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Biometals ; 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31552528


This study was conducted to investigate the damage caused by vanadium compounds and to explore the protective effects of berberine (BBR) in human umbilical vein endothelial cells (HUVECs). BBR is a biologically active small molecule found in Coptis rhizome, a remedy used in traditional Chinese medicine to treat diabetes. BBR has also been shown to lower blood glucose in diabetic patients. MTT assay was performed to observe the influence of bis(acetylacetonato)-oxidovanadium [VO(acac)2] or sodium metavanadate (NaVO3) and BBR on viability of HUVECs. The monolayer permeability of the HUVECs was assessed by measuring the transendothelial electrical resistance (TER). The endothelial nitric oxide synthase (eNOS) activity was detected by ELISA. Flow cytometry was performed to detect the generation of reactive oxygen species (ROS). The results showed that the viability of HUVECs was decreased by treatment with vanadium compounds 50-400 µM in a concentration-dependent manner, while 0.01-1 µM BBR effectively protected HUVECs from the inhibitory effects of vanadium compounds on cell viability. Also 100 and 200 µM VO(acac)2 induced high permeability and decreased eNOS activity in HUVECs. While 0.01-1 µM BBR showed no improvement in the permeability, and failed to reverse the VO(acac)2-induced changes of eNOS activity, but BBR treatment increased the eNOS activity in control cells. The addition of 200 µM VO(acac)2 significantly induced ROS generation in HUVECs, while 0.01 or 0.1 µM BBR reversed the change of ROS. In summary, BBR has protective effects in HUVECs damage induced by vanadium compounds, which is not mediated by eNOS, but related to reduced intracellular ROS.

Lancet Oncol ; 20(4): 591-600, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30880070


BACKGROUND: Identification of high-risk localised renal cell carcinoma is key for the selection of patients for adjuvant treatment who are at truly higher risk of reccurrence. We developed a classifier based on single-nucleotide polymorphisms (SNPs) to improve the predictive accuracy for renal cell carcinoma recurrence and investigated whether intratumour heterogeneity affected the precision of the classifier. METHODS: In this retrospective analysis and multicentre validation study, we used paraffin-embedded specimens from the training set of 227 patients from Sun Yat-sen University (Guangzhou, Guangdong, China) with localised clear cell renal cell carcinoma to examine 44 potential recurrence-associated SNPs, which were identified by exploratory bioinformatics analyses of a genome-wide association study from The Cancer Genome Atlas (TCGA) Kidney Renal Clear Cell Carcinoma (KIRC) dataset (n=114, 906 600 SNPs). We developed a six-SNP-based classifier by use of LASSO Cox regression, based on the association between SNP status and patients' recurrence-free survival. Intratumour heterogeneity was investigated from two other regions within the same tumours in the training set. The six-SNP-based classifier was validated in the internal testing set (n=226), the independent validation set (Chinese multicentre study; 428 patients treated between Jan 1, 2004 and Dec 31, 2012, at three hospitals in China), and TCGA set (441 retrospectively identified patients who underwent resection between 1998 and 2010 for localised clear cell renal cell carcinoma in the USA). The main outcome was recurrence-free survival; the secondary outcome was overall survival. FINDINGS: Although intratumour heterogeneity was found in 48 (23%) of 206 cases in the internal testing set with complete SNP information, the predictive accuracy of the six-SNP-based classifier was similar in the three different regions of the training set (areas under the curve [AUC] at 5 years: 0·749 [95% CI 0·660-0·826] in region 1, 0·734 [0·651-0·814] in region 2, and 0·736 [0·649-0·824] in region 3). The six-SNP-based classifier precisely predicted recurrence-free survival of patients in three validation sets (hazard ratio [HR] 5·32 [95% CI 2·81-10·07] in the internal testing set, 5·39 [3·38-8·59] in the independent validation set, and 4·62 [2·48-8·61] in the TCGA set; all p<0·0001), independently of patient age or sex and tumour stage, grade, or necrosis. The classifier and the clinicopathological risk factors (tumour stage, grade, and necrosis) were combined to construct a nomogram, which had a predictive accuracy significantly higher than that of each variable alone (AUC at 5 years 0·811 [95% CI 0·756-0·861]). INTERPRETATION: Our six-SNP-based classifier could be a practical and reliable predictor that can complement the existing staging system for prediction of localised renal cell carcinoma recurrence after surgery, which might enable physicians to make more informed treatment decisions about adjuvant therapy. Intratumour heterogeneity does not seem to hamper the accuracy of the six-SNP-based classifier as a reliable predictor of recurrence. The classifier has the potential to guide treatment decisions for patients at differing risks of recurrence. FUNDING: National Key Research and Development Program of China, National Natural Science Foundation of China, Guangdong Provincial Science and Technology Foundation of China, and Guangzhou Science and Technology Foundation of China.

Cancer Sci ; 108(8): 1620-1627, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28612496


We previously identified the important role of RIN1 expression in the prognosis of clear cell renal cell carcinoma (ccRCC). The role of RIN1 in ccRCC malignancy and underlying molecular mechanisms remain unclear. Here we report that ccRCC cells and tissues expressed more RIN1 than normal controls. Gain-of-function and loss-of-function studies demonstrated that RIN1 enhanced ccRCC cell growth, migration and invasion abilities in vitro and promoted tumor growth and metastasis in vivo. Mechanistic studies revealed that RIN1 has an activating effect on EGFR signaling in ccRCC. In addition, we unveil Rab25, a critical GTPase in ccRCC malignancy, as a functional RIN1 interacting partner. Knockdown of Rab25 eliminated the augmentation of carcinoma cell proliferation, migration and invasion by ectopic RIN1. We also confirmed that RIN1 and Rab25 expression correlates with the overall-survival of ccRCC patients from TCGA. These findings suggest that RIN1 plays an important oncogenic role in ccRCC malignancy by activation of EGFR signaling through interacting with Rab25, and RIN1 could be employed as an effective therapeutic target for ccRCC.

Carcinoma de Células Renais/patologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Renais/patologia , Regulação para Cima , Proteínas rab de Ligação ao GTP/metabolismo , Animais , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Receptores ErbB/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/metabolismo , Camundongos , Metástase Neoplásica , Transplante de Neoplasias , Transdução de Sinais , Análise de Sobrevida
Oncotarget ; 8(13): 21461-21471, 2017 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-28423523


PURPOSE: To examine the role of miR-106b-5p in regulating the cancer stem-cell-like phenotype in clear cell renal cell carcinomas (ccRCC). EXPERIMENTAL DESIGN: Real-time PCR was performed to evaluate miR-106b-5p levels in ccRCC cell lines and patients specimens. A series of in vivo and in vitro assays were performed to confirm the effect of miR-106b-5p on ccRCC stemness phenotype. RESULTS: ccRCC cells and tissues expressed more miR-106b-5p than normal controls. Gain- and loss-of-function studies demonstrated that overexpression of miR-106b-5p in ccRCC cells increased the spheres formation ability and the proportion of side population cells. Ectopic expression of miR-106b-5p in ccRCC cells increased tumour growth rates and the number of metastatic colonies in the lungs by using an orthotopic kidney cancer model and a tail vein injection model, respectively. Mechanistic studies revealed that, miR-106b-5p has an activating effect on Wnt/ß-catenin signalling. miR-106p-5p overexpression simultaneously targets multiple negative regulators of the Wnt/ß-catenin pathway, namely, LZTFL1, SFRP1 and DKK2. In addition, we also confirmed that miR-106b-5p and its targets expression correlates with the overall-survival of ccRCC patients from TCGA. CONCLUSIONS: These findings suggest that miR-106b-5p mediates the constitutive activation of Wnt/ß-catenin signalling, likely serving as a potential therapeutic target for ccRCC.

Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , MicroRNAs/biossíntese , Células-Tronco Neoplásicas/patologia , Via de Sinalização Wnt/fisiologia , Animais , Western Blotting , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/genética , Xenoenxertos , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Camundongos , MicroRNAs/genética , Fenótipo , Reação em Cadeia da Polimerase , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real
BMC Public Health ; 13: 599, 2013 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-23786855


BACKGROUND: Metabolic risk factors and abnormalities such as obesity and hypertension are rapidly rising among the Chinese population following China's tremendous economic growth and widespread westernization of lifestyle in recent decades. Limited information is available about the current burden of metabolic syndrome (MetS) in China. METHODS: We analyzed data on metabolic risk factors among 22,457 adults aged ≥ 32 years participating in the "Zhabei Health 2020" survey (2009-2010), a cross-sectional study of a representative sample of community residents in Zhabei District. We defined MetS using Chinese-specific cut-off points for central obesity according to consensus criteria recently endorsed by several international and national organizations in defining MetS in different populations worldwide. We used a multiple logistic regression model to assess the associations of potential risk factors with MetS. RESULTS: The unadjusted prevalence of the MetS was 35.1% for men and 32.5% for women according to the consensus criteria for Chinese. The prevalence increased progressively from 12.1% among participants aged 32-45 years to 45.4% among those aged ≥ 75 years. Age, smoking, family history of diabetes, and education are significantly associated with risk of MetS. CONCLUSIONS: The MetS is highly prevalent and has reached epidemic proportion in Chinese urban adult community residents.

Síndrome Metabólica/epidemiologia , População Urbana/estatística & dados numéricos , Adulto , Fatores Etários , Idoso , China/epidemiologia , Estudos Transversais , Diabetes Mellitus/epidemiologia , Feminino , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Masculino , Síndrome Metabólica/etiologia , Síndrome Metabólica/genética , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/epidemiologia , Prevalência , Fatores de Risco , Fatores Sexuais , Fumar/epidemiologia , Classe Social