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1.
DNA Cell Biol ; 40(10): 1251-1260, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34491823

RESUMO

Microsatellite instability (MSI) is emerging as a promising subtype related to immunotherapy in gastric cancer (GC). However, the underlying mechanism between MSI and microsatellite stability (MSS) remains unclear. In this study, we conducted a weighted gene co-expression network analysis and found that the expression of heterogeneous nuclear ribonucleoprotein L (HNRNPL) was significantly increased in MSI GC compared with MSS GC. This finding was further validated in public GC cohorts and commercialized human GC tissue microarray. The significant negative correlation with the expression of mismatch repair protein mutL homolog 1 (MLH1) may be one of the potential mechanisms for the upregulation of HNRNPL expression in MSI GC (R = -0.689, p = 8.59e-11). In addition, HNRNPL expression was markedly upregulated in GC tissues compared with adjacent normal tissues. High HNRNPL expression also predicted a poor prognosis in GC patients. Finally, gene set enrichment analysis revealed that high HNRNPL MSI GC samples were highly positive associated with the biological functions of inflammation and cell proliferation, such as interferon gamma response, MYC targets, E2F targets, and G2/M checkpoints. In conclusion, HNRNPL could be a new MSI-associated prognostic biomarker in GC and could be a new target for the MSI GC treatment.


Assuntos
Biomarcadores Tumorais/genética , Instabilidade Genômica , Repetições de Microssatélites , Ribonucleoproteínas/genética , Neoplasias Gástricas/genética , Idoso , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Ribonucleoproteínas/metabolismo , Neoplasias Gástricas/patologia , Regulação para Cima
2.
Mol Neurobiol ; 58(11): 5649-5666, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34383254

RESUMO

The sigma-1 receptor (Sig-1R) is encoded by the SIGMAR1 gene and is a nonopioid transmembrane receptor located in the mitochondrial-associated endoplasmic reticulum membrane (MAM). It helps to locate endoplasmic reticulum calcium channels, regulates calcium homeostasis, and acts as a molecular chaperone to control cell fate and participate in signal transduction. It plays an important role in protecting neurons through a variety of signaling pathways and participates in the regulation of cognition and motor behavior closely related to neurodegenerative diseases. Based on its neuroprotective effects, Sig-1R has now become a breakthrough target for alleviating Alzheimer's disease and other neurodegenerative diseases. This article reviews the most cutting-edge research on the function of Sig-1R under normal or pathologic conditions and target drugs of the sigma-1 receptor in neurodegenerative diseases.

3.
Front Pharmacol ; 12: 653887, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33981233

RESUMO

Background: Metabolic activity is the basic life activity of organisms and the fundamental for maintaining body functions. With the improvement of living standards, the incidence of metabolic disorder is also increasing. At present, most of the clinical treatment strategies and meta-analysis for metabolic disorder uncover that combined medicines with berberine ameliorate several metabolic disorders. However, evidence to disclose the therapeutic effect of berberine treatment alone and the possible factors affecting the efficacy is limited. Therefore, we have formulated strict inclusion criteria and selected more reliable data for meta-analysis through more refined screening strategies to provide evidence and guidance for clinical decision-making and understand the effect of berberine treatment alone and the factors affecting its efficacy. Methods and results: Using meta-analysis of "Cochrane Handbook for Systematic Reviews of Interventions" as guidelines, we searched PubMed, GeenMedical, Cochrane library, and china national knowledge infrastructure (CNKI) for trials reporting clinical treatment data of berberine. Another 417 trials were included through other sources to increase confidence in results. Among the 1,660 related documents retrieved from the four databases, 18 eligible documents were selected for analysis. Given the differences in trial design and measurement units, we used the standardized mean difference (SMD) method to eliminate the differences and then summarize the data for analysis. The main factors are triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), homeostasis model assessment-insulin resistance (HOMA-IR), and fasting plasma glucose (FPG). Random-effect model analysis was performed: TG (SMD: 0.94; 95%CI: 0.49,1.38; p = 0.00), TC (SMD: 1.06; 95%CI: 0.64, 1.48; p = 0.00), LDL (SMD: 1.77; 95%CI: 1.11,2.44; p = 0.00), HDL (SMD: -1.59; 95%CI: -2.32, -0.85; p = 0.00), HOMA-IR (SMD: 1.25; 95%CI: 0.25,2.24; p = 0.01), and FPG (SMD: 0.65; 95%CI: 0.28,1.03; p = 0.00). This study aimed to conduct a systematic review and meta-analysis of the literature to evaluate the therapeutic effect of berberine singly on metabolic diseases. Conclusion: Berberine can improve obesity and hyperlipidemia by reducing TG, TC, and LDL and increasing HDL; reduce insulin resistance to improve type Ⅱ diabetes; and prevent diabetic encephalopathy.

4.
Biofactors ; 47(4): 587-599, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33740285

RESUMO

IR (insulin resistance) in diabetic brain gave rise to the generation of toxic factor Aß42 and axon collapse which were the marker of AD (Alzheimer's disease)-like lesions in the circumstance of diabetes mellitus. But the underling molecular mechanism was not clear. Chronic HGHI (high glucose and high insulin) exposure accelerates IR has been reported in type II diabetes models. Berberine has been shown to promising effect for IR in vitro and in vivo. This study demonstrates the protective effect and the underlying mechanism of berberine on HGHI-induced IR. HGHI-induced cells were used to mimic the hyperinsulinemia resulting in IR. Berberine was used to uncover the mechanisms for the treatment of hyperinsulinemia in IR model. Morris water maze (MWM), PET imaging, CCK8 assay, ELISA assay, glucose kits, microscopy, and western blot analysis were performed to evaluate the protective effects of berberine. Berberine-improved HGHI-induced IR was correlated with the increase of glucose application in neurons. Meanwhile, the expressions of Pi3K, as well as GLUT3, PKCε, and APP were downregulated in the model, while p-IRS Ser307 was upregulated compared with Normal group. Fortunately, these scenes were reversed by berberine administration. Furthermore, berberine decreased GSK3ß Y216 expressions, inhibited the production of oligomer Aß42 and extended neuronal axon. The monomeric berberine treatment improves IR that may be involved in glucose effective application, rectifying the related proteins of the aberrant insulin pathway. Additionally, it suppressed the generation of Aß42 and ameliorated neuron axon damage. Finally, berberine improves DM (diabetes mellitus)-induced cognitive impairment.

5.
Zhongguo Zhong Yao Za Zhi ; 45(6): 1460-1464, 2020 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-32281361

RESUMO

To evaluate the efficacy and safety of acupuncture combined with modified Xiangfu Decoction in the treatment of menopausal insomnia case by liver Qi stagnation. Totally 120 cases were randomly divided into the control group(60 cases) and the treatment group(60 cases). Estazolam and acupuncture combined with modified Xiangfu Decoction were given for 16 weeks. Before and after treatment, Epworth sleepiness scale(ESS), Pittsburgh sleep quality index(PSQI), Hamilton anxiety scale(HAMA) and traditional Chinese medicine(TCM) syndrome score were compared between the two groups. Polysomnography monitor was used to monitor sleep progress and sleep structure. Serum LH, FSH and E_2 were determined. The clinical efficacy and incidence of adverse reactions were observed. Four cases were lost during the study. The total effective rate in the treatment group was 91.5%, which was higher than that in the control group 75.4%(P<0.05). After treatment, the scores of clinical symptoms(ESS, PSQI, HAMA, TCM symptoms) in the treatment group were significantly reduced(P<0.05), and lower than that in the control group(P<0.05). TST, SE in the treatment group were increased(P<0.05), while AWT, SL, AT in the treatment group were decreased(P<0.05), and the improvement was more significant than that in the control group(P<0.05). S_1 in the treatment group was decreased(P<0.05), whereas S_2, S_(3+4), REM in the treatment group were increased(P<0.05), and the improvement was more significant than that in the control group(P<0.05). The contents of LH and FSH in the treatment group were significantly reduced(P<0.05), while the content of E_2 was significantly increased(P<0.05), and the changes were more significant than those in the control group(P<0.05). The incidence of adverse reactions in the control group was 8.8%, which was higher than 1.7% in the treatment group(P<0.05). Acupuncture combined with modified Xiangfu Decoction could significantly improve the sleep status of menopausal insomnia cases caused by liver Qi stagnation, with a lower incidence of adverse reactions, and so is worthy of clinical promotion and application.


Assuntos
Terapia por Acupuntura , Medicamentos de Ervas Chinesas/uso terapêutico , Menopausa , Distúrbios do Início e da Manutenção do Sono/terapia , Feminino , Humanos , Fígado , Medicina Tradicional Chinesa , Qi , Resultado do Tratamento
6.
J Immunother Cancer ; 8(1)2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32152220

RESUMO

BACKGROUND: Interferon-α (IFN-α) plays a pivotal role in host antitumor immunity, and the evasion of IFN-α signaling pathway can lead to IFN-α resistance during the treatment of cancer. Although the interplay between IFN-α and tumor cells has been extensively investigated in differentiated tumor cells, much less attention has been directed to tumor-repopulating cells (TRCs). METHODS: Three-dimentional soft fibrin matrix was used to select and grow highly malignant and tumorigenic melanoma TRCs. The regulation of integrin ß3 (ITGB3)-c-SRC-STAT signaling pathway in melanoma TRCs was investigated both in vitro and in vivo. The relevant mRNA and protein expression levels were analyzed by qRT-PCR and western blot analysis. Immunoprecipitation and chromatin immunoprecipitation (ChIP) followed by qPCR (ChIP-qPCR) assays were performed to detect protein-protein and protein-DNA interactions. The clinical impacts of retinoic acid inducible gene-I (RIG-I) were assessed in melanoma datasets obtained from The Cancer Genome Atlas and Gene Expression Omnibus profiles. RESULTS: IFN-α-induced apoptosis was decreased in melanoma TRCs. Compared with conventional flask-cultured cells, IFN-α-mediated STAT1 activation was diminished in melanoma TRCs. Decreased expression of RIG-I in melanoma TRCs led to diminished activation of STAT1 via enhancing the interaction between Src homology region 2 domain-containing phosphatase-1 and STAT1. In addition, low expression levels of RIG-I correlated with poor prognosis in patients with melanoma. STAT3 was highly phosphorylated in TRCs and knockdown of STAT3 reversed the downregulation of RIG-I in TRCs. Knockdown of STAT3 resulted in STAT1 activation and increased expression of the pro-apoptosis genes in IFN-α-treated TRCs. Combined treatment of STAT3 inhibitor and IFN-α increased the apoptosis rate of TRCs. Disruption of ITGB3/c-SRC/STAT3 signaling pathway significantly elevated the efficiency of IFN-α-induced apoptosis of TRCs. CONCLUSIONS: In melanoma TRCs, ITGB3-c-SRC-STAT3 pathway caused RIG-I repression and then affect STAT1 activation to cause resistance to IFN-α-induced apoptosis. RIG-I is a prognostic marker in patients with melanoma. Combination of STAT3 inhibitor and IFN-α could enhance the efficacy of melanoma treatment. Our findings may provide a new concept of combinatorial treatment for future immunotherapy.


Assuntos
Proteína DEAD-box 58/metabolismo , Integrina beta3/metabolismo , Interferon-alfa/farmacologia , Melanoma Experimental/tratamento farmacológico , Melanoma/tratamento farmacológico , Proteínas Proto-Oncogênicas pp60(c-src)/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proteína DEAD-box 58/antagonistas & inibidores , Proteína DEAD-box 58/genética , Regulação para Baixo , Feminino , Células Hep G2 , Humanos , Fatores Imunológicos/farmacologia , Melanoma/imunologia , Melanoma/metabolismo , Melanoma/patologia , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Prognóstico , Receptores Imunológicos , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais , Taxa de Sobrevida
7.
Cell Mol Immunol ; 17(12): 1233-1244, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-31649305

RESUMO

Despite their mutual antagonism, inflammation and immunosuppression coexist in tumor microenvironments due to tumor and immune cell interactions, but the underlying mechanism remains unclear. Previously, we showed that tumor cell-derived microparticles induce an M2 phenotype characterized by immunosuppression in tumor-infiltrating macrophages. Here, we further showed that lung cancer microparticles (L-MPs) induce macrophages to release a key proinflammatory cytokine, IL-1ß, thus promoting lung cancer development. The underlying mechanism involves the activation of TLR3 and the NLRP3 inflammasome by L-MPs. More importantly, tyrosine kinase inhibitor treatment-induced L-MPs also induce human macrophages to release IL-1ß, leading to a tumor-promoting effect in a humanized mouse model. These findings demonstrated that in addition to their anti-inflammatory effect, L-MPs induce a proinflammatory phenotype in tumor-infiltrating macrophages, promoting the development of inflammatory and immunosuppressive tumor microenvironments.


Assuntos
Carcinogênese/patologia , Micropartículas Derivadas de Células/metabolismo , Reprogramação Celular , Interleucina-1beta/metabolismo , Neoplasias Pulmonares/metabolismo , Macrófagos/metabolismo , Animais , Cálcio/metabolismo , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Ligantes , Ativação Linfocitária/imunologia , Lisossomos/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , RNA não Traduzido/genética , RNA não Traduzido/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptor 3 Toll-Like/metabolismo , Regulação para Cima
8.
Oncogene ; 38(44): 6970-6984, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31409901

RESUMO

Clinical applications of antiangiogenic agents profoundly affect tumor cell behaviors via the resultant hypoxia. To date, how the hypoxia regulates tumor cells remains unclear. Here, we show that hypoxia promotes the growth of human breast tumorigenic cells that repopulate tumors [tumor-repopulating cells (TRCs)] in vitro and in vivo. This stimulating effect is ascribed to hypoxia-induced reactive oxygen species (ROS) that activates Akt and NF-κB, dependent on the attenuated tricarboxylic acid (TCA) cycle. We find that fumarate is accumulated in the TCA cycle of hypoxic TRCs, leading to glutathione succination, NADPH/NADP+ decrease, and an increase in ROS levels. Mechanistically, hypoxia-increased HIF-1α transcriptionally downregulates the expression of mitochondrial phosphoenolpyruvate carboxykinase (PCK2), leading to TCA cycle attenuation and fumarate accumulation. These findings reveal that hypoxia-reprogrammed TCA cycle promotes human breast TRCs growth via a HIF-1α-downregulated PCK2 pathway, implying a need for a combination of an antiangiogenic therapy with an antioxidant modulator.


Assuntos
Neoplasias da Mama/patologia , Hipóxia Celular/fisiologia , Ciclo do Ácido Cítrico/fisiologia , Neoplasias da Mama/metabolismo , Regulação para Baixo , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Células-Tronco Neoplásicas/metabolismo , Fosfoenolpiruvato Carboxiquinase (ATP)/metabolismo , Microambiente Tumoral
9.
Redox Biol ; 20: 451-457, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30439686

RESUMO

Metabolic reprogramming is a feature of cancer cells and crucial for tumor growth and metastasis. Interferon-γ (IFNγ) is a cytokine that plays a pivotal role in host antitumor immunity. However, little is known about the roles of metabolic reprogramming in immune responses. Here, we show that colon cancer cells reprogram metabolism to coordinate proper cellular responses to IFNγ by downregulating mitochondrial pyruvate carrier (MPC)1 and 2 via STAT3 signaling. Forced overexpression of MPC promote the production of reactive oxygen species and enhance the apoptosis induced by IFNγ in colon cancer cells. Moreover, inhibiting STAT3 sensitize the antitumor efficacy of IFN-γ against colon cancer cells. Our findings present a previously unrecognized mechanism that colon cancer manipulate to resist IFNγ mediated antitumor immunity that have implications for targeting a unique aspect of this disease.


Assuntos
Neoplasias do Colo/metabolismo , Interferon gama/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Piruvatos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Transporte Biológico , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos , Mitocôndrias/genética , Modelos Biológicos , Oxirredução , Pró-Proteína Convertase 1/genética , Pró-Proteína Convertase 1/metabolismo , Pró-Proteína Convertase 2/genética , Pró-Proteína Convertase 2/metabolismo
10.
J Exp Clin Cancer Res ; 37(1): 259, 2018 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-30373678

RESUMO

BACKGROUND: Lysosome-associated agents have been implicated as possible chemo-sensitizers and immune regulators for cancer chemotherapy. We investigated the potential roles and mechanisms of hydroxychloroquine (HCQ) in combination with chemotherapy in lung cancer treatment. METHODS: The effects of combined treatment on non-small cell lung cancer (NSCLC) were investigated using cell viability assays and animal models. The influence of HCQ on lysosomal pH was evaluated by lysosomal sensors and confocal microscopy. The effects of HCQ on the tumour immune microenvironment were analysed by flow cytometry. RESULTS: HCQ elevates the lysosomal pH of cancer cells to inactivate P-gp while increasing drug release from the lysosome into the nucleus. Furthermore, single HCQ therapy inhibits lung cancer by inducing macrophage-modulated anti-tumour CD8+ T cell immunity. Moreover, HCQ could promote the transition of M2 tumour-associated macrophages (TAMs) into M1-like macrophages, leading to CD8+ T cell infiltration into the tumour microenvironment. CONCLUSIONS: HCQ exerts anti-NSCLC cells effects by reversing the drug sequestration in lysosomes and enhancing the CD8+ T cell immune response. These findings suggest that HCQ could act as a promising chemo-sensitizer and immune regulator for lung cancer chemotherapy in the clinic.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Hidroxicloroquina/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Células A549 , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Hidroxicloroquina/farmacologia , Neoplasias Pulmonares/patologia , Lisossomos/química , Lisossomos/efeitos dos fármacos , Macrófagos/patologia , Camundongos , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Cancer Immunol Res ; 6(9): 1046-1056, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30002156

RESUMO

Despite the frequency of lung metastasis and its associated mortality, the mechanisms behind metastatic tumor cell survival and colonization in the lungs remain elusive. Here, we show that tumor cell-released microparticles (T-MPs) from the primary tumor site play a critical role in the metastatic process. The T-MPs remodeled the lung parenchyma via a macrophage-dependent pathway to create an altered inflammatory and mechanical response to tumor cell invasion. Mechanistically, we show that circulating T-MPs readily enter the lung parenchyma where they are taken up by local macrophages and induce CCL2 production. CCL2 recruits CD11b+Ly6Chigh inflammatory monocytes to the lungs where they mature into F4/80+CD11b+Ly6C- macrophages that not only produce IL6 but also trigger fibrin deposition. IL6 and the deposited fibrin facilitate the survival and growth of tumor-repopulating cells in the lungs by providing chemical and mechanical signals, respectively, thus setting the stage for lung metastasis. These data illustrate that T-MPs reprogram the lung microenvironment promoting metastasis. Cancer Immunol Res; 6(9); 1046-56. ©2018 AACR.


Assuntos
Micropartículas Derivadas de Células/imunologia , Inflamação , Neoplasias Pulmonares/patologia , Macrófagos/imunologia , Metástase Neoplásica/imunologia , Animais , Micropartículas Derivadas de Células/patologia , Feminino , Pulmão/citologia , Pulmão/imunologia , Neoplasias Pulmonares/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microambiente Tumoral/imunologia
12.
Cancer Immunol Res ; 6(9): 1057-1068, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30018046

RESUMO

Tumor cell-derived microparticles (T-MP) contain tumor antigen profiles as well as innate signals, endowing them with vaccine potential; however, the precise mechanism by which DCs present T-MP antigens to T cells remains unclear. Here, we show that T-MPs activate a lysosomal pathway that is required for DCs presenting tumor antigens of T-MPs. DCs endocytose T-MPs to lysosomes, where T-MPs increase lysosomal pH from 5.0 to a peak of 8.5 via NOX2-catalyzed reactive oxygen species (ROS) production. This increased pH, coupled with T-MP-driven lysosomal centripetal migration, promotes the formation of MHC class I-tumor antigen peptide complexes. Concurrently, endocytosis of T-MPs results in the upregulation of CD80 and CD86. T-MP-increased ROS activate lysosomal Ca2+ channel Mcoln2, leading to Ca2+ release. Released Ca2+ activates transcription factor EB (TFEB), a lysosomal master regulator that directly binds to CD80 and CD86 promoters, promoting gene expression. These findings elucidate a pathway through which DCs efficiently present tumor antigen from T-MPs to CD8+ T cells, potentiating T-MPs as a novel tumor cell-free vaccine with clinical applications. Cancer Immunol Res; 6(9); 1057-68. ©2018 AACR.


Assuntos
Apresentação do Antígeno , Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/imunologia , Micropartículas Derivadas de Células/imunologia , Células Dendríticas/imunologia , Animais , Antígeno B7-1/genética , Antígeno B7-2/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Vacinas Anticâncer/imunologia , Diferenciação Celular , Células Cultivadas , Endocitose/imunologia , Feminino , Antígenos de Histocompatibilidade Classe I/imunologia , Lisossomos/fisiologia , Melanoma Experimental , Camundongos , Camundongos Endogâmicos C57BL
13.
Oncoimmunology ; 6(6): e1309487, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28680743

RESUMO

Stem cell-like tumor-repopulating cells (TRCs) have a critical role in establishing a tumor immunosuppressive microenvironment. However, means to enhance antitumor immunity by disrupting TRCs are absent. Our previous studies have shown that tumor cell-derived microparticles (T-MPs) preferentially abrogate TRCs by delivering antitumor drugs into nuclei of TRCs. Here, we show that low dose irradiation (LDI) enhances the effect of cisplatin-packaging T-MPs (Cis-MPs) on TRCs, leading to inhibiting tumor growth in different tumor models. This antitumor effect is not due to the direct killing of tumor cells but is T cell-dependent and relies on macrophages for their efficacy. The underlying mechanism is involved in therapeutic reprograming macrophages from tumor-promotion to tumor-inhibition by disrupting TRCs and curtailing their vicious education on macrophages. These findings provide a novel strategy to reset macrophage polarization and confer their function more like M1 than M2 types with highly promising potential clinical applications.

14.
Biochem Biophys Res Commun ; 491(1): 104-111, 2017 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-28709865

RESUMO

PURPOSE: The present study was to evaluate the prognostic value of protein expression of Pofut1 and Notch1 signaling in breast cancer. MATERIAL AND METHODS: Formalin-fixed paraffin-embedded 314 breast specimens including 174 infiltrating ductal carcinoma(IDC), 50 ductal carcinoma in situ(DCIS) and 90 adjacent normal tissue(ANT) were immunohistochemically examined to evaluate the protein expression of Pofut1, activated Notch1(N1IC) and Slug on specimens. Survival analysis was performed by Kaplan-Meier method and Cox's proportional-hazards model. A online database was computationally used to further explore the prognostic role of Pofut1 and Notch1 mRNA expression by Kaplan-Meier Plotter. RESULTS: Pofut1, Slug and N1IC expression were significantly increased in IDC compared to ANT(all p < 0.05). High expression of Pofut1, Slug and N1IC were associated with tumor aggressiveness including lymph node metastasis (LNM: p = 0.005 for Pofut1, p < 0.001 for N1IC, p = 0.017 for Slug), advanced stage(p = 0.039 for Pofut1, p = 0.025 for N1IC) and higher histological grade(p = 0.001 for N1IC). Additionally, high expression of Pofut1 was found to be significantly associated with high expressions of N1IC and Slug in IDC(r = 0.244, p = 0.001; r = 0.374, p < 0.001, respectively), similar correlation was also observed between high N1IC and Slug expression(r = 0.496, p < 0.001). Moreover, Kaplan-Meier and Cox's regression analysis indicated the significant prognostic value of elevated Pofut1, N1IC, Slug expressions, positive LNM and advanced tumor stage for the prediction of a shorter disease-free survival (DFS) and overall survival(OS). The web-based analysis also suggested a significant association of high Pofut1 and Notch1 mRNA expression with worse survival outcome. CONCLUSION: Our findings suggested that overexpression of Pofut1 and activated Notch1 signaling may be associated with a poor prognosis in breast cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Fucosiltransferases/metabolismo , Receptor Notch1/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , China/epidemiologia , Feminino , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Prevalência , Prognóstico , Reprodutibilidade dos Testes , Fatores de Risco , Sensibilidade e Especificidade , Taxa de Sobrevida , Regulação para Cima
15.
Onco Targets Ther ; 9: 2049-56, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27103831

RESUMO

BACKGROUND: Previous studies have investigated the associations between the common polymorphisms in FAS/FASL genes and lung cancer risk; however, the results remain inconsistent and inconclusive. Hence, we performed a meta-analysis to reassess the relationships between FAS rs2234767 and FASL rs763110 polymorphisms and the risk of lung cancer. METHODS: Eligible studies retrieved by an electronic search were pooled to calculate the strength of the associations using the odds ratio (OR) and 95% confidence interval (95% CI). RESULTS: A total of 13 case-control studies involving 39,736 subjects (9,237 cases and 10,838 controls on FAS rs2234767 and 8,957 cases and 10,704 controls on FASL rs763110) were included in the meta-analysis. The results showed a significant association between FAS rs2234767 polymorphism and increased risk of lung cancer (A vs G: OR =1.07, 95% CI =1.01-1.13; AA vs GG: OR =1.23, 95% CI =1.06-1.43; AA vs GA + GG: OR =1.24, 95% CI =1.08-1.43). Similar association was also observed in Asian population (AA vs GA + GG: OR =1.30, 95% CI =1.01-1.67) and in the studies with large sample size (A vs G: OR =1.07, 95% CI =1.00-1.14; AA vs GG: OR =1.30, 95% CI =1.07-1.58). However, no significant association between FASL rs763110 polymorphism and lung cancer risk was found other than in the Asian population (CC vs TC + TT: OR =1.35, 95% CI =1.01-1.80). CONCLUSION: The meta-analysis indicated that FAS rs2234767 polymorphism was significantly associated with an increased risk of lung cancer and FASL rs763110 polymorphism may not contribute to susceptibility to lung cancer other than in Asian population.

16.
Int J Clin Exp Med ; 8(3): 3935-45, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26064295

RESUMO

The current meta-analysis incorporating 15 case-control studies involving 4,138 cases and 4,269 controls was performed on the basis of a systematical search in electronic databases for a more precise estimation on the associations of three common polymorphisms -765 G>C (rs20417), -1195G>A (rs689466) and +8473 C>T (rs5275) in Cyclooxygenase-2 (Cox-2) gene with the susceptibility to bladder cancer. The results showed that there was a significant association between rs5275 polymorphism and bladder cancer risk (C vs. T; OR=0.84; CC vs. TT: OR=0.76), especially among Chinese (CC vs. TC+TT: OR=0.48) and American (C vs. T; OR=0.83; TC vs. TT: OR=0.73; CC+TC vs. TT: OR=0.73). and the rs20417 polymorphism was significantly associated with an increased risk of bladder cancer among Chinese (C vs. G: OR=1.46; GC vs. GG: OR=1.49; CC+GC vs. GG: OR=1.51) and Indian (GC vs. GG: OR=1.63; CC+GC vs. GG: OR=1.46), but a reduced risk among American (C vs. G: OR=0.81; GC vs. GG: OR=0.76; CC+GC vs. GG: OR=0.76). Additionally, we found that the rs689466 polymorphism was associated with a decreased risk of bladder cancer in Indian (GA vs. GG: OR=0.68; AA vs. GG: OR=0.39).The present meta-analysis suggests that Cox-2 rs5275 polymorphism may contribute to the risk of bladder cancer, particularly among Chinese and American. The rs20417 polymorphism may play a protective role in the development of bladder cancer in Indian and Chinese but act as a risk factor among American, while the rs689466 polymorphism was more likely to be associated with a decreased risk of bladder cancer in Indian.

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