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BACKGROUND: Immune checkpoint inhibitors (ICIs) provide modest but unsatisfactory benefits for extensive-stage small cell lung cancer (ES-SCLC). Developing strategies for treating ES-SCLC is critical. METHODS: We preliminarily explored the outcomes of salvage low-dose radiotherapy (LDRT) plus ICI on refractory SCLC patients. Next, we evaluated the combinational efficacy in murine SCLC. The tumor immune microenvironment (TIME) was analyzed for mechanistic study. Subsequently, we conducted a multicenter, prospective phase II trial that administered concurrent thoracic LDRT plus chemoimmunotherapy to treatment-naive ES-SCLC patients (MATCH trial, NCT04622228). The primary endpoint was confirmed objective response rate (ORR), and the key secondary endpoints included progression-free survival (PFS) and safety. FINDINGS: Fifteen refractory SCLC patients treated with LDRT plus ICI were retrospectively reviewed. The ORR was 73.3% (95% confidence interval [CI], 44.9-92.2). We identified a specific dose of LDRT (15 Gy/5 fractions) that exhibited growth retardation and improved survival in murine SCLC when combined with ICIs. This combination recruited a special T cell population, TCF1+ PD-1+ CD8+ stem-like T cells, from tumor-draining lymph nodes into the TIME. The MATCH trial showed a confirmed ORR of 87.5% (95% CI, 75.9-94.8). The median PFS was 6.9 months (95% CI, 5.4-9.3). CONCLUSIONS: These findings verified that LDRT plus chemoimmunotherapy was safe, feasible, and effective for ES-SCLC, warranting further investigation. FUNDING: This research was funded by West China Hospital (no. ZYJC21003), the National Natural Science Foundation of China (no. 82073336), and the MATCH trial was fully funded by Roche (China) Holding Ltd. (RCHL) and Shanghai Roche Pharmaceuticals Ltd. (SRPL).
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A variety of malignancies preferentially meet energy demands through the glycolytic pathway. Hypoxiainduced cancer cell adaptations are essential for tumor development. However, in cancerous glycolysis, the functional importance and underlying molecular mechanism of prolyl hydroxylase domain protein 2 (PHD2) have not been fully elucidated. Gain and lossoffunction assays were conducted to evaluate PHD2 functions in colon cancer cells. Glucose uptake, lactate production and intracellular adenosine5'triphosphate/adenosine diphosphate ratio were measured to determine glycolytic activities. Protein and gene expression levels were measured by western blot analysis and reverse transcriptionquantitative PCR, respectively. The human colon cancer xenograft model was used to confirm the role of PHD2 in tumor progression in vivo. Functionally, the data demonstrated that PHD2 knockdown leads to increased glycolysis, while PHD2 overexpression resulted in suppressed glycolysis in colorectal cancer cells. In addition, the glycolytic activity was enhanced without PHD2 and normalized after PHD2 reconstitution. PHD2 was shown to inhibit colorectal tumor growth, suppress cancer cell proliferation and improve tumorbearing mice survival in vivo. Mechanically, it was found that PHD2 inhibits the expression of critical glycolytic enzymes (glucose transporter 1, hexokinase 2 and phosphoinositidedependent protein kinase 1). In addition, PHD2 inhibited Ikkßmediated NFκB activation in a hypoxiainducible factor1αindependent manner. In conclusion, the data demonstrated that PHD2/Ikkß/NFκB signaling has critical roles in regulating glycolysis and suggests that PHD2 potentially suppresses colorectal cancer.
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Neoplasias do Colo , Neoplasias Colorretais , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Glicólise , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Quinase I-kappa B/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Pró-Colágeno-Prolina Dioxigenase/metabolismo , Prolil Hidroxilases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de SinaisRESUMO
X-ray induced photodynamic therapy (X-PDT) circumvents the poor penetration depth of conventional PDT with minimal radio-resistance generation. However, conventional X-PDT typically requires inorganic scintillators as energy transducers to excite neighboring photosensitizers (PSs) to generate reactive oxygen species (ROS). Herein, a pure organic aggregation-induced emission (AIE) nanoscintillator (TBDCR NPs) that can massively generate both type I and type II ROS under direct X-ray irradiation is reported for hypoxia-tolerant X-PDT. Heteroatoms are introduced to enhance X-ray harvesting and ROS generation ability, and AIE-active TBDCR exhibits aggregation-enhanced ROS especially less oxygen-dependent hydroxyl radical (HOâ¢- , type I) generation ability. TBDCR NPs with a distinctive PEG crystalline shell to provide a rigid intraparticle microenvironment show further enhanced ROS generation. Intriguingly, TBDCR NPs show bright near-infrared fluorescence and massive singlet oxygen and HOâ¢- generation under direct X-ray irradiation, which demonstrate excellent antitumor X-PDT performance both in vitro and in vivo. To the best of knowledge, this is the first pure organic PS capable of generating both 1 O2 and radicals (HOâ¢- ) in response to direct X-ray irradiation, which shall provide new insights for designing organic scintillators with excellent X-ray harvesting and predominant free radical generation for efficient X-PDT.
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Fotoquimioterapia , Espécies Reativas de Oxigênio , Raios X , Fármacos Fotossensibilizantes/químicaRESUMO
The main objective of this study was to compare the pharmacokinetic (PK) bioequivalence of two capecitabine tablets and explore the different PK profiles of various tumors in Chinese patients with cancer. All 76 patients with a confirmed cancer diagnosis were included in this study. A single dose of 2000 mg of test or reference capecitabine (Xeloda, Hoffmann-La Roche) was orally administered postprandially. After 24 hours of washout, the patients were administered the test or the reference capecitabine alternately. PK samples were taken at the time of predose up to 6 hours postdose. Bioequivalence evaluation was performed using the geometric mean ratios of peak concentration in plasma (Cmax) , area under the concentration-time curve from time 0 to 6 h (AUC0-t) , and area under the concentration-time curve from time 0 to infinity (AUC0-∞ ) for capecitabine and 5-fluorouracil (5-FU). In this study, 90% confidence intervals of test/reference mean ratios of Cmax , AUC0-t , AUC0-∞ of capecitabine and 5-FU were in the range of 80%-125%. Both the test and reference capecitabine regimens were well tolerated in this study. Furthermore, we found that patients with esophageal-gastrointestinal cancers had higher exposure to capecitabine and a shorter time to Cmax (Tmax) than those with breast cancer. In conclusion, a single oral dose of 2000 mg of test capecitabine tablets after postprandial administration was bioequivalent to the reference drug.
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Capecitabina , Neoplasias , Humanos , Área Sob a Curva , Disponibilidade Biológica , Capecitabina/farmacocinética , População do Leste Asiático , Fluoruracila , Neoplasias/tratamento farmacológico , ComprimidosRESUMO
Gemcitabine is commonly used to treat various cancer types, including human non-small cell lung cancer (NSCLC). However, even cases that initially respond rapidly commonly develop acquired resistance, limiting our ability to effectively treat advanced NSCLC. To gain insight for developing a strategy to overcome gemcitabine resistance, the present study investigated the mechanism of gemcitabine resistance in NSCLC according to the involvement of ATP-binding cassette subfamily B member 6 (ABCB6) and heme biosynthesis. First, an analysis of ABCB6 expression in human NSCLCs was found to be associated with poor prognosis and gemcitabine resistance in a hypoxia-inducible factor (HIF)-1-dependent manner. Further experiments showed that activation of HIF-1α/ABCB6 signaling led to intracellular heme metabolic reprogramming and a corresponding increase in heme biosynthesis to enhance the activation and accumulation of catalase. Increased catalase levels diminished the effective levels of reactive oxygen species, thereby promoting gemcitabine-based resistance. In a mouse NSCLC model, inhibition of HIF-1α or ABCB6, in combination with gemcitabine, strongly restrained tumor proliferation, increased tumor cell apoptosis, and prolonged animal survival. These results suggest that, in combination with gemcitabine-based chemotherapy, targeting HIF-1α/ABCB6 signaling could result in enhanced tumor chemosensitivity and, thus, may improve outcomes in NSCLC patients.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Transportadores de Cassetes de Ligação de ATP , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Catalase/metabolismo , Catalase/uso terapêutico , Linhagem Celular Tumoral , Desoxicitidina/análogos & derivados , Heme/metabolismo , Humanos , Fator 1 Induzível por Hipóxia/metabolismo , Fator 1 Induzível por Hipóxia/uso terapêutico , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos , GencitabinaRESUMO
BACKGROUND: Oncostatin M (OSM) has been reported to be a key regulating factor in the process of tumor development. Previous studies have demonstrated both the promotion and inhibition effects of OSM in tumors, therefore inspiring controversies. However, no systematic assessment of OSM across various cancers is available, and the mechanisms behind OSM-related cancer progression remain to be elucidated. METHODS: Based on The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, we conducted a pan-cancer analysis on OSM to explore its tumor-related functions across cancers as well as its correlations with specific molecules, cells in the tumor microenvironment. Considering the results of pan-cancer analysis, we chose the specific tumor glioblastoma multiforme (GBM) to screen out the OSM-induced signaling pathways and intercellular communications in tumor progression. Wound scratch assay, invasion assay and qRT-PCR were performed to verify the biological effects of OSM on glioblastoma cells. RESULTS: Higher OSM level was found in most tumor tissues compared with corresponding normal tissues, and the enhanced OSM expression was observed to be strongly related to patients' poor prognosis in several cancers. Moreover, the expression of OSM was associated with stromal and immune cell infiltration in the tumor microenvironment, and OSM-related immune checkpoint and chemokine co-expression were also observed. Our results suggested that OSM could communicate extensively with the tumor microenvironment. Taking GBM as an example, our study found that two critical signaling pathways in OSM-related tumor progression by KEGG enrichment analysis: Jak-STAT and NF-κB pathways. Single-cell RNA sequencing data analysis of GBM revealed that OSM was mainly secreted by microglia, and cell-cell interaction analysis proved that OSM-OSMR is an important pathway for OSM to stimulate malignant cells. In vitro, OSM treatment could facilitate the migration and invasion of glioblastoma cells, meanwhile promote the proneural-mesenchymal transition. The administration of STAT3 inhibitors effectively suppressed the OSM-mediated biological effects, which proved the key role of STAT3 in OSM signaling. CONCLUSION: Taken together, our study provides a comprehensive understanding with regard to the tumor progression under the regulation of OSM. OSM seems to be closely related to chronic inflammation and tumor development in the tumor microenvironment. As an important inflammatory factor in the tumor microenvironment, OSM may serve as a potential immunotherapeutic target for cancer treatment, especially for GBM.
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Bone metastasis is associated with significant morbidity for cancer patients and results in a reduced quality of life. The bone marrow is a fertile soil containing a complex composition of immune cells that may actually provide an immune-privileged niche for disseminated tumor cells to colonize and proliferate. In this unique immune milieu, multiple immune cells including T cells, natural killer cells, macrophages, dendritic cells, myeloid-derived suppressor cells, and neutrophils are involved in the process of bone metastasis. In this review, we will discuss the crosstalk between immune cells in bone microenvironment and their involvement with cancer cell metastasis to the bone. Furthermore, we will highlight the anti-tumoral and pro-tumoral function of each immune cell type that contributes to bone metastasis. We will end with a discussion of current therapeutic strategies aimed at sensitizing immune cells.
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Neoplasias Ósseas/imunologia , Neoplasias Ósseas/secundário , Sistema Imunitário/imunologia , Imunoterapia/métodos , Microambiente Tumoral/imunologia , Células Dendríticas/imunologia , Humanos , Células Matadoras Naturais/imunologia , Macrófagos/imunologia , Células Supressoras Mieloides/imunologia , Metástase Neoplásica , Neutrófilos/imunologia , Qualidade de Vida , Linfócitos T/imunologiaRESUMO
Clinical studies have revealed that breast cancers contain regions of intratumoral hypoxia (reduced oxygen availability), which activates hypoxia-inducible factors (HIFs). The relationship between intratumoral hypoxia, distant metastasis and cancer mortality has been well established. A major mechanism by which intratumoral hypoxia contributes to disease progression is through induction of the breast cancer stem cell (BCSC) phenotype. BCSCs are a small subpopulation of cells with the capability for self-renewal. BCSCs have been implicated in resistance to chemotherapy, disease recurrence, and metastasis. In this review, we will discuss our current understanding of the molecular mechanisms underlying HIF-dependent induction of the BCSC phenotype in response to hypoxia or chemotherapy.
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Neoplasias da Mama/patologia , Hipóxia Celular/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Células-Tronco Neoplásicas/patologia , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismoRESUMO
Cancer cells re-program their metabolic machinery to meet the requirements of malignant transformation and progression. Glutaminase 1 (GLS1) was traditionally known as a mitochondrial enzyme that hydrolyzes glutamine into glutamate and fuels rapid proliferation of cancer cells. However, emerging evidence has now revealed that GLS1 might be a novel oncogene involved in tumorigenesis and progression of human cancers. In this study, we sought to determine whether GLS1 implicated in invasion and metastasis of colorectal carcinoma, and its underlying molecular mechanism. By analyzing a large set of clinical data from online datasets, we found that GLS1 is overexpressed in cancers compared with adjacent normal tissues, and associated with increased patient mortality. Immunohistochemical analysis of GLS1 staining showed that high GLS1 expression is significantly correlated with lymph node metastasis and advanced clinical stage in colorectal cancer patients. To investigate the underlying mechanism, we analyzed the Cancer Genome Atlas database and found that GLS1 mRNA expression is associated with a hypoxia signature, which is correlated with an increased risk of metastasis and mortality. Furthermore, reduced oxygen availability increases GLS1 mRNA and protein expression, due to transcriptional activation by hypoxia-inducible factor 1. GLS1 expression in colorectal cancer cells is required for hypoxia-induced migration and invasion in vitro and for tumor growth and metastatic colonization in vivo.
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Neoplasias Colorretais/metabolismo , Glutaminase/metabolismo , Animais , Carcinogênese , Hipóxia Celular/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Progressão da Doença , Glutaminase/genética , Células HT29 , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos SCID , Metástase Neoplásica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Análise de SobrevidaRESUMO
Cellular senescence is an important tumor-suppressive mechanism. However, acquisition of a senescence-associated secretory phenotype (SASP) in senescent cells has deleterious effects on the tissue microenvironment and, paradoxically, promotes tumor progression. In a drug screen, we identified melatonin as a novel SASP suppressor in human cells. Strikingly, melatonin blunts global SASP gene expression upon oncogene-induced senescence (OIS). Moreover, poly(ADP-ribose) polymerase-1 (PARP-1), a sensor of DNA damage, was identified as a new melatonin-dependent regulator of SASP gene induction upon OIS. Here, we report two different but potentially coherent epigenetic strategies for melatonin regulation of SASP. The interaction between the telomeric repeat-containing RNA (TERRA) and PARP-1 stimulates the SASP, which was attenuated by 67.9% (illustrated by the case of IL8) by treatment with melatonin. Through binding to macroH2A1.1, PARP-1 recruits CREB-binding protein (CBP) to mediate acetylation of H2BK120, which positively regulates the expression of target SASP genes, and this process is interrupted by melatonin. Consequently, the findings provide novel insight into melatonin's epigenetic role via modulating PARP-1 in suppression of SASP gene expression in OIS-induced senescent cells. Our studies identify melatonin as a novel anti-SASP molecule, define PARP-1 as a new target by which melatonin regulates SASP, and establish a new epigenetic paradigm for a pharmacological mechanism by which melatonin interrupts PARP-1 interaction with the telomeric long noncoding RNA(lncRNA) or chromatin.
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Senescência Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Melatonina/farmacologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Linhagem Celular , Células Cultivadas , Senescência Celular/genética , Fibroblastos/metabolismo , Humanos , Pulmão/citologia , Poli(ADP-Ribose) Polimerase-1/genéticaRESUMO
Metastasis is the leading cause of breast cancer mortality. Previous studies have implicated hypoxia-induced changes in the composition and stiffness of the extracellular matrix (ECM) in the metastatic process. Therefore, the contribution of potential ECM-binding receptors in this process was explored. Using a bioinformatics approach, the expression of all integrin receptor subunits, in two independent breast cancer patient datasets, were analyzed to determine whether integrin status correlates with a validated hypoxia-inducible gene signature. Subsequently, a large panel of breast cancer cell lines was used to validate that hypoxia induces the expression of integrins that bind to collagen (ITGA1, ITGA11, ITGB1) and fibronectin (ITGA5, ITGB1). Hypoxia-inducible factors (HIF-1 and HIF-2) are directly required for ITGA5 induction under hypoxic conditions, which leads to enhanced migration and invasion of single cells within a multicellular 3D tumor spheroid but did not affect migration in a 2D microenvironment. ITGB1 expression requires HIF-1α, but not HIF-2α, for hypoxic induction in breast cancer cells. ITGA5 (α5 subunit) is required for metastasis to lymph nodes and lungs in breast cancer models, and high ITGA5 expression in clinical biopsies is associated with an increased risk of mortality.Implications: These results reveal that targeting ITGA5 using inhibitors that are currently under consideration in clinical trials may be beneficial for patients with hypoxic tumors. Mol Cancer Res; 15(6); 723-34. ©2017 AACR.
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Neoplasias da Mama/patologia , Regulação Neoplásica da Expressão Gênica , Integrina alfa5beta1/genética , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Neoplasias da Mama/genética , Hipóxia Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Integrina alfa5beta1/metabolismo , Integrina beta1/genética , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Regiões Promotoras Genéticas , Esferoides Celulares/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Because colorectal cancer (CRC) stem-like cells (CCS-like cells) contribute to poor patient prognosis, these cells are a potential target for CRC therapy. However, the mechanism underlying the maintenance of CCS-like cell properties remains unclear. Here, we found that patients with advanced stage CRC expressed high levels of polycomb group protein enhancer of zeste homologue 2 (EZH2). High expression of EZH2 in tumor tissues correlated with poor patient prognosis. Conversely, silencing EZH2 reduced CRC cell proliferation. Surprisingly, EZH2 was more highly expressed in the CCS-like cell subpopulation than in the non-CCS-like cell subpopulation. EZH2 knockdown significantly reduced the CD133+/CD44+ subpopulation, suppressed mammosphere formation, and decreased the expression of self-renewal-related genes and strongly impaired tumor-initiating capacity in a re-implantation mouse model. Gene expression data from 433 human CRC specimens from TCGA database and in vitro results revealed that EZH2 helped maintain CCS-like cell properties by activating the Wnt/ß-catenin pathway. We further revealed that p21cip1-mediated arrest of the cell cycle at G1/S phase is required for EZH2 activation of the Wnt/ß-catenin pathway. Moreover, the specific EZH2 inhibitor EPZ-6438, a clinical trial drug, prevented CRC progression. Collectively, these findings revealed EZH2 maintaining CCS-like cell characteristics by arresting the cell cycle at the G1/S phase. These results indicate a new approach to CRC therapy.
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Proliferação de Células/genética , Neoplasias Colorretais/patologia , Proteína Potenciadora do Homólogo 2 de Zeste/fisiologia , Células-Tronco Neoplásicas/patologia , Via de Sinalização Wnt , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/metabolismo , Via de Sinalização Wnt/genética , Adulto Jovem , beta Catenina/genética , beta Catenina/metabolismoRESUMO
Elevated levels of C-reactive protein (CRP) partially induced by polymorphisms in the CRP gene have been associated with human cancer. The purpose of this study was to test the hypothesis that CRP gene polymorphisms (+942G>C, 1846C>T) modify inherited susceptibility to cancer. We systematically identified the publications addressing the association of CRP gene polymorphisms with cancer susceptibility. Studies that fulfilled all inclusion criteria were considered eligible in this meta-analysis. We analyzed a total of 8 case-control studies. Individuals with the CC genotype were found to have an almost 4 fold higher risk of cancer than those with the GG or GC and GG genotypes. A significant association was also indicated in subgroup of colorectal cancer. Meta-analysis of 1846C>T polymorphism showed increased cancer risk in relation to the 1846 TT genotype (TT vs. CC: OR = 1.15, 95% CI = 1.01-1.31; TT vs. CT + CC; OR = 1.17, 95% CI = 1.03-1.32). Similar results were suggested in Caucasian populations and colorectal cancer. These data suggest that both +942G>C and 1846C>T polymorphisms in the CRP gene may influence cancer susceptibility.
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Proteína C-Reativa/genética , Neoplasias Colorretais/genética , Polimorfismo de Nucleotídeo Único , Alelos , Estudos de Casos e Controles , Neoplasias Colorretais/patologia , Bases de Dados Factuais , Predisposição Genética para Doença , Genótipo , Humanos , Razão de Chances , Fatores de Risco , População Branca/genéticaRESUMO
Existing data have shown a major effect of glutathione S-transferase (GST) single-nucleotide polymorphisms on activities of detoxification-related enzymes, and it is the functional importance that leads to extensive research on the association of GST polymorphisms with the risk of developing brain tumor. Previously reported associations, nevertheless, remain inconsistent. This study aimed to reevaluate the association with new information from recent research articles. We weekly searched multiple databases, aiming to cover all studies looking at the associations being examined in this work. Eligibility of studies was evaluated based on predesigned inclusion criteria. To assess the association of GST polymorphisms with brain tumor risk, we calculated genotypic ORs by comparing the number of genotypes between cases and controls. We also detected interstudy heterogeneity, publication bias, and single studies' influence. A total of 13 research articles were identified through databases and hand search. We found significantly elevated risk of brain tumor associated with GSTT1 null status in individuals of European ethnicity (OR 1.46, 95% CI 1.12-1.92). In the analysis of GSTP1 I105V, we observed that Val/Val genotype compared to the Ile/Ile genotype was more prone to a reduced brain tumor risk (OR 0.77, 95% CI 0.64-0.93). Such major effects were similarly seen for GSTP1 A114V (OR 1.14, 95% CI 1.01-1.29 for Val/Val + Ala/Val vs. Ala/Ala). When data were limited to glioma, we found a significant elevation associated with the combination of Val/Val and Ala/Val genotypes (OR 1.18, 95% CI 1.01-1.37). However, no clear association was detected between other polymorphisms investigated and glioma. These statistical data suggest that some of the polymorphisms at GST loci are possibly associated with the genetic risk of brain tumor.
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Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/genética , Predisposição Genética para Doença , Glutationa Transferase/genética , Polimorfismo Genético , Heterogeneidade Genética , Humanos , Modelos Genéticos , Razão de Chances , Fatores de RiscoRESUMO
Within DNA repair genes, there lie a number of single nucleotide polymorphisms that may impair protein function and attenuate DNA repair capability, resulting in genomic instability and individual predisposition to malignancies. The purpose of this study was to assess the previously reported inconsistent association of polymorphisms in ERCC1 (rs11615, rs3212986), ERCC2 (rs13181, rs1799793, rs238406), and ERCC5 (rs17655) with the development of brain tumors. In the present work, we carried out a comprehensive meta-analysis of results from all published data (5 data sets for rs11615, 7 for rs3212986, 11 for rs13181, 5 for rs1799793, 3 for rs238406, and 4 for rs17655) to evaluate risk of brain tumors contributed by the polymorphisms being investigated. Either the analytic method described by Mantel and Haenszel or that proposed by DerSimonian and Laird was properly used to summarize the risk estimates (OR and 95% CI). Data analyses were done with Stata version 12.0. Meta-analyses were performed for all polymorphisms, and only rs3212986 in the ERCC1 gene showed a significant association with glioma incidence. In the homozygote comparison, we found 1.26-fold elevated risk of glioma in relation to presence of the AA genotype (OR = 1.26, 95% CI = 1.05-1.52, P OR = 0.013, P heterogeneity = 0.849, I(2) = 0.0%). We also noted that individuals with the rs3212986-AA as compared to those with rs3212986-CC/CA had a 28% higher risk to develop glioma (OR = 1.28, 95% CI = 1.06-1.53, P OR = 0.008, Pheterogeneity = 0.808, I(2) = 0.0%). No major effects were observed for Caucasians or Asians in subgroup analysis by ethnicity. ERCC1 rs3212986 is a common single nucleotide polymorphism and may contribute toward individual susceptibility for glioma. Further research in this filed is required to verify the association obtained based on a relatively small number.
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Neoplasias Encefálicas/genética , Carcinogênese/genética , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Transcrição/genética , Proteína Grupo D do Xeroderma Pigmentoso/genética , Heterogeneidade Genética , Predisposição Genética para Doença , Humanos , Razão de Chances , Viés de Publicação , Fatores de RiscoRESUMO
A number of epidemiological studies have assessed the association of -1304Tâ>âG polymorphism in the MKK4 gene and risk of cancer, but the results lack of statistical power due to the limited subjects used in these studies. This study was devised to identify the genetic effects of the -1304Tâ>âG polymorphism on cancer risk in a large meta-analysis.Eligible studies were identified by searching both Chinese and English databases. General as well as subgroup analyses were performed for 8 independent case-control publications with a total of 4623 cases and 5256 cancer-free controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the association.Overall, this meta-analysis showed that the association between the -1304Tâ>âG polymorphism and cancer risk was statistically significant (GG vs TT: ORâ=â0.63, 95% CI, 0.52-0.75; GGâ+âTG vs TT: ORâ=â0.85, 95% CI, 0.79-0.91; GG vs TGâ+âTT: ORâ=â0.67, 95% CI, 0.56-0.80; G vs T: ORâ=â0.82, 95% CI, 0.77-0.88; TG vs TT: ORâ=â0.86, 95% CI, 0.79-0.93).Our meta-analysis reveals that the presence of the -1304Tâ>âG polymorphism is likely to decrease risk of cancer. Future larger studies are necessary to validate the current finding.
Assuntos
DNA/genética , Predisposição Genética para Doença , MAP Quinase Quinase 4/genética , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Genótipo , Humanos , Neoplasias/enzimologiaRESUMO
Increased expression of CD47 has been reported to enable cancer cells to evade phagocytosis by macrophages and to promote the cancer stem cell phenotype, but the molecular mechanisms regulating CD47 expression have not been determined. Here we report that hypoxia-inducible factor 1 (HIF-1) directly activates transcription of the CD47 gene in hypoxic breast cancer cells. Knockdown of HIF activity or CD47 expression increased the phagocytosis of breast cancer cells by bone marrow-derived macrophages. CD47 expression was increased in mammosphere cultures, which are enriched for cancer stem cells, and CD47 deficiency led to cancer stem cell depletion. Analysis of datasets derived from thousands of patients with breast cancer revealed that CD47 expression was correlated with HIF target gene expression and with patient mortality. Thus, CD47 expression contributes to the lethal breast cancer phenotype that is mediated by HIF-1.
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Neoplasias da Mama/metabolismo , Antígeno CD47/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Fator 1 Induzível por Hipóxia/metabolismo , Células-Tronco Neoplásicas/fisiologia , Fagocitose/fisiologia , Evasão Tumoral/fisiologia , Análise de Variância , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Primers do DNA , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Fator 1 Induzível por Hipóxia/farmacologia , Immunoblotting , Luciferases , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Triple negative breast cancer (TNBC) accounts for 10-15% of all breast cancer but is responsible for a disproportionate share of morbidity and mortality because of its aggressive characteristics and lack of targeted therapies. Chemotherapy induces enrichment of breast cancer stem cells (BCSCs), which are responsible for tumor recurrence and metastasis. Here, we demonstrate that chemotherapy induces the expression of the cystine transporter xCT and the regulatory subunit of glutamate-cysteine ligase (GCLM) in a hypoxia-inducible factor (HIF)-1-dependent manner, leading to increased intracellular glutathione levels, which inhibit mitogen-activated protein kinase kinase (MEK) activity through copper chelation. Loss of MEK-ERK signaling causes FoxO3 nuclear translocation and transcriptional activation of the gene encoding the pluripotency factor Nanog, which is required for enrichment of BCSCs. Inhibition of xCT, GCLM, FoxO3, or Nanog blocks chemotherapy-induced enrichment of BCSCs and impairs tumor initiation. These results suggest that, in combination with chemotherapy, targeting BCSCs by inhibiting HIF-1-regulated glutathione synthesis may improve outcome in TNBC.
Assuntos
Antineoplásicos/química , Cobre/química , Glutationa/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Células-Tronco Neoplásicas/citologia , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Linhagem Celular Tumoral , Quelantes/química , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , MAP Quinase Quinase Quinases/metabolismo , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos SCID , Transplante de Neoplasias , Oligonucleotídeos/genética , Paclitaxel/química , Fenótipo , Fosforilação , RNA Mensageiro/metabolismoRESUMO
Several epidemiological studies have focused on the role of nuclear factor-kappa-B inhibitor-alpha (NFKBIA) -881 A>G polymorphism in cancer susceptibility. However, the published data have led to contentious results. This study was designed to examine the association between -881 A>G polymorphism and cancer risk.Comprehensive search of PubMed, Web of science and Embase, identified a total of 5 case-control studies. To assess the association, comparison among all subjects plus subgroup analysis by ethnicity was performed and odds ratio (OR) along with 95% confidence interval (CI) was calculated with the fixed-effect model or the random-effects model dependent on the heterogeneity.The pooling data consisting of 1965 cancer cases and 2717 cancer-free controls demonstrated no significant association with overall cancer risk. However, the subgroup of Asian populations showed statistical evidence for an increase in risk of cancer (GG vs. AA, OR, 2.14; 95% CI, 1.03-4.46; GGâ+âGA vs. AA, OR, 1.22; 95% CI, 1.01-1.47; GG vs. GAâ+âAA, OR, 2.09; 95% CI, 1.01-4.34).This investigation on the association of -881 A>G polymorphism and cancer susceptibility reveals that -881 A>G polymorphism may act as a candidate for cancer development in Asian populations.
Assuntos
Biomarcadores Tumorais/genética , Predisposição Genética para Doença , Proteínas I-kappa B/genética , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Povo Asiático/genética , Estudos de Associação Genética , Marcadores Genéticos , Humanos , Modelos Estatísticos , Inibidor de NF-kappaB alfa , Neoplasias/etnologiaRESUMO
We aimed to determine the indecisive association between tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1) Thr209Arg polymorphism and inherited susceptibility to cancer. A meta-analysis combining data on 9,517 individuals was performed to assess the association between TRAIL-R1 Thr209Arg and cancer incidence. The summary ORs with 95% CI calculated with the fixed effects model suggested that Thr209Arg was not significantly associated with cancer susceptibility (homozygous model: OR 0.98, 95% CI 0.88-1.09; heterozygous model: OR 0.95, 95% CI 0.87-1.04; allele frequency model: OR 0.99, 95% CI 0.94-1.05; dominant model: OR 0.98, 95% CI 0.91-1.05; recessive model: OR 1.01, 95% CI 0.92-1.10). Stratified analysis by ethnicity and cancer type yielded similar null associations. These statistical data suggest that Thr209Arg in exon 4 of the TRAIL-R1 gene may not represent a modifier of susceptibility to cancer.