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1.
Pharmacol Res ; : 104352, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31323332

RESUMO

Mammalian / mechanistic target of rapamycin (mTOR) is a critical sensor of environmental cues that regulates cellular macromolecule synthesis and metabolism in eukaryotes. DNA methylation is the most well-studied epigenetic modification that is capable of regulating gene transcription and affecting genome stability. Both dysregulation of mTOR signaling and DNA methylation patterns have been shown to be closely linked to tumor progression and serve as promising targets for cancer therapy. Although their respective roles in tumorigenesis have been extensively studied, whether molecular interplay exists between them is still largely unknown. In this review, we provide a brief overview of mTOR signaling, DNA methylation as well as related serine and one-carbon metabolism, one of the most critical aspects of metabolic reprogramming in cancer. Based on the latest understanding regarding the regulation of metabolic processes by mTOR signaling as well as interaction between metabolism and epigenetics, we further discuss how serine and one-carbon metabolism may serve as a bridge that links mTOR signaling and DNA methylation to promote tumor growth. Elucidating their relationship may provide novel insight for cancer therapy in the future.

2.
Cell Death Dis ; 10(7): 479, 2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31209222

RESUMO

Cancer metastasis is the main cause of death in breast cancer (BC) patients. Therefore, prediction and treatment of metastasis is critical for enhancing the survival of BC patients. In this study, we aimed to identify biomarkers that can predict metastasis of BC and elucidate the underlying mechanism of the functional involvement of such markers in metastasis. miRNA expression profile was analyzed using a custom microarray system in 422 BC tissues. The relationship between the upregulated miR-665, metastasis and survival of BC was analyzed and verified in another set of 161 BC samples. The biological function of miR-665 in BC carcinogenesis was explored with in vitro and in vivo methods. The target gene of miR-665 and its signaling cascade were also analyzed. There are 399 differentially expressed miRNAs between BC and noncancerous tissues, of which miR-665 is the most upregulated miRNA in the BC tissues compared with non-tumor breast tissues (P < 0.001). The expression of miR-665 predicts metastasis and poor survival in 422 BC patients, which is verified in another 161 BC patients and 2323 BC cases from online databases. Ectopic miR-665 expression promotes epithelial-mesenchymal transition (EMT), proliferation, migration and invasion of BC cells, and increases tumor growth and metastasis of BC in mice. Bioinformatics, luciferase assay and other methods showed that nuclear receptor subfamily 4 group A member 3 (NR4A3) is a target of miR-665 in BC. Mechanistically, we demonstrated that miR-665 promotes EMT, invasion and metastasis of BC via inhibiting NR4A3 to activate MAPK/ERK kinase (MEK) signaling pathway. Our study demonstrates that miR-665 upregulation is associated with metastasis and poor survival in BC patients, and mechanistically, miR-665 enhances progression of BC via NR4A3/MEK signaling pathway. This study provides a new potential prognostic biomarker and therapeutic target for BC patients.

3.
J Transl Med ; 17(1): 186, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31159814

RESUMO

BACKGROUND: Early diagnosis is critical to reduce the mortality caused by nasopharyngeal carcinoma (NPC). MicroRNAs (miRNAs) are dysregulated and play important roles in carcinogenesis. Therefore, this study aimed to identify diagnostically relevant circulating miRNA signatures in patients with NPC. METHODS: Total RNA was extracted from whole blood samples obtained from 120 patients with NPC, 30 patients with head-neck tumors (HNT), and 30 healthy subjects (HSs), and examined by using a custom microarray. The expression levels of four miRNAs identified by using the microarray were validated with quantitative real-time reverse transcription polymerase chain reaction. The 120 patients with NPC and 30 HSs were randomly assigned to training group-1 and validation group-1, respectively. By using significance analysis of microarray (SAM), the specific miRNA expression profiles in whole blood from patients with NPC are obtained. By using lasso regression and adaptive boosting, a diagnostic signature was identified in training group-1, and its accuracy was verified in validation group-1. By using the same methods, another signature to distinguish patients with NPC from those with HNT and HSs was identified in training group-2 and confirmed in validation group-2. RESULTS: There were 117 differentially expressed miRNAs (upregulated and downregulated fold change ≥ 1.5) between the patients with NPC and HSs, among which an 8-miRNA signature was identified with 96.43% sensitivity and 100% specificity [area under the curve (AUC) = 0.995] to diagnose NPC in training group-1 and 86.11% sensitivity and 88.89% specificity (AUC = 0.941) in validation group-1. Compared with traditional Epstein-Barr virus (EBV) seromarkers, this signature was more specific for NPC. Furthermore, a 16-miRNA signature to differentiate NPC from HNT and HS (HNT-HS) was established from 164 differentially expressed miRNAs, which diagnosed NPC and HNT-HS with 100% accuracy (AUC = 1.000) in training group-2 and 87.04% (AUC = 0.924) in validation group-2. CONCLUSIONS: The present study identified two miRNA signatures for the highly accurate diagnosis and differential diagnosis of patients with NPC from HSs and patients with HNT. The identified miRNAs might represent novel serological biomarkers and potential therapeutic targets for NPC.

4.
Ying Yong Sheng Tai Xue Bao ; 30(5): 1580-1588, 2019 May.
Artigo em Chinês | MEDLINE | ID: mdl-31107014

RESUMO

The typhoon outbreaks of 1986 caused many gaps in the cold temperate coniferous forest and Betula errmanii forest on the western and southern slopes in the Changbai Mountain. In 2017, a research area at the 1600-1800 m altitude in Changbai Mountain was established to explore the damage and changes of forest vegetation disturbed by the typhoon in cold temperate zone and to reveal the regulation of damage on vegetation and post-disaster change as well as the driving factors. The remote sensing data were used to classify research area based on the degree of vegetation damage and post-disaster change. A total of 40 plots were set up for vegetation survey. According to the damage degree of forest structure, three levels of severity of damage to vegetation in the cold temperate zone of Changbai Mountain were classified including gently, moderately, and severely damaged, in which moderately damaged area was largest, followed by gently damaged area and severely damaged area. Tree damage significantly differed among three level areas, with 20%, 50% and 85% reduction of the abundance of dominant trees in gently, moderately and severely damaged areas, respectively. The wind resistance ability of B. errmanii was higher than that of Picea jezoensis. The wind resistance ability of B. errmanii with larger diameter grade was higher than that of those with smaller diameter grade. The severity of damage to vegetation was strongly correlated with slope, with lower severity on the steeper slop area. From 1987 to 2017, the vegetation of wind disaster area significantly changed. The study area could be classified into three levels based on the degree of changing: fast, medium, and slow, with largest area in medium changed, followed by slowly and fast changed. The degree of vegetation changes was strongly correlated with altitude, with slower change at higher altitude area. The recovery rate of trees was slow, with P. jezoensis recovering slightly quicker than B. errmanii. The vegetation change mainly occurred in shrub and herb layers. Shrub layer recovered better than the herb layer in the fast changed area, while herb layer recovered better than the shrub layer in the medium changed area. In the slowly changed area, herb layer was generally low and dense with varying shrub layer.


Assuntos
Desastres , Ecossistema , Vento , China , Clima , Monitoramento Ambiental , Árvores
5.
Leukemia ; 2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30953029

RESUMO

New prognostic factors are needed to establish indications for haematopoietic stem cell transplantation (HSCT) in first complete remission (CR1) for T-cell lymphoblastic lymphoma (T-LBL) patients. We used microarray to compare T-LBL tissue samples (n = 75) and fetal thymus tissues (n = 20), and identified 35 differentially expressed miRNAs. Using 107 subjects as the training group, we developed a five-miRNA-based classifier to predict patient survival with LASSO Cox regression: lower risk was associated with better prognosis (disease-free survival (DFS): hazard ratio (HR) 4.548, 95% CI 2.433-8.499, p < 0.001; overall survival (OS): HR 5.030, 95% CI 2.407-10.513, p < 0.001). This classifier displayed good performance in the internal testing set (n = 106) and the independent external set (n = 304). High risk was associated with more favorable response to HSCT (DFS: HR 1.675, 95% CI 1.127-2.488, p = 0.011; OS: HR 1.602, 95% CI 1.055-2.433, p = 0.027). When combined with ECOG-PS and/or NOTCH1/FBXW7 status, this classifier had even better prognostic performance in patients receiving HSCT (DFS: HR 2.088, 95% CI 1.290-3.379, p = 0.003; OS: HR 1.996, 95% CI 1.203-3.311, p = 0.007). The five-miRNA classifier may be a useful prognostic biomarker for T-LBL adults, and could identify subjects who could benefit from HSCT.

6.
Mol Cancer Ther ; 17(12): 2610-2621, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30224431

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common and deadly human cancers. The 5-year survival rate is very low. Unfortunately, there are few efficacious therapeutic options. Until recently, Sorafenib has been the only available systemic drug for advanced HCC. However, it has very limited survival benefits, and new therapies are urgently needed. In this study, we investigated the anti-HCC activity of carfilzomib, a second-generation, irreversible proteasome inhibitor, as a single agent and in combination with sorafenib. In vitro, we found that carfilzomib has moderate anticancer activity toward liver cancer cells, but strongly enhances the ability of sorafenib to suppress HCC cell growth, proliferation, migration, invasion, and survival. Remarkably, the drug combination exhibits even more potent antitumor activity when tested in animal tumor models. Mechanistically, the combined treatment activates caspase-dependent and endoplasmic reticulum stress/CHOP-mediated apoptotic pathways, and suppresses epithelial-mesenchymal transition. In conclusion, our results demonstrate that the combination of carfilzomib and sorafenib has synergistic antitumor activities against HCC, providing a potential therapeutic strategy to improve the mortality and morbidity of HCC patients.

7.
Artif Cells Nanomed Biotechnol ; : 1-8, 2018 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-30146920

RESUMO

Untargeted delivery as well as low efficacy are two main obstacles for effective breast cancer therapy. Here in this study, we surface modified silica nanoparticles (SLN) with Trastuzumab (Tra) to construct a tumor-targeting carrier (Tra-SLN) for specific drug delivery to human epidermal growth factor receptor 2 (HER2) overexpressing breast cancer cells. In addition, Tra-SLN could also loaded with broad-spectrum anticancer drug doxorubicin (DOX) to finally construct a drug delivery system (DDS) capable of co-delivering Tra and DOX (Tra-SLN/DOX). Our results demonstrated that the as-prepared Tra-SLN/DOX was nanoscale particles with spheroid appearance which showed preferable stability in physiological environments. In addition, the Tra-SLN/DOX could specifically target to HER2 overexpressed MCF-7 cells. Both in vitro and in vivo experiments revealed that the Tra-SLN/DOX exerted enhanced anticancer efficacy when compared with Tra or DOX alone. It was suggested that Tra-SLN/DOX might be a promising platform for enhanced therapy of breast cancer.

8.
J Cancer ; 9(16): 2807-2816, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30123349

RESUMO

Using genome-wide screening and TCGA-based data analysis, we identified a DNA methylation-related gene named metallothionein-1G (MT1G), which may play an important role in hepatocellular carcinoma (HCC). In this study, we found that MT1G expression was silenced in 4/6 HCC cell lines and negatively related to aberrant promoter hypermethylation. Its mRNA level was restored with demethylation treatment. Moreover, MT1G downregulation at both the transcriptional and protein level was also detected in 8 pairs of clinical HCC samples compared with its expression in adjacent normal tissues. Ectopic expression of MT1G in silenced HCC cell lines inhibited colony formation, suppressed cell migration and invasion, and repressed xenograft tumor growth in nude mice. In contrast, knockdown of MT1G by short hairpin RNA showed the opposite effect on cell proliferation and the malignant phenotype. Moreover, our data showed that MT1G suppressed tumor invasion and metastasis mainly through regulating the expression of proteins in the matrix metalloproteinase family (MMP) and modulating the epithelial-mesenchymal transition (EMT) process. To our surprise, the data from TCGA showed that hypermethylation of MT1G is associated with good survival of HCC patients. In conclusion, our study demonstrated that MT1G acts as a tumor suppressor gene in HCC development, but its clinical potential in HCC requires further evaluation.

9.
Mol Cell ; 70(3): 502-515.e8, 2018 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-29727620

RESUMO

Nutrients are not only organic compounds fueling bioenergetics and biosynthesis, but also key chemical signals controlling growth and metabolism. Nutrients enormously impact the production of reactive oxygen species (ROS), which play essential roles in normal physiology and diseases. How nutrient signaling is integrated with redox regulation is an interesting, but not fully understood, question. Herein, we report that superoxide dismutase 1 (SOD1) is a conserved component of the mechanistic target of rapamycin complex 1 (mTORC1) nutrient signaling. mTORC1 regulates SOD1 activity through reversible phosphorylation at S39 in yeast and T40 in humans in response to nutrients, which moderates ROS level and prevents oxidative DNA damage. We further show that SOD1 activation enhances cancer cell survival and tumor formation in the ischemic tumor microenvironment and protects against the chemotherapeutic agent cisplatin. Collectively, these findings identify a conserved mechanism by which eukaryotes dynamically regulate redox homeostasis in response to changing nutrient conditions.

10.
Biochim Biophys Acta Gene Regul Mech ; 1861(4): 338-343, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29407795

RESUMO

MAF1 was discovered as a master repressor of Pol III-dependent transcription in response to diverse extracellular signals, including growth factor, nutrient and stress. It is regulated through posttranslational mechanisms such as phosphorylation. A prominent upstream regulator of MAF1 is the mechanistic target of rapamycin (mTOR) pathway. mTOR kinase directly phosphorylates MAF1, controlling its localization and transcriptional activity. In mammals, MAF1 has also been shown to regulate Pol I- and Pol II-dependent transcription. Interestingly, MAF1 modulates Pol II activity both as a repressor and activator, depending on specific target genes, to impact on cellular growth and metabolism. While MAF1 represses genes such as TATA-binding protein (TBP) and fatty acid synthase (FASN), it activates the expression of PTEN, a major tumor suppressor and an inhibitor of the mTOR signaling. Increasing evidence indicates that MAF1 plays an important role in different aspects of normal physiology, lifespan and oncogenesis. Here we will review the current knowledge on MAF1 in growth, metabolism, aging and cancer. This article is part of a Special Issue entitled: SI: Regulation of tRNA synthesis and modification in physiological conditions and disease edited by Dr. Boguta Magdalena.


Assuntos
Envelhecimento/metabolismo , Crescimento/fisiologia , Fator de Transcrição MafB/fisiologia , Neoplasias/metabolismo , Animais , Humanos , Redes e Vias Metabólicas , Modelos Biológicos , Domínios Proteicos , Processamento de Proteína Pós-Traducional , RNA Polimerase III/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/fisiologia
11.
Cell Death Dis ; 9(1): 2, 2018 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-29305578

RESUMO

Epithelial cell adhesion molecule (EpCAM) is known to be highly expressed in a variety of epithelial carcinomas, and it is involved in cell adhesion and proliferation. However, its expression profile and biological function in nasopharyngeal carcinoma (NPC) remains unclear. In this study, higher expression of EpCAM was found in NPC samples compared with non-cancer nasopharyngeal mucosa by qRT-PCR. Additionally, immunohistochemistry (IHC) analysis of NPC specimens from 64 cases showed that high EpCAM expression was associated with metastasis and shorter survival. Multivariate survival analysis identified high EpCAM expression as an independent prognostic factor. Ectopic EpCAM expression in NPC cells promoted epithelial-mesenchymal transition (EMT), induced a cancer stem cell (CSC)-like phenotype, and enhanced metastasis in vitro and in vivo without an effect on cell proliferation. Notably, EpCAM overexpression reduced PTEN expression and increased the level of AKT, mTOR, p70S6K and 4EBP1 phosphorylation. Correspondingly, an AKT inhibitor and rapamycin blocked the effect of EpCAM on NPC cell invasion and stem-like phenotypes, and siRNA targeting PTEN rescued the oncogenic activities in EpCAM knockdown NPC cells. Our data demonstrate that EpCAM regulates EMT, stemness and metastasis of NPC cells via the PTEN/AKT/mTOR pathway.

12.
Hepatology ; 67(6): 2271-2286, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29220539

RESUMO

Hepatocellular carcinoma (HCC) is a male-dominant cancer, and androgen receptor (AR) has been linked to the pathogenesis of HCC. However, AR expression and its precise role in HCC remain controversial. Moreover, previous antiandrogen and anti-AR clinical trials in HCC failed to demonstrate clinical benefits. In this study, we found that AR is overexpressed in the nucleus of approximately 37% of HCC tumors, which is significantly associated with advanced disease stage and poor survival. AR overexpression in HCC cells markedly alters AR-dependent transcriptome, stimulates oncogenic growth, and determines therapeutic response to enzalutamide, a second generation of AR antagonist. However, AR inhibition evokes feedback activation of AKT-mTOR (mechanistic target of rapamycin) signaling, a central regulator for cell growth and survival. On the other hand, mTOR promotes nuclear AR protein expression by restraining ubiquitin-dependent AR degradation and enhancing AR nuclear localization, providing a mechanistic explanation for nuclear AR overexpression in HCC. Finally, cotargeting AR and mTOR shows significant synergistic anti-HCC activity and decreases tumor burden by inducing apoptosis in vivo. CONCLUSION: Nuclear AR overexpression is associated with the progression and prognosis of HCC. However, enzalutamide alone has limited therapeutic utility attributed to feedback activation of the AKT-mTOR pathway. Moreover, mTOR drives nuclear AR overexpression. Cotargeting AR and mTOR is a promising therapeutic strategy for HCC. (Hepatology 2018;67:2271-2286).


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Receptor Cross-Talk , Receptores Androgênicos/fisiologia , Serina-Treonina Quinases TOR/fisiologia , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Núcleo Celular , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Feniltioidantoína/análogos & derivados , Feniltioidantoína/uso terapêutico , Receptores Androgênicos/biossíntese , Receptores Androgênicos/genética , Células Tumorais Cultivadas
13.
Front Mol Neurosci ; 10: 348, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29163026

RESUMO

Objective: Establishing a practical procedure to generate induced pluripotent stem cells (iPSCs) and induced neural stem cells (iNSCs) from human urine cells (UCs). In this report, we optimized a non-integrative protocol to generate patient-specific iPSC and iNSC lines with high reprogramming efficiency. Methods: UCs were electroporated with the pEP4-EO2S-ET2K and pEP4-M2L plasmids containing the OCT4, SOX2, KLF4, SV40LT, c-MYC, and LIN28 genes, and then cultured with N2B27 medium plus four small molecule compounds (A83-01, PD0325901, Thiazovivin, and CHIR99021). When iPSC or iNSC clones emerged, the medium was replaced with mTeSR1 or neural growth medium. Morphological changes were seen at day 4-7. After day 10, the clones were picked up when the clone diameter exceeded 1 mm. Results: iPSCs and iNSCs were successfully derived from UCs with up to 80 clones/well. These iPSCs and iNSCs showed typical hESC or NSC morphology and were self-renewable. The iPSCs had pluripotency to differentiate into the three germinal layers and displayed high levels of expression of pluripotency markers SOX2, NANOG, OCT4, SSEA-4, TRA-1-60, TRA-1-81, and alkaline phosphatase (AP). They maintained normal karyotype and had no transgene expression or genomic integration. The iNSCs were positive for NSC markers NESTIN, PAX6, SOX2, and OLIG2. Conclusion: The optimized protocol is an easy and fast procedure to yield both iPSC and iNSC lines from a convenient source of human urine in a single experiment.

14.
Exp Ther Med ; 14(4): 3247-3252, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28912875

RESUMO

Burdock (Arctium lappa L.) leaves generate a considerable amount of waste following burdock root harvest in Taiwan. To increase the use of burdock leaves, the present study investigated the optimal methods for producing burdock leaf extract (BLE) with high antioxidant polyphenolic content, including drying methods and solvent extraction concentration. In addition, the elastase and tyrosinase inhibitory activity of BLE was examined. Burdock leaves were dried by four methods: Shadow drying, oven drying, sun drying and freeze-drying. The extract solution was then subjected to total polyphenol content analysis and the method that produced BLE with the highest amount of total antioxidant components was taken forward for further analysis. The 1,1-diphenyl-2-pycrylhydrazyl scavenging, antielastase and antityrosinase activity of the BLE were measured to enable the evaluation of the antioxidant and skin aging-associated enzyme inhibitory activities of BLE. The results indicated that the total polyphenolic content following extraction with ethanol (EtOH) was highest using the freeze-drying method, followed by the oven drying, shadow drying and sun drying methods. BLE yielded a higher polyphenol content and stronger antioxidant activity as the ratio of the aqueous content of the extraction solvent used increased. BLE possesses marked tyrosinase and elastase inhibitory activities, with its antielastase activity notably stronger compared with its antityrosinase activity. These results indicate that the concentration of the extraction solvent was associated with the antioxidant and skin aging-associated enzyme inhibitory activity of BLE. The reactive oxygen species scavenging theory of skin aging may explain the tyrosinase and elastase inhibitory activity of BLE. In conclusion, the optimal method for obtaining BLE with a high antioxidant polyphenolic content was freeze-drying followed by 30-50% EtOH extraction. In addition, the antielastase and antityrosinase activities of the BLE produced may be aid in the development of skincare products with antiwrinkle and skin-evening properties.

15.
PLoS One ; 12(9): e0184969, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28931080

RESUMO

MicroRNAs (miRNAs) are short noncoding RNAs that play critical roles in human malignancies and can be used as biomarkers for cancer. Until now, a number of biomarkers for prognosis of glioblastoma (GBM) have been reported in tumor tissues but only a few biomarkers in circulating fluid. Using a custom microarray, we previously identified 19 differentially expressed miRNAs in serum of patients with GBM. In this study, we investigated whether 3 of the 19 miRNAs in serum could be used as prognostic biomarkers for patients with GBM. We first validated the serum levels of 3 candidate miRNAs in an independent cohort of 24 GBM patients and 12 healthy volunteers by real-time quantitative reverse transcription PCR (qRT-PCR), and then evaluated the prognostic value of these miRNAs in a total of 36 GBM patients. The results show that the serum levels of the 3 miRNAs (miR-451a, miR-485-3p and miR-4298) determined by qRT-PCR are significantly different between 24 GBM patients and 12 healthy volunteers (all P <0.05) and are in concordance with the results of microarray analysis. High serum level of miR-451a is correlated with positive tumor O(6)-methylguanine-DNA methyltransferase (MGMT) expression (P = 0.040). Survival analysis showed that low serum miR-485-3p level is associated with poor progression-free survival (PFS) (P < 0.004) and overall survival (OS) (P < 0.023). Furthermore, univariate and multivariate Cox analyses demonstrated that that serum miR-485-3p expression is a significant independent prognostic factor for PFS and OS in GBM patients. In conclusion, serum miR-485-3p level is reduced and might be a potential prognostic biomarker in GBM patients.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Encefálicas/mortalidade , Glioblastoma/mortalidade , MicroRNAs/genética , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/sangue , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Estudos de Casos e Controles , Terapia Combinada , Metilases de Modificação do DNA/sangue , Enzimas Reparadoras do DNA/sangue , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Glioblastoma/sangue , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Taxa de Sobrevida , Proteínas Supressoras de Tumor/sangue , Adulto Jovem
16.
Cell Cycle ; 16(18): 1673-1682, 2017 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-28841361

RESUMO

p53R2 is a p53-inducible ribonucleotide reductase subunit involved in deoxyribonucleotide biosynthesis and DNA repair. Although p53R2 has been linked to human cancer, its role in cervical cancer remains unknown. In this study, we investigated the expression and clinical significance of p53R2 in early-stage cervical cancer. p53R2 expression is significantly upregulated at both mRNA and protein levels in cervical cancer cells and tissues, compared with that in matched normal cervical cells and tissues, respectively. p53R2 overexpression is associated with increased risk of pelvic lymph node metastasis (PLNM, p = 0.001) and cancer relapse (p = 0.009). Patients with high p53R2 expression have a shorter overall survival (OS) and disease-free survival (DFS). p53R2 is an independent factor for predicting OS and DFS of cervical cancer patients. We further show that p53R2 is important for oncogenic growth, migration and invasion in cervical cancer cells. Mechanistically, p53R2 promotes Akt signaling and epithelial-mesenchymal transition (EMT). In conclusion, our study demonstrates for the first time that p53R2 protein is overexpressed in early-stage cervical cancer and unravels some unconventional oncogenic functions of p53R2. p53R2 may be a useful prognostic biomarker and therapeutic target for cervical cancer.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Progressão da Doença , Transição Epitelial-Mesenquimal , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ribonucleotídeo Redutases/metabolismo , Transdução de Sinais , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação para Baixo/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Metástase Neoplásica , Prognóstico , Análise de Sobrevida
17.
Aging (Albany NY) ; 9(6): 1565-1584, 2017 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-28657540

RESUMO

Hepatocellular carcinoma (HCC) is a common cancer with very poor survival due to lack of reliable biomarker for early diagnosis. In this study, we investigated microRNA (miRNA) profile of whole blood with a custom microarray containing probes for 1849 miRNA species in a total 213 successive subjects who were divided into a discovery set and a validation set. An 88-miRNA signature was established to diagnose health controls (HC), chronic hepatitis B (CHB), liver cirrhosis (LC) and HCC with 100% accuracy in the discovery set using Fisher discriminant analysis. This diagnostic signature was confirmed in the validation set with accuracy rates of 100%, 95.2%, 93.7% and 98.4% for HC, CHB, LC and HCC patients, respectively. Compared with AFP, the only available non-invasive and routinely used biomarker for diagnosis of HCC, the 88-miRNA signature has much higher accuracy (99.5% vs 76.5%), sensitivity (100% vs 63.8%), and specificity (99.2% vs 84.2%). More importantly, the signature detects small HCCs (<3cm) with 100% (17/17) accuracy while AFP has only 64.7% (11/17). In conclusion, we have identified a powerful and sensitive blood 88-miRNA signature for diagnosing early HCC and other chronic liver diseases (CHB and LC) with a high accuracy.


Assuntos
Carcinoma Hepatocelular/diagnóstico , Detecção Precoce de Câncer/métodos , Hepatite B Crônica/diagnóstico , Neoplasias Hepáticas/diagnóstico , MicroRNAs/sangue , Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/metabolismo , Feminino , Humanos , Cirrose Hepática/diagnóstico , Neoplasias Hepáticas/metabolismo , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Sensibilidade e Especificidade
18.
Ophthalmic Res ; 58(3): 162-167, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28651253

RESUMO

PURPOSE: To investigate the association of interleukin (IL)-6 with proliferative diabetic retinopathy (PDR) of type 2 diabetes (T2D) in a Chinese population. METHODS: Two subtypes of the IL-6 promoter (-174 and -572 G/C) were genotyped in 215 T2D patients with PDR and 207 T2D patients with a normal retinal function (controls) using the PCR-RFLP method. The mRNA and protein expression of IL-6 was examined by real-time PCR. RESULTS: T2D patients with PDR had a significantly higher frequency of IL-6 -174 GC (OR 0.58; 95% CI 0.34-0.99; p = 0.011) and IL-6 -572 GG (OR 0.53; 95% CI 0.24-1.14; p = 0.016) than T2D controls. The mRNA expressions of the rs1800795 GC and rs1800796 GG genotype were significantly increased compared to other cases (Fsig = 0.002, p = 0.001, respectively), followed by a relative increase in IL-6 in protein. CONCLUSIONS: IL-6 genotypes of rs1800795 GC and rs1800796 GG might point to a relatively high risk for T2D patients suffering from PDR in a Chinese population and they were associated with elevation of IL-6 expression in both mRNA and protein.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Retinopatia Diabética/genética , Predisposição Genética para Doença , Interleucina-6/genética , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/genética , China/epidemiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Retinopatia Diabética/sangue , Retinopatia Diabética/epidemiologia , Ensaio de Imunoadsorção Enzimática , Feminino , Frequência do Gene , Genótipo , Humanos , Incidência , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos
19.
World J Gastroenterol ; 23(14): 2575-2584, 2017 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-28465642

RESUMO

AIM: To explore the effects of omeprazole on chemoradiotherapy efficacy and tumor recurrence in rectal cancer. METHODS: The medical data of 125 rectal cancer patients who received the same neoadjuvant chemoradiotherapy (CRT) followed by surgery were retrospectively collected. Patients who received omeprazole (OME) orally at a dose of 20 mg at least once daily for six days and/or intravenously at 40 mg a day were recognized as eligible OME users (EOU). Otherwise, patients were regarded as non-eligible OME users (non-EOU). Moreover, a preferred OME dose cut-off of 200 mg on tumor recurrence was obtained by receiver operating characteristic (ROC) curves. Patients were divided into two groups: the effective OME group (EOG, OME ≥ 200 mg) and the non-effective OME group (non-EOG, OME < 200 mg). RESULTS: The good response rate of CRT efficacy (50.8%) in EOU was significantly increased compared with non-EOU (30.6%) (P = 0.02). The recurrence rate in the EOG was 10.3%, which was significantly lower compared with 31.3% in non-EOG (P = 0.025). The good response rate of CRT efficacy in EOG was 55.2%, which was obviously higher compared with 36.5% in non-EOG, with a significant difference (P = 0.072). Multivariate Cox analysis demonstrated that OME (non-EOG and EOG) was an independent and significant impact factor for DFS (P = 0.048, HR = 0.30, 95%CI: 0.09-0.99). CONCLUSION: When applied as an adjuvant drug in cancer treatment for relieving common side effects of chemotherapy, omeprazole has a synergetic effect in improving CRT efficacy and decreasing rectal cancer recurrence.


Assuntos
Quimiorradioterapia Adjuvante , Terapia Neoadjuvante , Omeprazol/administração & dosagem , Inibidores da Bomba de Prótons/administração & dosagem , Neoplasias Retais/terapia , Administração Intravenosa , Administração Oral , Adolescente , Adulto , Idoso , Área Sob a Curva , Quimiorradioterapia Adjuvante/efeitos adversos , Distribuição de Qui-Quadrado , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Terapia Neoadjuvante/efeitos adversos , Recidiva Local de Neoplasia , Omeprazol/efeitos adversos , Modelos de Riscos Proporcionais , Inibidores da Bomba de Prótons/efeitos adversos , Curva ROC , Neoplasias Retais/patologia , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
20.
Aging (Albany NY) ; 9(4): 1326-1340, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28455969

RESUMO

Bone morphogenetic protein-2 (BMP2) is a secreted protein that highly expressed in a variety of cancers and contributes to cell proliferation, migration, invasiveness, mobility, metastasis and EMT. However, its clinical significance and biological function in nasopharyngeal carcinoma (NPC) remain unknown up to now. Up-regulation of BMP2 was first observed in NPC cell lines by a genome-wide transcriptome analysis in our previous study. In this study, BMP2 mRNA was detected by qRT-PCR and data showed that it was upregulated in NPC compared with non-cancerous nasopharynx samples. Immunohistochemistry (IHC) analysis in NPC specimens revealed that high BMP2 expression was significantly associated with clinical stage, distant metastasis and shorter survival of NPC patients. Moreover, overexpression of BMP2 in NPC cells promoted cell proliferation, migration, invasiveness and epithelial-mesenchymal transition (EMT). Mechanistically, BMP2 overexpression increase phosphorylated protein level of mTOR, S6K and 4EBP1. Correspondingly, mTORC1 inhibitor rapamycin blocked the effect of BMP2 on NPC cell proliferation and invasion. In conclusion, our results suggest that BMP2 overexpression in NPC enhances proliferation, invasion and EMT of tumor cells through the mTORC1 signaling pathway.


Assuntos
Proteína Morfogenética Óssea 2/farmacologia , Proliferação de Células/efeitos dos fármacos , Alvo Mecanístico do Complexo 1 de Rapamicina/efeitos dos fármacos , Neoplasias Nasofaríngeas/patologia , Invasividade Neoplásica/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Neoplasias Nasofaríngeas/genética , Metástase Neoplásica , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptores da Colecistocinina/biossíntese , Transdução de Sinais/efeitos dos fármacos , Transcriptoma/genética , Regulação para Cima/efeitos dos fármacos
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