Hunan Key Laboratory of Pharmacogenetics

Changsha, China

Hunan Key Laboratory of Pharmacogenetics

Changsha, China
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Yin J.-Y.,Central South University | Yin J.-Y.,Hunan Key Laboratory of Pharmacogenetics | Yin J.-Y.,Hunan Province Cooperation Innovation Center for Molecular Target New Drug Study | Meng X.-G.,Zhengzhou No 7 Peoples Hospital | And 19 more authors.
Acta Pharmacologica Sinica | Year: 2015

Aim: Eukaryotic translation initiation factor 3 subunit A (eIF3a) plays critical roles in regulating the initiation of protein translation, and eIF3a is highly expressed in lung cancer. In this study, we investigated the association of the positively selected SNPs of eIF3a with the response to and toxicity of platinum-based chemotherapy in Chinese patients with non-small cell lung cancer (NSCLC). Methods: SNP data for eIF3a locus were downloaded from HapMap database. For each SNP, haplotype, LD profile and population differentiation were analyzed. The long-range haplotype (LRH) test was employed to identify positively selected SNPs of eIF3a. A total of 325 NSCLC patients were enrolled and genotyped for these SNPs. Results: Five positively selected (rs1409314, rs4752219, rs4752220, rs7091672 and rs10510050) and 5 non-positively selected SNPs (rs10886342, rs11198804, rs2275112, rs10787899 and rs4752269) were identified in the LRH test. However, none of them was correlated with the platinum-based chemotherapy response. In contrast, 4 of the positively selected SNPs (rs1409314, rs4752219, rs4752220 and rs7091672) were significantly correlated with the toxicities tested (neutropenia, anemia, thrombocytopenia, emesis and hepatotoxicity). In addition, rs10510050 was significantly correlated with thrombocytopenia, emesis and hepatotoxicity. None of the 5 non-positively selected SNPs was correlated with the 5 toxicities. Conclusion: The positively selected SNPs of eIF3a are significantly correlated with platinum-based chemotherapy toxicities in Chinese NSCLC patients. © 2015 CPS and SIMM All rights reserved 1671-4083/15 $32.00.

Wen J.,Central South University | Wen J.,Hunan Key Laboratory of Pharmacogenetics | Zeng M.,Central South University | Shu Y.,University of Maryland, Baltimore | And 11 more authors.
Age | Year: 2015

Cisplatin (CDDP) nephrotoxicity is one of the most common side effects in cancer treatment, causing the disruption of chemotherapy. In this study, we analyzed the influence of nongenetic factors on CDDP-induced nephrotoxiciy using the data from 182 CDDP-treated and 52 carboplatin (CBP)-treated patients. The mean change of eGFR (100 % to baseline) in CDDP-treated patients was −9.2 %, which was significantly lower than that in the population with CBP therapy. By using the chi-squared test and multivariate logistic regression analysis, age (≥50 years) is found associated with CDDP-induced nephrotoxicity, with odds ratio (OR) of 9.167 and 11.771, respectively. Three- and 18-month-old mice were employed to study the age-dependent susceptibility of CDDP-induced nephrotoxicity. Biochemical parameters, histopathogical examination, and mRNA biomarkers indicated that old mice were subjected to more severe kidney injury. In addition, old mice accumulated more CDDP in kidney than young mice, and the protein level of CDDP efflux transporter, MATE1, in aged mice kidney was 35 % of that in young mice. Moreover, inflammatory receptor TLR4 was higher in the kidney of old mice, indicating the alteration of inflammatory signaling in old mice. After CDDP administration, the induced alterations of TNF-α, ICAM-1, and TLR4 were more extensive in old mice. To summarize, aging increased the susceptibility of CDDP-induced renal function decline or nephrotoxicity. © 2015, The Author(s).

Zhuo W.,Central South University | Zhuo W.,Hunan Key Laboratory of Pharmacogenetics | Hu L.,Central South University | Hu L.,Hunan Key Laboratory of Pharmacogenetics | And 7 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2014

Pregnane X receptor (PXR) is a member of the nuclear receptor superfamily that differently expresses not only in human normal tissues but also in numerous types of human cancers. PXR can be activated by many endogenous substances and exogenous chemicals, and thus affects chemotherapeutic effects and intervenes drug-drug interactions by regulating its target genes involving drug metabolism and transportation, cell proliferation and apoptosis, and modulating endobiotic homeostasis. Tissue and context-specific regulation of PXR contributes to diverse effects in the treatment for numerous cancers. Genetic variants of PXR lead to intra- and inter-individual differences in the expression and inducibility of PXR, resulting in different responses to chemotherapy in PXR-positive cancers. The purpose of this review is to summarize and discuss the role of PXR in the metabolism and clearance of anticancer drugs. It is also expected that this review will provide insights into PXR-mediated enhancement for chemotherapeutic treatment, prediction of drug-drug interactions and personalized medicine. © 2014 Springer-Verlag.

Guo Z.,Central South University | Guo Z.,Hunan Key Laboratory of Pharmacogenetics | Shu Y.,University of Maryland, Baltimore | Zhou H.,Central South University | And 4 more authors.
Carcinogenesis | Year: 2014

Radiogenomics is the whole genome application of radiogenetics, which focuses on uncovering the underlying genetic causes of individual variation in sensitivity to radiation. There is a growing consensus that radiosensitivity is a complex, inherited polygenic trait, dependent on the interaction of many genes involved in multiple cell processes. An understanding of the genes involved in processes such as DNA damage response and oxidative stress response, has evolved toward examination of how genetic variants, most often, single nucleotide polymorphisms (SNPs), may influence interindividual radioresponse. Many experimental approaches, such as candidate SNP association studies, genome-wide association studies and massively parallel sequencing are being proposed to address these questions. We present a review focusing on recent advances in association studies of SNPs to radiotherapy response and discuss challenges and opportunities for further studies. We also highlight the clinical perspective of radiogenomics in the future of personalized treatment in radiation oncology. © The Author 2014.

He H.,Central South University | He H.,Hunan Key Laboratory of Pharmacogenetics | He H.,Central University of Costa Rica | Yin J.-Y.,Central South University | And 18 more authors.
Clinical Therapeutics | Year: 2014

Purpose Resistance to the antiemetic ondansetron is still a major problem resulting in discomfort and poor compliance with chemotherapy in acute myeloid leukemia (AML) patients. Based on our hypothesis that this clinical resistance to ondansetron is associated with ABCB1 genetic polymorphisms, we investigated whether ABCB1 gene variations affect the efficacy of ondansetron in chemotherapy-induced nausea and vomiting. Methods AML patients (n = 215) treated for 3 days with high-dose cytarabine were enrolled in this study. Thirty minutes before the beginning of chemotherapy, 8 mg ondansetron was administered intravenously, followed by 24 mg by continuous infusion and 8 mg intravenously, once per day, until 2 days after chemotherapy. Chemotherapy-induced nausea and vomiting occurrence in the acute and delayed phases was calculated. ABCB1 and CYP2D6 polymorphisms were analyzed by allele-specific matrix-assisted laser desorption. Basic clinical characteristics of the AML patients were collected from medical records. Findings No differences in genotype distribution frequencies of ABCB1 polymorphisms and haplotypes were observed in patients with different CYP2D6-predicted phenotypes. During the acute phase, patients with the CG haplotype (C3435T and G2677T) were associated with a high risk of grade 3/4 nausea and vomiting (P = 0.003 and P = 0.026, respectively). After adjustment for age, sex, smoking status, alcohol drinking status, body surface area, body mass index, and Eastern Cooperative Oncology Group-Performance Status, multivariate survival analysis implicated the CG haplotype as a predictive marker of the risk of grade 3/4 chemotherapy-induced nausea and vomiting in AML patients (P = 0.003 and P = 0.039, respectively). In addition, a significant association between the 3435CC genotype and grade 3/4 vomiting in AML patients was observed (P = 0.016). However, no association between these ABCB1 gene polymorphisms and ondansetron efficacy was found in the delayed phase. Implications These findings suggest that ABCB1 gene polymorphisms are associated with antiemetic efficacy of ondansetron in the acute phase after high-dose cytarabine chemotherapy in AML patients. © 2014 Elsevier HS Journals, Inc.

Cheng F.H.C.,National Chung Cheng University | Aguda B.D.,DiseasePathways LLC | Tsai J.-C.,National Chung Cheng University | Kochanczyk M.,Polish Academy of Sciences | And 8 more authors.
PLoS ONE | Year: 2014

Accumulating data indicate that cancer stem cells contribute to tumor chemoresistance and their persistence alters clinical outcome. Our previous study has shown that ovarian cancer may be initiated by ovarian cancer initiating cells (OCIC) characterized by surface antigen CD44 and c-KIT (CD117). It has been experimentally demonstrated that a microRNA, namely miR-193a, targets c-KIT mRNA for degradation and could play a crucial role in ovarian cancer development. How miR-193a is regulated is poorly understood and the emerging picture is complex. To unravel this complexity, we propose a mathematical model to explore how estrogen-mediated up-regulation of another target of miR-193a, namely E2F6, can attenuate the function of miR-193a in two ways, one through a competition of E2F6 and c-KIT transcripts for miR-193a, and second by binding of E2F6 protein, in association with a polycomb complex, to the promoter of miR-193a to downregulate its transcription. Our model predicts that this bimodal control increases the expression of c-KITand that the second mode of epigenetic regulation is required to generate a switching behavior in c-KIT and E2F6 expressions. Additional analysis of the TCGA ovarian cancer dataset demonstrates that ovarian cancer patients with low expression of EZH2, a polycomb-group family protein, show positive correlation between E2F6 and c-KIT. We conjecture that a simultaneous EZH2 inhibition and anti-estrogen therapy can constitute an effective combined therapeutic strategy against ovarian cancer. © 2014 Cheng et al.

Wen J.,Central South University | Wen J.,Hunan Key Laboratory of Pharmacogenetics | Luo J.,Central South University | Luo J.,Hunan Key Laboratory of Pharmacogenetics | And 7 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2015

Multidrug-resistant protein 4 (MRP4), a member of the C subfamily of ATP-binding cassette transporters, is distributed in a variety of tissues and a number of cancers. As a drug transporter, MRP4 is responsible for the pharmacokinetics and pharmacodynamics of numerous drugs, especially antiviral drugs, antitumor drugs, and diuretics. In this regard, the functional role of MRP4 is affected by a number of factors, such as genetic mutations; tissue-specific transcriptional regulations; post-transcriptional regulations, including miRNAs and membrane internalization; and substrate competition. Unlike other C family members, MRP4 is in a pivotal position to transport cellular signaling molecules, through which it is tightly connected to the living activity and physiologic processes of cells and bodies. In the context of several cancers in which MRP4 is overexpressed, MRP4 inhibition shows striking effects against cancer progression and drug resistance. In this review, we describe the role of MRP4 more specifically in both healthy conditions and disease states, with an emphasis on its potential as a drug target. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Li H.,Central South University | Li H.,Hunan Key Laboratory of Pharmacogenetics | Jing X.,Central South University | Jing X.,Hunan Key Laboratory of Pharmacogenetics | And 4 more authors.
Journal of Central South University (Medical Sciences) | Year: 2013

Hyperlipidemia is one of the most important risk factors for atherosclerosis, coronary heart disease and other cardiovascular diseases. It is the main effect of lipid-lowering drugs to reduce the plasma low-density lipoprotein or to enhance high-density lipoprotein. Niemann-Pick Cl like 1 protein (NPClLl), acyl-coenzyme A: cholesterol acyltransferases (ACAT), ATP binding cassette transporter G member 5 and member 8 (ABCG5/G8), microsomal triglyceride transfer protein (MTP), monoacylglycerol acyltransferase, diacylglycerol acyltransferases (MAGT), peroxisome proliferator-activated receptor (PPAR), farnesoid X receptor (FXR), and proprotein convertase subtilisin/kexin type 9 (PCSK9) play key roles in the metabolism of lipid, which are regarded as the targets of anti-hyperlipidemia drugs and evidence for clinic choice of lipid-lowering drugs. These proteins are considered as breakthrough points for new lipid-lowering drug development.

Gao Y.-F.,Central South University | Gao Y.-F.,Hunan Key Laboratory of Pharmacogenetics | Wang Z.-B.,Central South University | Wang Z.-B.,Hunan Key Laboratory of Pharmacogenetics | And 14 more authors.
Tumor Biology | Year: 2016

With the development of whole genome and transcriptome sequencing technologies, a growing body of long non-coding RNAs (lncRNAs) has been identified and is receiving increasing attention. LncRNAs are non-protein encoding transcripts whose functions are crucial for advancing our comprehensive understanding of biological processes in human health and diseases, specifically glioma. It has been established that lncRNAs are differently expressed in the central nervous system and may play a vital role in glioma. As of June 2016, 20 lncRNAs have been identified that may play a role in glioma pathogenesis. Investigation into the role of lncRNAs in glioma may help to identify potential biomarkers which can improve the diagnosis and treatment of glioma. In this paper, we review current understanding of the function of lncRNAs in glioma initiation and progression. © 2016 International Society of Oncology and BioMarkers (ISOBM)

Zhan M.,Shen Zhen Childrens Hospital | Wen F.,Shen Zhen Childrens Hospital | Liu L.,Jiangxi Provincial Cancer Hospital | Chen Z.,Shen Zhen Childrens Hospital | And 3 more authors.
Tumor Biology | Year: 2016

Lung cancer is the most common cause of cancer-related deaths worldwide, and non-small cell lung cancer (NSCLC) accounts for 80 to 85 % of all lung cancer. Although the standard treatment regimen has been established, long-term survival for NSCLC patients is still generally poor. The histone demethylase Jumonji domain containing 1A (JMJD1A) has been proposed as an oncogene in several types of human cancer, but its clinical significance and functional roles in NSCLC remain largely unclear. In the present study, JMJD1A was frequently upregulated in NSCLC compared with para-carcinoma tissues. JMJD1A knockdown significantly inhibited NSCLC cell growth, migration, and invasion in vitro and tumorigenesis in vivo. Further experiments demonstrated that JMJD1A knockdown could decrease the expression of EZH2, which has been shown to play a crucial role in the carcinogenesis of NSCLC and, in turn, increase the expression of anti-tumor microRNA let-7c. Also, let-7c directly targeted the 3′-untranslated regions of JMJD1A and EZH2. Taken together, JMJD1A could promote NSCLC tumorigenesis. JMJD1A/EZH2/let-7c constituted a feedback loop and might represent a promising therapeutic target for NSCLC. © 2016 International Society of Oncology and BioMarkers (ISOBM)

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