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1.
Mol Cell Biochem ; 479(3): 629-642, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37140813

RESUMO

Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. Chemotherapy is the mainstay of treatment for patients with CRC in II-IV stages. Resistance to chemotherapy occurs commonly, which results in treatment failure. Therefore, the identification of novel functional biomarkers is essential for recognizing high-risk patients, predicting recurrence, and developing new therapeutic strategies. Herein, we assessed the roles of KIAA1549 in promoting tumor development and chemoresistance in colorectal cancer. As a result, we found that KIAA1549 expression is up-regulation in CRC. Public databases revealed a progressive up-regulation of KIAA1549 expression from adenomas to carcinomas. Functional characterization uncovered that KIAA1549 promotes tumor malignant phenotypes and boosts the chemoresistance of CRC cells in an ERCC2-dependent manner. Inhibition of KIAA1549 and ERCC2 effectively enhanced the sensitivity to chemotherapeutic drugs oxaliplatin and 5-fluorouracil. Our findings suggest that endogenous KIAA1549 might function as a tumor development-promoting role and trigger chemoresistance in colorectal cancer partly by upregulating DNA repair protein ERCC2. Hence, KIAA1549 could be an effective therapeutic target for CRC and inhibition of KIAA1549 combined with chemotherapy might be a potential therapeutic strategy in the future.


Assuntos
Neoplasias Colorretais , Humanos , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Oxaliplatina/farmacologia , Oxaliplatina/uso terapêutico , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Fatores de Transcrição/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteína Grupo D do Xeroderma Pigmentoso/genética , Proteína Grupo D do Xeroderma Pigmentoso/metabolismo
2.
Cell Death Dis ; 14(8): 488, 2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-37524692

RESUMO

With technological advancements, radiotherapy (RT) has become an effective non-surgical treatment for hepatocellular carcinoma (HCC), comprehensively improving the local control rate of patients with HCC. However, some patients with HCC still experience radio-resistance, cancer recurrence, and distant metastasis following RT. Our previous study has revealed that hexokinase 2 (HK2), a potent oncogene, was overexpressed in radio-resistant HCC cell lines; however, its role in HCC radio-resistance remains elusive. Here, we confirmed the upregulation of HK2 in HCC tissue, which is related to unfavorable prognosis in patients with HCC, and demonstrated that HK2 exerts a radio-resistant role by attenuating apoptosis and promoting proliferation in HCC cell lines. HK2 downregulation combined with ionizing radiation showed an excellent synergistic lethal effect. Mechanistically, HK2 alleviated ionizing radiation-mediated apoptosis by complexing with pro-apoptotic protein aminoacyl tRNA synthetase complex interacting multifunctional protein 2 (AIMP2) while enhancing its autophagic lysosomal-dependent degradation, thereby increasing radio-resistance of HCC. Pharmacologically, ketoconazole, an FDA-approved antifungal drug, served as an inhibitor of HK2 and synergistically enhanced the efficacy of RT. Our results indicated that HK2 played a vital role in radio-resistance and could be a potential therapeutic target for improving RT efficacy in HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Autofagia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/radioterapia , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Hexoquinase/genética , Hexoquinase/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/metabolismo , Recidiva Local de Neoplasia , Proteínas Nucleares/farmacologia
3.
Med Oncol ; 40(2): 73, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36607478

RESUMO

Colorectal cancer (CRC) is the third leading malignancy worldwide in both new cases and deaths. Neoadjuvant radiotherapy is the standard preoperative regimens for locally advanced patients. However, approximately 50% of patients develop recurrence and metastasis after radiotherapy, which is largely due to the radiation resistance properties of the tumor, and the internal mechanism has not been elucidated. Here we found that CEMIP expression is up-regulated in a variety of tumor types, particularly in CRC. Public databases and clinical samples revealed that CEMIP expression is significantly higher in tumor tissues than in adjacent normal tissues in patients with locally advanced CRC who received neoadjuvant chemoradiotherapy, and it is closely related to the poor prognosis. Functional characterization uncovered that downregulation of CEMIP expression can enhance the radiosensitivity of CRC cells, which is confirmed to be achieved by promoting DNA damage and apoptosis. In vivo studies further verified that CEMIP knockdown can significantly improve the radiosensitivity of subcutaneously implanted colorectal tumors in mice, suggesting that CEMIP may be a radiation-resistant gene in CRC. Mechanistically, EGFR/PI3K/Akt signaling pathway is hypothesized to play a key role in CEMIP mediating radiation resistance. These results provide a potential new strategy targeting CEMIP gene for the comprehensive treatment of locally advanced CRC patients.


Assuntos
Neoplasias Colorretais , Animais , Camundongos , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/radioterapia , Neoplasias Colorretais/metabolismo , Regulação para Baixo , Fosfatidilinositol 3-Quinases/metabolismo , Tolerância a Radiação/genética , Hialuronoglucosaminidase/genética
4.
BMC Med ; 20(1): 365, 2022 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-36258210

RESUMO

BACKGROUND: Radiotherapy (RT) is one of the major therapeutic approaches to hepatocellular carcinoma (HCC). Ionizing radiation (IR) inducing the generation of reactive oxygen species (ROS) leads to a promising antitumor effect. However, the dysregulation of the redox system often causes radioresistance and impairs the efficacy of RT. Increasing evidence indicates that nuclear protein 1 (NUPR1) plays a critical role in redox reactions. In this study, we aim to explore the role of NUPR1 in maintaining ROS homeostasis and radioresistance in HCC. METHODS: The radioresistant role of NUPR1 was determined by colony formation assay, comet assay in vitro, and xenograft tumor models in vivo. Probes for ROS, apoptosis assay, and lipid peroxidation assay were used to investigate the functional effect of NUPR1 on ROS homeostasis and oxidative stress. RNA sequencing and co-immunoprecipitation assay were performed to clarify the mechanism of NUPR1 inhibiting the AhR/CYP signal axis. Finally, we analyzed clinical specimens to assess the predictive value of NUPR1 and AhR in the radiotherapeutic efficacy of HCC. RESULTS: We demonstrated that NUPR1 was upregulated in HCC tissues and verified that NUPR1 increased the radioresistance of HCC in vitro and in vivo. NUPR1 alleviated the generation of ROS and suppressed oxidative stress, including apoptosis and lipid peroxidation by downregulating cytochrome P450 (CYP) upon IR. ROS scavenger N-acetyl-L-cysteine (NAC) and CYP inhibitor alizarin restored the viability of NUPR1-knockdown cells during IR. Mechanistically, the interaction between NUPR1 and aryl hydrocarbon receptor (AhR) promoted the degradation and decreased nuclear translation of AhR via the autophagy-lysosome pathway, followed by being incapable of CYP's transcription. Furthermore, genetically and pharmacologically activating AhR abrogated the radioresistant role of NUPR1. Clinical data suggested that NUPR1 and AhR could serve as novel biomarkers for predicting the radiation response of HCC. CONCLUSIONS: Our findings revealed the role of NUPR1 in regulating ROS homeostasis and oxidative stress via the AhR/CYP signal axis upon IR. Strategies targeting the NUPR1/AhR/CYP pathway may have important clinical applications for improving the radiotherapeutic efficacy of HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas Nucleares/metabolismo , Acetilcisteína , Transdução de Sinais , Homeostase , Sistema Enzimático do Citocromo P-450/metabolismo , Linhagem Celular Tumoral , Apoptose
5.
Cell Death Discov ; 8(1): 431, 2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36307402

RESUMO

Nuclear protein 1 (NUPR1) is a transcriptional coregulator that has been implicated in the development of various cancer types. In addition, de novo fatty acid synthesis plays a pivotal role in hepatocellular carcinoma (HCC) development. However, little is currently known on the role of NUPR1 in hepatocellular carcinoma. In this study, bioinformatics analysis was conducted to analyze the expression level, prognosis value and enriched pathways of NUPR1 in Liver Hepatocellular Carcinoma (LIHC). We found that NUPR1 was significantly upregulated in human hepatocellular carcinoma cells compared with normal hepatocytes from LIHC patients in TCGA cohorts and our patients. Kaplan-Meier analysis and COX proportional hazard progression model showed that high expression of NUPR1 was correlated with a poor prognosis of LIHC patients. CCK-8, EdU and colony formation assays were performed to explore the effect of NUPR1 on the proliferation of HCC cells, then wound healing and transwell migration assays were performed to evaluate the effects of NUPR1 on cell migration. Furthermore, subcutaneous xenograft models were established to study tumor growth. Results showed that NUPR1 overexpression correlated with a highly proliferative and aggressive phenotype. In addition, NUPR1 knockdown significantly inhibited hepatocellular carcinoma cell proliferation and migration in vitro and hindered tumorigenesis in vivo. Mechanistically, endogenous NUPR1 could interact with sterol regulatory element binding protein 1 (SREBP1) and upregulated lipogenic gene expression of fatty acid synthase (FASN), resulting in the accumulation of lipid content. Moreover, pharmacological or genetic blockade of the NUPR1-SREBP1/FASN pathway enhanced anticancer activity in vitro and in vivo. Overall, we identified a novel function of NUPR1 in regulating hepatocellular carcinoma progression via modulation of SREBP1-mediated de novo lipogenesis. Targeting NUPR1-SREBP1/FASN pathway may be a therapeutic alternative for hepatocellular carcinoma.

6.
Hepatology ; 75(6): 1386-1401, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-34580888

RESUMO

BACKGROUND AND AIMS: Poor response to ionizing radiation (IR) due to resistance remains a clinical challenge. Altered metabolism represents a defining characteristic of nearly all types of cancers. However, how radioresistance is linked to metabolic reprogramming remains elusive in hepatocellular carcinoma (HCC). APPROACH AND RESULTS: Baseline radiation responsiveness of different HCC cells were identified and cells with acquired radio-resistance were generated. By performing proteomics, metabolomics, metabolic flux, and other functional studies, we depicted a metabolic phenotype that mediates radiation resistance in HCC, whereby increased glucose flux leads to glucose addiction in radioresistant HCC cells and a corresponding increase in glycerophospholipids biosynthesis to enhance the levels of cardiolipin. Accumulation of cardiolipin dampens the effectiveness of IR by inhibiting cytochrome c release to initiate apoptosis. Mechanistically, mammalian target of rapamycin complex 1 (mTORC1) signaling-mediated translational control of hypoxia inducible factor-1α (HIF-1α) and sterol regulatory element-binding protein-1 (SREBP1) remodels such metabolic cascade. Targeting mTORC1 or glucose to cardiolipin synthesis, in combination with IR, strongly diminishes tumor burden. Finally, activation of glucose metabolism predicts poor response to radiotherapy in cancer patients. CONCLUSIONS: We demonstrate a link between radiation resistance and metabolic integration and suggest that metabolically dismantling the radioresistant features of tumors may provide potential combination approaches for radiotherapy in HCC.


Assuntos
Carcinoma Hepatocelular , Cardiolipinas , Glucose , Neoplasias Hepáticas , Tolerância a Radiação , Carcinoma Hepatocelular/metabolismo , Cardiolipinas/metabolismo , Linhagem Celular Tumoral , Glucose/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia , Neoplasias Hepáticas/genética , Alvo Mecanístico do Complexo 1 de Rapamicina , Proteína de Ligação a Elemento Regulador de Esterol 1
7.
Br J Cancer ; 125(5): 734-747, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34188196

RESUMO

BACKGROUND: SLC2A5 is a high-affinity fructose transporter, which is frequently upregulated in multiple human malignant tumours. However, the function and molecular mechanism of SLC2A5 in colorectal cancer (CRC) remain unknown. METHODS: We detected the expression levels of SLC2A5 in CRC tissues and CRC cell lines by western blotting, qRT-PCR and immunohistochemistry. CRC cell lines with stable overexpression or knockdown of SLC2A5 were constructed to evaluate the functional roles of SLC2A5 in vitro through conventional assays. An intrasplenic inoculation model was established in mice to investigate the effect of SLC2A5 in promoting metastasis in vivo. Methylation mass spectrometry sequencing, methylation specific PCR, bisulphite sequencing PCR, ChIP-qPCR and luciferase reporter assay were performed to investigate the molecular mechanism underlying transcriptional activation of SLC2A5. RESULTS: We found that SLC2A5 was upregulated in colorectal tumour tissues. Functionally, a high level of SLC2A5 expression was associated with increased invasion and metastasis capacities of CRC cells both in vitro and in vivo. Mechanistically, we unveiled that S100P could integrate to a specific region of SLC2A5 promoter, thereby reducing its methylation levels and activating SLC2A5 transcription. CONCLUSIONS: Our results reveal a novel mechanism that S100P mediates the promoter demethylation and transcription activation of SLC2A5, thereby promoting the metastasis of CRC.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Neoplasias Colorretais/patologia , Metilação de DNA , Transportador de Glucose Tipo 5/genética , Transportador de Glucose Tipo 5/metabolismo , Proteínas de Neoplasias/metabolismo , Regulação para Cima , Animais , Células CACO-2 , Estudos de Casos e Controles , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Células HT29 , Humanos , Masculino , Camundongos , Metástase Neoplásica , Transplante de Neoplasias , Regiões Promotoras Genéticas , Ativação Transcricional
8.
Front Cell Infect Microbiol ; 10: 541178, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33194790

RESUMO

Radiation enteritis (RE) is a common complication in cancer patients receiving radiotherapy. Although studies have shown the changes of this disease at clinical, pathological and other levels, the dynamic characteristics of local microbiome and metabolomics are hitherto unknown. We aimed to examine the multi-omics features of the gut microecosystem, determining the functional correlation between microbiome and lipid metabolites during RE activity. By delivering single high-dose irradiation, a RE mouse model was established. High-throughput 16S rDNA sequencing and global lipidomics analysis were performed to examine microbial and lipidomic profile changes in the gut microecosystem. Spearman correlation analysis was used to determine the functional correlation between bacteria and metabolites. Clinical samples were collected to validate the above observations. During RE activity, the intestinal inflammation of the mice was confirmed by typical signs, symptoms, imaging findings and pathological evidences. 16S datasets revealed that localized irradiation dramatically altered the gut microbial composition, resulting in a decrease ratio of Bacteroidetes to Firmicutes. Lipidomics analysis indicated the remarkable lipidomic profile changes in enteric epithelial barrier, determining that glycerophospholipids metabolism was correlated to RE progression with the highest relevance. Spearman correlation analysis identified that five bacteria-metabolite pairs showed the most significant functional correlation in RE, including Alistipes-PC(36:0e), Bacteroides-DG(18:0/20:4), Dubosiella-PC(35:2), Eggerthellaceae-PC(35:6), and Escherichia-Shigella-TG(18:2/18:2/20:4). These observations were partly confirmed in human specimens. Our study provided a comprehensive description of microbiota dysbiosis and lipid metabolic disorders in RE, suggesting strategies to change local microecosystem to relieve radiation injury and maintain homeostasis.


Assuntos
Enterite , Microbioma Gastrointestinal , Lesões por Radiação , Animais , Humanos , Lipídeos , Metaboloma , Camundongos , RNA Ribossômico 16S/genética
9.
Aging (Albany NY) ; 12(19): 19641-19659, 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33049716

RESUMO

While cancer immunotherapy has been remarkably successful in some malignancies, some cancers derive limited benefit from current immunotherapies. Here, we combined immune landscape signatures with hepatocellular carcinoma clinical and prognostic features to classify them into distinct subtypes. The immunogenomic profiles, stromal cell features and immune cell composition of the subtypes were then systematically analyzed. Two independent prognostic indexes were established based on 6 immune-related genes and 17 differentially expressed genes associated with stromal cell content. These indexes were significantly correlated with tumor mutation burden, deficient DNA mismatch repair and microsatellite instability. In addition, tumor-infiltrating lymphocytes, including activated NK cells, resting memory CD4 T-cells, eosinophils, and activated mast cells were significantly correlated with hepatocellular carcinoma survival. In conclusion, we have comprehensively described the immune landscape signatures and identified prognostic immune-associated biomarkers of hepatocellular carcinoma. Our findings highlight potential novel avenues for improving responses to immunotherapy.

10.
Asian J Pharm Sci ; 15(1): 121-128, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32175024

RESUMO

Gene-based therapeutics has emerged as a promising approach for human cancer therapy. Among a variety of non-viral vectors, polymer vectors are particularly attractive due to their safety and multivalent groups on their surface. This study focuses on guanidinylated O-carboxymethyl chitosan (GOCMCS) along with poly-ß-amino ester(PBAE) for siRNA delivery. Binding efficiency of PBAE/siRNA/GOCMCS nanoparticles were characterized by gel electrophoresis. The siRNA-loaded nanoparticles were found to be stable in the presence of RNase A, serum and BALF respectively. Fine particle fraction (FPF) which was determined by a two-stage impinger (TSI) was 57.8% ±â€¯2.6%. The particle size and zeta potential of the nanoparticles were 153.8 ±â€¯12.54 nm and + 12.2 ±â€¯4.94 mV. In vitro cell transfection studies were carried out with A549 cells. The cellular uptake was significantly increased. When the cells were incubated with siSurvivin-loaded nanoparticles, it could induce 26.83% ±â€¯0.59% apoptosis of A549 cells and the gene silencing level of survivin expression in A549 cells were 30.93% ±â€¯2.27%. The results suggested that PBAE/GOCMCS nanoparticle was a very promising gene delivery carrier.

11.
Carcinogenesis ; 41(5): 678-688, 2020 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-31306481

RESUMO

Upregulation of histone methyltransferase SET domain bifurcated 1 (SETDB1) is associated with poor prognosis in cancer patients. However, the mechanism of oncogenicity of SETDB1 in cancer is hitherto unknown. Here, we show that SETDB1 is upregulated in human colorectal cancer (CRC) where its level correlates with poor clinical outcome. Ectopic SETDB1 promotes CRC cell proliferation, whereas SETDB1 attenuation inhibits this process. Flow cytometry reveals that SETDB1 promotes proliferation by driving the CRC cell cycle from G0/G1 phase to S phase. Mechanistically, SETDB1 binds directly to the STAT1 promoter region resulting in increased STAT1 expression. Functional characterization reveals that STAT1-CCND1/CDK6 axis is a downstream effector of SETDB1-mediated CRC cell proliferation. Furthermore, SETDB1 upregulation is sufficient to accelerate in vivo proliferation in xenograft animal model. Taken together, our results provide insight into the upregulation of SETDB1 within CRC and can lead to novel treatment strategies targeting this cell proliferation-promoting gene.


Assuntos
Biomarcadores Tumorais/metabolismo , Proliferação de Células , Neoplasias Colorretais/patologia , Ciclina D1/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Fator de Transcrição STAT1/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Movimento Celular , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Ciclina D1/genética , Quinase 6 Dependente de Ciclina/genética , Regulação Neoplásica da Expressão Gênica , Histona-Lisina N-Metiltransferase/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fator de Transcrição STAT1/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
12.
EBioMedicine ; 50: 122-134, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31761617

RESUMO

BACKGROUND: Metastasis of rhabdomyosarcoma (RMS) is the primary cause of tumour-related deaths. Previous studies have shown that overexpression of the guanine nucleotide exchange factor T (GEFT) is correlated with a poorer RMS prognosis, but the mechanism remains largely unexplored. METHODS: We focused on determining the influence of the GEFT-Rho-GTPase signalling pathway and the epithelial-mesenchymal transition (EMT) or mesenchymal-epithelial transition (MET) on RMS progression and metastasis by using RMS cell lines, BALB/c nude mice and cells and molecular biology techniques. FINDINGS: GEFT promotes RMS cell viability, migration, and invasion; GEFT also inhibits the apoptosis of RMS cells and accelerates the growth and lung metastasis of RMS by activating the Rac1/Cdc42 pathways. Interestingly, GEFT upregulates the expression levels of N-cadherin, Snail, Slug, Twist, Zeb1, and Zeb2 and reduces expression level of E-cadherin. Thus, GEFT influences the expression of markers for EMT and MET in RMS cells via the Rac1/Cdc42-PAK1 pathways. We also found that the level of GEFT gene promoter methylation in RMS is lower than that in normal striated muscle tissue. Significant differences were observed in the level of GEFT gene methylation in different histological subtypes of RMS. INTERPRETATION: These findings suggest that GEFT accelerates the tumourigenicity and metastasis of RMS by activating Rac1/Cdc42-PAK signalling pathway-induced EMT; thus, it may serve as a novel therapeutic target. FUND: This work was supported by grants from the National Natural Science Foundation of China (81660441, 81460404, and 81160322) and Shihezi University Initiative Research Projects for Senior Fellows (RCZX201447). Funders had no role in the design of the study, data collection, data analysis, interpretation, or the writing of this report.


Assuntos
Transição Epitelial-Mesenquimal/genética , Rabdomiossarcoma/genética , Rabdomiossarcoma/metabolismo , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Proteína cdc42 de Ligação ao GTP/metabolismo , Quinases Ativadas por p21/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular , Metilação de DNA , Modelos Animais de Doenças , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Xenoenxertos , Humanos , Masculino , Camundongos , Oncogenes , Rabdomiossarcoma/patologia , Transdução de Sinais
13.
Spectrochim Acta A Mol Biomol Spectrosc ; 195: 210-214, 2018 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-29414580

RESUMO

In order to develop NIR BODIPY for mitochondria targeting imaging agents and metal sensors, a side chain modified BODIPY (BPN) was synthesized and spectroscopically characterized. BPN has NIR emission at 765nm when excited at 704nm. The emission at 765nm responded differently to Cu2+ and Mn2+ ions, respectively. The BPN coordinated with Cu2+ forming [BPNCu]2+ complex with quenched emission, while Mn2+ induced aggregation of BPN with specific fluorescence enhancement. Moreover, BPN can be applied to monitor Cu2+ in live cells and image mitochondria. Further, BPN was used as sensor for the detection of Cu2+ ions in serum with linear detection range of 0.45µM-36.30µM. Results indicate that BPN is a good sensor for the detection of Cu2+ in serum and image mitochondria. This study gives strategies for future design of NIR sensors for the analysis of metal ions in blood.


Assuntos
Compostos de Boro/química , Cobre/sangue , Corantes Fluorescentes/química , Mitocôndrias/metabolismo , Imagem Molecular/métodos , Espectrometria de Fluorescência/métodos , Animais , Técnicas Biossensoriais , Fluorescência , Humanos , Células MCF-7 , Camundongos
14.
J Drug Target ; 25(5): 451-462, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28110554

RESUMO

This study developed a pH-sensitive anionic system composed of guanidinylated O-carboxymethyl chitosan (GOCMCS) and N-2-hydroxypropyltimehyl ammonium chloride chitosan (N-2-HACC) for efficient siRNA delivery to the lungs following nebulization. About 16.8% of guanidine groups were incorporated into O-carboxymethyl chitosan (OCMCS) with the aid of O-methylisourea. Gel electrophoresis images demonstrated that siRNA was successfully encapsulated in nanoparticles ranging from 150 to 180 nm with zeta potential of about -17 mV. The nanoparticles containing GOCMCS existed superior transfection performance compared with their amino-based analogs. The evaluation in vitro revealed that nanoparticles were internalized into A549 cells by energy-dependent endocytosis, then achieved endosomal escape by direct transmembrane penetration of guanidine moieties as well as swelling behavior of nanoparticles due to the pH sensitivity of GOCMCS. The mRNA level of survivin gene was down-regulated to 6.9% using GOCMCS/N-2-HACC/siSurvivin NPs. The survivin siRNA mediated by nanoparticles caused 30% of cell growth inhibition and induced 19.45% of cell apoptosis, which was comparable to Lipofectamin2000. After nebulization of siRNA-loaded nanoparticles, the stability of siRNA was maintained and fine particle fractions were detected by two-stage impinger that accounted for more than 60%. These results suggested that GOCMCS/N-2-HACC nanoparticles possessed potential as safe and efficient carrier for siRNA pulmonary delivery.


Assuntos
Quitosana/análogos & derivados , Guanidina/química , Pulmão/metabolismo , Nebulizadores e Vaporizadores , Compostos de Amônio Quaternário/administração & dosagem , RNA Interferente Pequeno/administração & dosagem , Células A549 , Ânions , Quitosana/administração & dosagem , Quitosana/química , Citometria de Fluxo , Humanos , Técnicas In Vitro , Compostos de Amônio Quaternário/química
15.
Histol Histopathol ; 31(3): 329-37, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26544916

RESUMO

The GLI1 and MDM2 genes are amplified or exhibit copy number gains in rhabdomyosarcoma (RMS). Here, we used immunohistochemistry to determine the relationships between GLI1 and MDM2 protein expression and several clinicopathological variables of RMS. GLI1 and MDM2-positivity rates were 61.36% and 13.64%, respectively. GLI1 expression correlated with presence of the PAX3-FOXO1 fusion gene (P=0.040) and lymph node metastasis (P=0.034), and a significant association was found between GLI1 expression and overall survival (OS) (P=0.008). However, there was no association between MDM2 expression and any of the clinicopathological parameters or OS. Thus, GLI1 may be a biomarker of poor prognosis in RMS patients, and could itself be a therapeutic target. This contrasts with the apparent lack of clinical importance of MDM2 in RMS pathology, at least in the cohorts we examined.


Assuntos
Biomarcadores Tumorais/análise , Rabdomiossarcoma/patologia , Neoplasias de Tecidos Moles/patologia , Fatores de Transcrição/biossíntese , Criança , Pré-Escolar , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Prognóstico , Proteínas Proto-Oncogênicas c-mdm2/análise , Proteínas Proto-Oncogênicas c-mdm2/biossíntese , Rabdomiossarcoma/metabolismo , Rabdomiossarcoma/mortalidade , Neoplasias de Tecidos Moles/metabolismo , Neoplasias de Tecidos Moles/mortalidade , Análise Serial de Tecidos , Fatores de Transcrição/análise , Proteína GLI1 em Dedos de Zinco
16.
Int J Clin Exp Pathol ; 8(7): 8563-7, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26339434

RESUMO

BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS), previously known as malignant fibrous histiocytoma, comprises a series of high-grade soft tissue sarcomas, which fail to exhibit any specific line of differentiation by using currently available ancillary techniques. Studies on gene mutation screening occurring in UPS are rarely conducted. In this study, we described a case of UPS and analyzed its mutation changes. We detected 19 hotspot oncogenes in the case. To the best of our knowledge, this study is the first to use a high-throughput OncoCarta panel 1.0 and MassARRAY system to detect 238 known mutations in 19 hotspot oncogenes in UPS. In this study, our result revealed two missense mutations, namely, KRAS mutation (35G > A, G12D) and PIK3CA mutation (1636C > A, Q546K) in the case.


Assuntos
Biomarcadores Tumorais/genética , Diferenciação Celular , Histiocitoma Fibroso Maligno/genética , Histiocitoma Fibroso Maligno/patologia , Mutação de Sentido Incorreto , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Sarcoma/genética , Sarcoma/patologia , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Idoso , Biomarcadores Tumorais/análise , Biópsia , Classe I de Fosfatidilinositol 3-Quinases , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Histiocitoma Fibroso Maligno/enzimologia , Histiocitoma Fibroso Maligno/cirurgia , Humanos , Imuno-Histoquímica , Fenótipo , Sarcoma/enzimologia , Sarcoma/cirurgia , Neoplasias de Tecidos Moles/enzimologia , Neoplasias de Tecidos Moles/cirurgia , Coxa da Perna
17.
Exp Mol Pathol ; 98(3): 446-54, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25773680

RESUMO

Soft tissue sarcomas (STSs) are comparatively rare malignant tumors with poor prognosis. STSs predominantly arise from mesenchymal differentiation. MicroRNA-34b/c, the transcriptional targets of tumor suppressor p53, possesses tumor suppressing property. Hypermethylation of miR-34b/c has been associated with tumorigenesis and the progression of various cancers. To determine whether aberrant miR-34b/c methylation occurs in STSs, we quantitatively evaluated the methylation level of miR-34b/c in 57 STS samples and 20 cases of peripheral blood from healthy volunteers serving as normal controls by using matrix-assisted laser desorption ionization time-of-flight mass spectrometry. We found that miRNA34b/c is more frequently methylated in STSs (0.157±0.028) than in normal controls (0.098±0.012, p=0.038). Furthermore, the methylation levels of CpG_1.2.3, CpG_4.5.6.7, and CpG_11.12.13 of miR-34b/c were significantly higher in the STS group than in the normal control group (p<0.001). No significant differences in the methylation levels within miR-34b/c were observed between specific reciprocal translocations in STSs and nonspecific reciprocal translocations in STSs (0.146±0.039 vs. 0.168±0.035, p>0.05). The methylation levels of miR-34b/c in STSs were associated with clinical stage. The methylation levels of CpG_1.2.3, CpG_4.5.6.7, CpG_9.10, CpG_11.12.13, and CpG_14 in tumor-stage III/IV tissues were significantly higher than those in tumor-stage I/II tissues. Our findings indicated that DNA hypermethylation of the miR-34b/c is a relatively common event in STSs and is significantly correlated with late clinical stage in patients with STSs. Hypermethylation of the miR-34b/c may be pivotal in the oncogenesis and progression of STSs and may be a potential prognostic factor for STSs.


Assuntos
Metilação de DNA , MicroRNAs/genética , Sarcoma/metabolismo , Neoplasias de Tecidos Moles/genética , Adulto , Estudos de Casos e Controles , Ilhas de CpG , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sarcoma/diagnóstico , Neoplasias de Tecidos Moles/diagnóstico
18.
Int J Clin Exp Pathol ; 7(4): 1606-15, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24817957

RESUMO

Rhabdomyosarcoma (RMS) is one of the most common soft-tissue sarcomas in children and adolescents with poor prognosis. Yet, there is lack of effective prognostic biomarkers for RMS. The present study, therefore, aimed to explore potential biomarkers for RMS based on our previous findings using array comparative genomic hybridization. We investigated guanine nucleotide exchange factor, GEFT, at expression level in 45 RMS patients and 36 normal striated muscle controls using immunohistochemistry using tissue microarrays. The expression rate of GEFT in RMS samples (42/45, 93.33%) was significantly higher (P<0.05) than that in normal controls (5/36, 13.89%). Moreover, the overexpression rate of GEFT in RMS (31/45, 68.89%) was also significantly higher (P<0.05) than that in normal controls (0/36, 0.00%). Increased expression of GEFT correlated significantly with advanced disease stages (stages III/IV) (P=0.001), lymph node metastasis (P=0.019), and distant metastasis (P=0.004), respectively, in RMS patients. In addition, RMS patients having overexpressed GEFT experienced worse overall survival (OS) than those having low levels of GEFT (P=0.001). GEFT overexpression was determined to be an independent prognostic factor for poor OS in RMS patients (hazard ratio: 3.491, 95% confidence interval: 1.121-10.871, P=0.004). In conclusion, these observations provide the first evidence of GEFT overexpression in RMS and its correlations with disease aggressiveness and metastasis. These findings suggest that GEFT may serve as a promising biomarker predicting poor prognosis in RMS patients, thus implying its potential as a therapeutic target.


Assuntos
Biomarcadores Tumorais/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Rabdomiossarcoma/diagnóstico , Neoplasias de Tecidos Moles/diagnóstico , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Rabdomiossarcoma/metabolismo , Rabdomiossarcoma/mortalidade , Fatores de Troca de Nucleotídeo Guanina Rho , Neoplasias de Tecidos Moles/metabolismo , Neoplasias de Tecidos Moles/mortalidade , Taxa de Sobrevida , Adulto Jovem
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