated fatty acids activate the FABP4/CEBPα axis for neutral lipid biosynthesis in macrophagesDeficiency of FABP4 compromised unsaturated fatty acid-mediated lipid accumulation and utilization in macrophagesFABP4-mediated lipid metabolism in macrophages contributes to breast cancer metastasis.
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The fatty acid-binding protein 5 (FABP5) is a key player in psoriasis development. Therefore, characterizing the expression profile of FABP5 in various cell types within both layers of psoriatic skin is important. Here, we present a protocol that describes steps for an imiquimod-induced psoriasis mouse model and preparation of epidermal and dermal single-cell suspensions. We then detail procedures to detect the FABP5 expression profile in skin keratinocytes and immune cells using intracellular flow cytometry staining. For complete details on the use and execution of this protocol, please refer to Hao et al.1.
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Modelos Animais de Doenças , Proteínas de Ligação a Ácido Graxo , Citometria de Fluxo , Imiquimode , Psoríase , Pele , Animais , Psoríase/induzido quimicamente , Psoríase/metabolismo , Psoríase/patologia , Camundongos , Citometria de Fluxo/métodos , Proteínas de Ligação a Ácido Graxo/metabolismo , Pele/metabolismo , Pele/patologia , Queratinócitos/metabolismo , Queratinócitos/patologia , Proteínas de NeoplasiasRESUMO
Glioblastoma (GBM), the deadliest central nervous system cancer, presents a poor prognosis and scant therapeutic options. Our research spotlights OH2, an oncolytic viral therapy derived from herpes simplex virus 2 (HSV-2), which demonstrates substantial antitumor activity and favorable tolerance in GBM. The extraordinary efficacy of OH2 emanates from its unique mechanisms: it selectively targets tumor cells replication, powerfully induces cytotoxic DNA damage stress, and kindles anti-tumor immune responses. Through single-cell RNA sequencing analysis, we discovered that OH2 not only curtails the proliferation of cancer cells and tumor-associated macrophages (TAM)-M2 but also bolsters the infiltration of macrophages, CD4+ and CD8+ T cells. Further investigation into molecular characteristics affecting OH2 sensitivity revealed potential influencers such as TTN, HMCN2 or IRS4 mutations, CDKN2A/B deletion and IDO1 amplification. This study marks the first demonstration of an HSV-2 derived OV's effectiveness against GBM. Significantly, these discoveries have driven the initiation of a phase I/II clinical trial (ClinicalTrials.gov: NCT05235074). This trial is designed to explore the potential of OH2 as a therapeutic option for patients with recurrent central nervous system tumors following surgical intervention.
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Neoplasias Encefálicas , Glioblastoma , Terapia Viral Oncolítica , Vírus Oncolíticos , Humanos , Vírus Oncolíticos/genética , Glioblastoma/genética , Glioblastoma/terapia , Linfócitos T CD8-Positivos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapiaRESUMO
One of the hallmarks of intractable psoriasis is neutrophil infiltration in skin lesions. However, detailed molecular mechanisms of neutrophil chemotaxis and activation remain unclear. Here, we demonstrate a significant upregulation of epidermal fatty acid binding protein (E-FABP, FABP5) in the skin of human psoriasis and psoriatic mouse models. Genetic deletion of FABP5 in mice by global knockout and keratinocyte conditional (Krt6a-Cre) knockout, but not myeloid cell conditional (LysM-Cre) knockout, attenuates psoriatic symptoms. Immunophenotypic analysis shows that FABP5 deficiency specifically reduces skin recruitment of Ly6G+ neutrophils. Mechanistically, activated keratinocytes produce chemokines and cytokines that trigger neutrophil chemotaxis and activation in an FABP5-dependent manner. Proteomic analysis further identifies that FABP5 interacts with valosin-containing protein (VCP), a key player in NF-κB signaling activation. Silencing of FABP5, VCP, or both inhibits NF-κB/neutrophil chemotaxis signaling. Collectively, these data demonstrate dysregulated FABP5 as a molecular mechanism promoting NF-κB signaling and neutrophil infiltration in psoriasis pathogenesis.
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Neutrófilos , Psoríase , Animais , Humanos , Camundongos , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Inflamação/metabolismo , Queratinócitos/metabolismo , Neutrófilos/metabolismo , NF-kappa B/metabolismo , Proteômica , Psoríase/patologia , Proteína com Valosina/metabolismoRESUMO
IL-27 is a pleiotropic cytokine that exhibits stimulatory/regulatory functions on multiple lineages of immune cells and has a potential to be used as a therapeutic for cancer. We have recently demonstrated that administration of IL-27 producing adeno-associated virus (AAV-IL-27) exhibits potent inhibition of tumor growth in mouse models. In this study, we demonstrate that AAV-IL-27 treatment leads to significant expansion of CD11b+Gr1+ myeloid cells. AAV-IL-27-induced expansion of CD11b+Gr1+ cells is IL-27R-dependent and requires Stat3 signaling, but it is inhibited by Stat1 signaling. AAV-IL-27 treatment does not increase the self-renewal capacity of CD11b+Gr1+ cells but induces significant expansion of Lin-Sca1+c-Kit+ (LSK) and granulocyte-monocyte progenitor cells. Despite exhibiting significant suppression of T cells in vitro, IL-27-induced CD11b+Gr1+ cells lost the tumor-promoting activity in vivo and overall play an antitumor role. In tumors from AAV-IL-27-treated mice, CD11b+Gr1+ cells are largely F4/80+ and express high levels of MHC class I/II and M1 macrophage markers. Thus, IL-27 gene therapy induces Stat3-mediated expansion of CD11b+Gr1+ myeloid cells and promotes accumulation of M1 macrophages in the tumor microenvironment.
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Interleucina-27 , Camundongos , Animais , Microambiente Tumoral , Macrófagos , Células Mieloides , Linfócitos T , Antígeno CD11bRESUMO
Uterine corpus endometrial carcinoma (UCEC) is the most common cancer of the female reproductive tract. The overall survival of advanced and recurrent UCEC patients is still unfavourable nowadays. It is urgent to find a predictive biomarker and block tumorgenesis at an early stage. Plant homeodomain finger protein 6 (PHF6) is a key player in epigenetic regulation, and its alterations lead to various diseases, including tumours. Here, we found that PHF6 expression was upregulated in UCEC tissues compared with normal tissues. The UCEC patients with high PHF6 expression had poor survival than UCEC patients with low PHF6 expression. PHF6 mutation occurred in 12% of UCEC patients, and PHF6 mutation predicted favourable clinical outcome in UCEC patients. Depletion of PHF6 effectively inhibited HEC-1-A and KLE cell proliferation in vitro and decreased HEC-1-A cell growth in vivo. Furthermore, high PHF6 level indicated a subtype of UCECs characterized by low immune infiltration, such as CD3+ T-cell infiltration. While knockdown of PHF6 in endometrial carcinoma cells increased T-cell migration by promoting IL32 production and secretion. Taken together, our findings suggested that PHF6 might play an oncogenic role in UCEC patients. Thus, PHF6 could be a potential biomarker in predicting the prognosis of UCEC patients. Depletion of PHF6 may be a novel therapeutic strategy for UCEC patients.
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Carcinoma Endometrioide , Neoplasias do Endométrio , Feminino , Humanos , Epigênese Genética , Linfócitos T/metabolismo , Recidiva Local de Neoplasia/genética , Neoplasias do Endométrio/patologia , Útero/metabolismo , Carcinoma Endometrioide/genética , Proteínas Repressoras/genéticaRESUMO
To evade immune surveillance, tumors develop a hostile microenvironment that inhibits anti-tumor immunity. Recent immunotherapy breakthroughs that target the reinvigoration of tumor-infiltrating T lymphocytes (TIL) have led to unprecedented success in treating some cancers that are resistant to conventional therapy, suggesting that T cells play a pivotal role in anti-tumor immunity. In the hostile tumor microenvironment (TME), activated T cells are known to mainly rely on aerobic glycolysis to facilitate their proliferation and anti-tumor function. However, TILs usually exhibit an exhausted phenotype and impaired anti-tumor activity due to the limited availability of key nutrients (e.g., glucose) in the TME. Given that different T cell subsets have unique metabolic pathways which determine their effector function, this review introduces our current understanding of T cell development, activation signals and metabolic pathways. Moreover, emerging evidence suggests that fatty acid binding protein 5 (FABP5) expression in T cells regulates T cell lipid metabolism and function. We highlight how FABP5 regulates fatty acid uptake and oxidation, thus shaping the survival and function of different T cell subsets in the TME.
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Brain tumors, although rare, contribute to distinct mortality and morbidity at all ages. Although there are few therapeutic options for brain tumors, enhanced biological understanding and unexampled innovations in targeted therapies and immunotherapies have considerably improved patients' prognoses. Nonetheless, the reduced response rates and unavoidable drug resistance of currently available treatment approaches have become a barrier to further improvement in brain tumor (glioma, meningioma, CNS germ cell tumors, and CNS lymphoma) treatment. Previous literature data revealed that several different signaling pathways are dysregulated in brain tumor. Importantly, a better understanding of targeting signaling pathways that influences malignant behavior of brain tumor cells might open the way for the development of novel targeted therapies. Thus, there is an urgent need for a more comprehensive understanding of the pathogenesis of these brain tumors, which might result in greater progress in therapeutic approaches. This paper began with a brief description of the epidemiology, incidence, risk factors, as well as survival of brain tumors. Next, the major signaling pathways underlying these brain tumors' pathogenesis and current progress in therapies, including clinical trials, targeted therapies, immunotherapies, and system therapies, have been systemically reviewed and discussed. Finally, future perspective and challenges of development of novel therapeutic strategies in brain tumor were emphasized.
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Neoplasias Encefálicas , Glioma , Humanos , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/tratamento farmacológico , Encéfalo/patologia , Transdução de Sinais , ImunoterapiaRESUMO
IL-27 is a pleiotropic cytokine that exhibits stimulatory/regulatory functions on multiple lineages of immune cells including T lymphocytes. In this study, we demonstrate that IL-27 directly induces CCL5 production by T lymphocytes, particularly CD8+ T cells in vitro and in vivo. IL-27-induced CCL5 production is IL-27R-dependent. In CD4+ T cells, IL-27-induced CCL5 production was primarily dependent on Stat1 activation, whereas in CD8+ T cells, Stat1 deficiency does not abrogate CCL5 induction. A chromatin immunoprecipitation assay revealed that in the CCL5 promoter region, both putative Stat3 binding sites exhibit significant binding to Stat3, whereas only one out of four Stat1 binding sites displays moderate binding to Stat1. In tumor-bearing mice, IL-27 induced dramatic production of CCL5 in tumor-infiltrating T cells. IL-27-induced CCL5 appears to contribute to an IL-27-mediated antitumor effect. This is signified by diminished tumor inhibition in anti-CCL5- and IL-27-treated mice. Additionally, intratumor delivery of CCL5 mRNA using lipid nanoparticles significantly inhibited tumor growth. Thus, IL-27 induces robust CCL5 production by T cells, which contributes to antitumor activity.
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Interleucina-27 , Animais , Linfócitos T CD8-Positivos , Citocinas , Expressão Gênica , Lipossomos , Camundongos , NanopartículasRESUMO
Stem cells transplantation is the main method of tissue engineering regeneration treatment, the viability and therapeutic efficiency are limited. Scaffold materials also play an important role in tissue engineering, whereas there are still many limitations, such as rejection and toxic side effects caused by scaffold materials. Cell sheet engineering is a scaffold-free tissue technology, which avoids the side effects of traditional scaffolds and maximizes the function of stem cells. It is increasingly being used in the field of tissue regenerative medicine. Dental-derived mesenchymal stem cells (DMSCs) are multipotent cells that exist in various dental tissues and can be used in stem cell-based therapy, which is impactful in regenerative medicine. Emerging evidences show that cell sheets derived from DMSCs have better effects in the field of regenerative medicine applications. Extracellular matrix (ECM) is the main component of cell sheets, which is a dynamic repository of signalling biological molecules and has a variety of biological functions and may play an important role in the application of cell sheets. In this review, we summarized the application status, mechanisms that sheets and ECM may play and future prospect of DMSC sheets on regeneration medicine.
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Células-Tronco Mesenquimais , Engenharia Tecidual , Matriz Extracelular , Medicina Regenerativa/métodos , Células-Tronco , Engenharia Tecidual/métodos , Alicerces TeciduaisRESUMO
CD200-CD200R pathway regulates immune responses and has been implicated in the pathogenesis of a number of cancer types. CD200 blockade is considered a strategy for immunotherapy of CD200-positive cancers such as melanoma. Thus, it is critical to understand the potential impacts of CD200 blockade in a more human relevant tumor model. In this study, we evaluated these issues using the CD200+ Yumm1.7 mouse melanoma model. Yumm1.7 cells bear Braf/Pten mutations resembling human melanoma. We found that Yumm1.7 tumors grow significantly faster in CD200R-/- mice compared to wild type mice. Analysis of tumor immune microenvironment (TIME) revealed that tumors from CD200R-/- or anti-CD200 treated mice had downregulated immune cell contents and reduced TCR clonality compared to tumors from untreated wild type mice. T cells also showed impaired effector functions, as reflected by reduced numbers of IFN-γ+ and TNF-α+ T cells. Mechanistically, we found upregulation of the CCL8 gene in CD200R-/- tumors. In vitro co-culture experiments using Yumm1.7 tumor cells with bone marrow derived macrophages (BMDM) from WT and CD200R-/- mice confirmed upregulation of macrophage CCL8 in the absence of CD200-CD200R interaction. Finally, we found that anti-CD200 therapy failed to show efficacy either alone or in combination with checkpoint inhibitors such as anti-PD-1 or anti-CTLA4 in inhibiting Yumm1.7 tumor growth. Given that CD200R-deficiency or anti-CD200 treatment leads to reduced T cell responses in TME, using blockade of CD200 as an immunotherapy for cancers such as melanoma should be practiced with caution.
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Cytokines are one of the first immunotherapeutics utilized in trials of human cancers with significant success. However, due to their significant toxicity and often lack of efficacy, cytokines have given their spotlight to other cancer immunotherapeutics such as immune checkpoint inhibitors. Nevertheless, only a subset of cancer patients respond to checkpoint inhibitors. Therefore, developing a novel cytokine-based immunotherapy is still necessary. Among an array of cytokine candidates, IL-27 is a unique one that exhibits clear anti-tumor activity with low toxicity. Systemically delivered IL-27 by adeno-associated virus (AAV-IL-27) is very well tolerized by mice and exhibits potent anti-tumor activity in a variety of tumor models. AAV-IL-27 exerts its anti-tumor activity through directly stimulation of immune effector cells and systemic depletion of Tregs, and is particularly suitable for delivery in combination with checkpoint inhibitors or vaccines. Additionally, AAV-IL-27 can also be delivered locally to tumors to exert its unique actions. In this review, we summarize the evidence that support these points and propose AAV-delivered IL-27 as a potential immunotherapeutic for cancer.
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Plasmonics enables the manipulation of light beyond the optical diffraction limit1-4 and may therefore confer advantages in applications such as photonic devices5-7, optical cloaking8,9, biochemical sensing10,11 and super-resolution imaging12,13. However, the essential field-confinement capability of plasmonic devices is always accompanied by a parasitic Ohmic loss, which severely reduces their performance. Therefore, plasmonic materials (those with collective oscillations of electrons) with a lower loss than noble metals have long been sought14-16. Here we present stable sodium-based plasmonic devices with state-of-the-art performance at near-infrared wavelengths. We fabricated high-quality sodium films with electron relaxation times as long as 0.42 picoseconds using a thermo-assisted spin-coating process. A direct-waveguide experiment shows that the propagation length of surface plasmon polaritons supported at the sodium-quartz interface can reach 200 micrometres at near-infrared wavelengths. We further demonstrate a room-temperature sodium-based plasmonic nanolaser with a lasing threshold of 140 kilowatts per square centimetre, lower than values previously reported for plasmonic nanolasers at near-infrared wavelengths. These sodium-based plasmonic devices show stable performance under ambient conditions over a period of several months after packaging with epoxy. These results indicate that the performance of plasmonic devices can be greatly improved beyond that of devices using noble metals, with implications for applications in plasmonics, nanophotonics and metamaterials.
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Tumor-associated inflammation and immune responses are key components in the tumor microenvironment (TME) which regulate tumor growth, progression, and metastasis. Tumor-associated myeloid cells (TAMCs) are a group of cells that play multiple key roles including induction of tumor-associated inflammation/angiogenesis and regulation of tumor-specific T-cell responses. Thus, identification and characterization of key pathways that can regulate TAMCs are of critical importance for developing cancer immunotherapy. Recent studies suggest that CD200-CD200 receptor (CD200R) interaction may be important in regulating the TME via affecting TAMCs. In this chapter, we will give a brief overview of the CD200-CD200R axis, including the biology behind CD200-CD200R interaction and the role(s) it plays in tumor microenvironment and tumor growth, and activation/effector functions of T cells. We will also discuss CD200-CD200R's role as potential checkpoint molecules for cancer immunotherapy. Further investigation of the CD200-CD200R pathway will not only advance our understanding of tumor pathogenesis and immunity but also provide the rationale for CD200-CD200R-targeted immunotherapy of human cancer.
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Antígenos CD/metabolismo , Imunoterapia , Neoplasias/terapia , Receptores de Orexina/metabolismo , Microambiente Tumoral/imunologia , Antígenos CD/imunologia , Humanos , Células Mieloides/imunologia , Células Mieloides/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Receptores de Orexina/imunologiaRESUMO
The recent renaissance of lithium metal batteries as promising energy storage devices calls for in operando monitoring and control of electrochemical evolution of lithium metal morphologies. While the development of plasmonics has led to significant advancement in real-time and ultrasensitive chemical and biological sensing and surface-enhanced spectroscopies, alkali metals featured by ideal free electron gas models have long been regarded as promising plasmonic materials but seldom been explored due to their high chemical reactivity. Here, we demonstrate the in operando plasmonic monitoring of the electrochemical evolution of lithium metal during battery cycling by taking advantage of selective electrochemical deposition. The relationships between the evolving morphologies of lithium metal and in operando optical spectra are established both numerically and experimentally: Ordered growth of lithium particles shows clear size-dependent reflective dips due to hybrid surface plasmon resonances, while the formation of undesirable disordered lithium dendrites exhibits a flat spectroscopic profile with pure suppression in reflection intensity. Under the in operando plasmonic monitoring enabled by the microscopic morphology of metal, the differences of lithium evolutionary behaviors with different electrolytes can be conveniently identified without destruction. At the intersection of energy storage and plasmonics, it is expected that the ability to actively control and in operando plasmonically monitor electrochemical evolution of lithium metal can provide a promising platform for investigating lithium metal behavior during electrochemical cycling under various working conditions.
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ß-arrestin1 and NF-κB have been demonstrated to be associated with tumorigenesis, tumor progression, and metastasis. Thus far, there is nevertheless little study about these two molecules in lung adenocarcinoma. The aim of this study was to investigate the correlation between ß-arrestin1 and NF-κB expression and the clinicopathological characteristics in lung adenocarcinoma. A total of 115 surgically resected lung adenocarcinoma patients were recruited for the study. Expression of ß-arrestin1 and p65 were detected by immunohistochemistry (IHC) in lung adenocarcinoma tissue samples. Nuclear expression of ß-arrestin1 and p65 were observed in 39.1 % (45/115) and 46.1 % (53/115) cases of lung adenocarcinoma, respectively. And high expression of ß-arrestin1 had negative prognostic impact for overall survival (OS) and disease-free survival (DFS) (p = 0.034 and p = 0.033). In addition, overexpression of p65 indicated a significantly poor OS and DFS than those of lower-expression (p = 0.038 and p = 0.041). Furthermore, co-expression of nuclear ß-arrestin1 and p65 correlated with poorer OS and DFS in lung adenocarcinoma patients. Multivariate analysis using the Cox regression model confirmed that co-expression of nuclear ß-arrestin1 and p65 was an independent prognostic factor for tumor progression (p = 0.008). In conclusion, these data indicated that co-expression of nuclear ß-arrestin1 and p65 was a novel predictor for worse prognosis in patients with lung adenocarcinoma.
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Adenocarcinoma/genética , Arrestinas/biossíntese , Biomarcadores Tumorais/biossíntese , Neoplasias Pulmonares/genética , NF-kappa B/biossíntese , Fator de Transcrição RelA/biossíntese , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Adulto , Idoso , Arrestinas/genética , Biomarcadores Tumorais/genética , Carcinogênese/genética , Carcinoma de Células Escamosas , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , NF-kappa B/genética , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Fator de Transcrição RelA/genética , beta-ArrestinasRESUMO
Recently many studies have focused on the microRNA-34 (miR-34) family expression in various cancers; nevertheless, the controversial results of these studies still exist in identifying miR-34 members as new biomarkers of cancers. Therefore, we carried out this comprehensive meta-analysis of published studies that compared the miR-34 family expression profiles between cancer tissues and paired neighboring noncancerous tissues to systemically evaluate the findings globally and address the inconsistencies of pertinent literatures. The data included in this article were collected from Embase, PubMed and Web of Science up to December 2013. To overcome the difficulties that many raw data were unavailable and study methods were different, a vote-counting strategy was adopted to identify consistent markers in our analysis. Ultimately, a total of 23 cancers were reported in the 61 eligible studies, of which 46 studies provided fold-change value information. In the consistently reported cancer types, non-small cell lung cancer (NSCLC), glioma and nasopharyngeal carcinoma (NPC) ranked at the top with down-regulated feature. Cervical neoplasm was consistently reported to be over-expressed in the panel of each member of miR-34s. Subgroup analysis of miR-34 family expression demonstrated that colorectal cancer (CRC), gastric cancer (GC), hepatocellular carcinoma (HCC) and prostate cancer (PCa) were most frequently reported with inconsistent regulations. Our meta-analysis showed that miR-34 family members could be expected to become potential diagnostic and prognostic biomarkers in some types of human cancers. Further well-designed and larger sample studies are surely warranted to identify the role of the miR-34 family in the occurrence and development of tumors.
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Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismo , Carcinoma , Carcinoma Hepatocelular/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Colorretais/metabolismo , Feminino , Perfilação da Expressão Gênica , Glioma/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Neoplasias da Próstata/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias do Colo do Útero/metabolismoRESUMO
Recently, several molecular epidemiological studies have focused on the association between pri-miR-34b/c rs4938723 SNP and the susceptibility to different cancers. Due to the controversial rather than conclusive results, we performed this meta-analysis to assess more precise and comprehensive conclusion about the association. Data published until July 2014 were collected from PubMed, Embase, Web of Science, Chinese National Knowledge Infrastructure, Wanfang Data, Chinese BioMedical Literature Database, and VIP database of Chinese Journal. Ultimately, 13 articles with a total of 7,753 cases and 8,014 controls were considered eligible for inclusion. The odds ratio (OR) and its 95 % confidence interval (95%CI) were used to assess the strength of association. In the overall analysis, a significant association between pri-miR-34b/c rs4938723 polymorphism and increased cancer susceptibility was found in heterozygous model (TC vs. TT: OR = 1.148, 95%CI 1.034-1.275, P = 0.010) and dominant model (CC + TC vs. TT: OR =1.166, 95%CI 1.028-1.322, P = 0.017). In subgroup analysis of ethnicity, pri-miR-34b/c rs4938723 polymorphism was significantly associated with an increased cancer susceptibility for Asian population in heterozygous model (TC vs. TT: OR = 1.169, 95%CI 1.031-1.326, P = 0.015) and dominant model (CC + TC vs. TT: OR = 1.185, 95%CI 1.017-1.382, P = 0.030), whereas no significant association for Caucasian population was observed in any genetic models. Intriguingly, stratified analysis revealed opposite results that pri-miR-34b/c polymorphism contributed to susceptibility to hepatocellular carcinoma while reduced susceptibility to colorectal cancer and esophageal squamous cell cancer in Asians. Considering some limitation of our meta-analysis, future well-designed case-control studies with larger sample sizes are required to confirm our findings.
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Predisposição Genética para Doença , MicroRNAs/genética , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Alelos , Estudos de Associação Genética , Genótipo , Humanos , Neoplasias/diagnóstico , Razão de Chances , Viés de Publicação , Grupos Raciais/genéticaRESUMO
BACKGROUND: Twist and Snail are considered as key transcriptional repressors of E-cadherin tightly related to epithelial-to-mesenchymal transition (EMT) and cancer progression. Numerous studies have investigated the prognostic value of Twist and Snail. However, the published results were controversial or even opposite. Our article aimed to evaluate the prognostic role of Twist and Snail in patients with cancer. DESIGN: A comprehensive literature search of PubMed, Embase and Web of Science was conducted. Pooled hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) were assessed to quantify the prognostic role. RESULTS: The pooled HR with 38 studies for Twist was 2·18 (95% CI: 1·77-2·68, I(2) = 69·8%, P = 0·000) and for Snail with 40 studies was 1·58 (95% CI: 1·33-1·87, I(2) = 70·0%, P = 0·000), suggesting high Twist/Snail expression predicted poor prognosis related to all clinical outcomes. For Twist, the pooled HR for overall survival (OS) was 2·07 (95% CI: 1·63-2·63, I(2) = 72·6%, P = 0·000) and for progression-free/recurrence-free/metastasis-free/disease-free/cancer-free survival (PFS/RFS/MFS/DFS/CFS) was 2·36 (95% CI: 1·76-3·17, I(2) = 65·0%, P = 0·000). For Snail, the pooled HR for OS was 1·63 (95% CI: 1·33-1·99, I(2) = 70·8%, P = 0·000) and for PFS/RFS/MFS/DFS/CFS was 1·54 (95% CI: 1·17-2·02, I(2) = 59·1%, P = 0·001). All of those results were suggesting that high Twist/Snail expression was associated with poor prognosis. Furthermore, when grouped into different types of cancers, the pooled HRs were also calculated for the subgroups. No publication bias was found except studies evaluating all clinical outcomes of Twist (P = 0·006 for Begg's test and 0·006 for Egger's test). CONCLUSIONS: Elevated Twist or Snail expression in tumour tissue indicated poor prognosis for cancer.