Li Liu

Publications (52)269.23 Total impact

• Article: Genetic variants in HLA-DP/DQ contribute to risk of cervical cancer: A two-stage study in Chinese women.

  Jie Jiang, Ni Li, Yan Shen, Jibin Liu, Li Liu, Jiangbo Du, Yu Lei, Yang Wen, Lin Yang, Lanwei Guo, Kai Zhang, Fulin Qiang, Sumin Wang, Zhibin Hu, Min Dai, Hongbing Shen
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  ABSTRACT: OBJECTIVE: Human leukocyte antigens (HLA) play an important role in presenting virus antigens to immune cells that are responsible for the clearance of virus-infected cells and tumor cells. Herein, we evaluated whether genetic variants of HLA-DP and HLA-DQ are associated with cervical cancer risk. METHODS: We genotyped four single nucleotide polymorphisms (SNPs) in HLA-DP (rs3077 and rs9277535) and HLA-DQ (rs2856718 and rs7453920) in a two-stage case-control study with a total of 2317 cervical cancer cases and 2109 cancer-free controls using TaqMan allelic discrimination assay. RESULTS: We found consistently significant associations of HLA-DP rs3077 and rs9277535 with increased risks of cervical cancer (dominant genetic model: adjusted OR=1.51, 95% CI=1.32-1.71 for rs3077; adjusted OR=1.29, 95% CI=1.12-1.49 for rs9277535). When combining the effects of HLA-DP rs3077 and rs9277535, subjects carrying "≥1" variant alleles had a 1.55-fold increased risk of cervical cancer (95% CI=1.32-1.81), compared with those carrying "0" variant allele. And cervical cancer risk significantly increased with the increasing number of variant alleles of the two SNPs in a dose-dependent manner (P for trend=4.33×10-10). However, there were no significant associations for HLA-DQ rs2856718 and rs7453920 in our population. CONCLUSIONS: These findings indicate that HLA-DP rs3077 and rs9277535 were candidate susceptibility markers for cervical cancer in Chinese females. Further validation studies with different ethnic background, biological function analyses and especially HPV typing together were needed.
  Gynecologic Oncology 02/2013; · 3.89 Impact Factor
• Article: The Leptin Gene Family and Colorectal Cancer: Interaction with Smoking Behavior and Family History of Cancer.

  Li Liu, Rong Zhong, Sheng Wei, Hao Xiang, Jigui Chen, Duoshuang Xie, Jieyun Yin, Li Zou, Jingwen Sun, Wei Chen, Xiaoping Miao, Shaofa Nie
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  ABSTRACT: Pathologic condition associated with metabolic syndrome traits seems to increase the risk of colorectal cancer. One mechanism underlying this relationship may involve the growth-promoting effects of the circulation hormones associated with obesity and insulin resistance, such as leptin. A two-stage case-control study was used to explore the role of polymorphisms of Leptin (LEP) and Leptin receptor (LEPR), either alone or in combination with environmental factors in colorectal carcinogenesis. In stage 1, 20 single nucleotide polymorphisms (SNPs) that tag common SNPs in these two genes were genotyped among 470 cases and 458 controls. In stage 2, another population with 314 cases and 355 controls were genotyped for the two most promising SNPs from stage 1. LEPR rs12037879 only presented modestly increased colorectal cancer risk, with odds ratios of 1.41 (95% confidence interval [CI] 1.13-1.76) and 1.74 (95%CI 1.08-2.81) for GA and AA genotype when compared with GG genotype in combined population. Smokers carrying LEPR rs12037879 A allele presented 1.67-fold (95%CI 1.39-fold to 2.01-fold) increased colorectal cancer risk when compared with non-smokers carrying GG genotype in combined analysis. Individuals with family history of cancer harboring LEPR rs12037879 A allele showed 1.52-fold (95%CI: 1.24-fold to 1.86-fold) increased colorectal cancer risk, compared with individuals without family history of cancer harboring GG genotype. Multifactor gene-environment interaction analysis revealed significant interactions among LEPR rs12037879, LEPR rs6690625, smoking status and family history of cancer, exhibiting a gradient of increased colorectal cancer risk along with the increasing number of risk factors (P = 9.82×10(-10)). Our research supports that polymorphisms in LEPR may be associated with marginal increase in the risk for colorectal cancer. Moreover, this association could be strengthened by cigarette smoking and family history of cancer.
  PLoS ONE 01/2013; 8(4):e60777. · 4.09 Impact Factor
• Article: Genetic Variants in the Folate Pathway and the Risk of Neural Tube Defects: A Meta-Analysis of the Published Literature.

  Ti Zhang, Jiao Lou, Rong Zhong, Jing Wu, Li Zou, Yu Sun, Xuzai Lu, Li Liu, Xiaoping Miao, Guanglian Xiong
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  ABSTRACT: Neural Tube Defects (NTDs) are among the most prevalent and most severe congenital malformations worldwide. Polymorphisms in key genes involving the folate pathway have been reported to be associated with the risk of NTDs. However, the results from these published studies are conflicting. We surveyed the literature (1996-2011) and performed a comprehensive meta-analysis to provide empirical evidence on the association. We investigated the effects of 5 genetic variants from 47 study populations, for a total of 85 case-control comparisons MTHFR C677T (42 studies; 4374 cases, 7232 controls), MTHFR A1298C (22 studies; 2602 cases, 4070 controls), MTR A2756G (9 studies; 843 cases, 1006 controls), MTRR A66G (8 studies; 703 cases, 1572 controls), and RFC-1 A80G (4 studies; 1107 cases, 1585 controls). We found a convincing evidence of dominant effects of MTHFR C677T (OR 1.23; 95%CI 1.07-1.42) and suggestive evidence of RFC-1 A80G (OR 1.55; 95%CI 1.24-1.92). However, we found no significant effects of MTHFR A1298C, MTR A2756G, MTRR A66G in risk of NTDs in dominant, recessive or in allelic models. Our meta-analysis strongly suggested a significant association of the variant MTHFR C677T and a suggestive association of RFC-1 A80G with increased risk of NTDs. However, other variants involved in folate pathway do not demonstrate any evidence for a significant marginal association on susceptibility to NTDs.
  PLoS ONE 01/2013; 8(4):e59570. · 4.09 Impact Factor
• Article: Replication study in chinese population and meta-analysis supports association of the 5p15.33 locus with lung cancer.

  Juntao Ke, Rong Zhong, Ti Zhang, Lifeng Liu, Rui Rui, Na Shen, Yu Sun, Li Liu, Liming Cheng, Xiao-Ping Miao
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  ABSTRACT: Common genetic polymorphisms on chromosome 5p15.33, including rs401681 in cleft lip and palate transmembrane 1-like gene (CLPTM1L), have been implicated in susceptibility to lung cancer through genome-wide association studies (GWAS); however, subsequent replication studies yielded controversial results. A hospital-based case-control study in a Chinese population was conducted to replicate the association, and then a meta-analysis combining our non-overlapping new data and previously published data was performed to clearly discern the real effect of lung cancer susceptibility. In our study with 611 cases and 1062 controls, the minor allele T carrier (TT plus CT) group conferred an OR of 0.801 (95% CI = 0.654-0.981) under the dominant model. The meta-analysis comprising 9111 cases and 11424 controls further confirmed the significant association in the dominant model (OR = 0.842, 95% CI = 0.795-0.891). By stratified analysis, we revealed that ethnicity and study design might constitute the source of between-study heterogeneity. Besides, the sensitivity and cumulative analyses indicated the high stability of the results. The results from our case-control study and meta-analysis provide convincing evidence that rs401681 is significantly associated with lung cancer risk.
  PLoS ONE 01/2013; 8(4):e62485. · 4.09 Impact Factor
• Article: Association between XRCC1 and XRCC3 polymorphisms and colorectal cancer risk: a meta-analysis of 23 case-control studies.

  Li Liu, Lin Miao, Guozhong Ji, Fulin Qiang, Zheng Liu, Zhining Fan
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  ABSTRACT: Several potential functional polymorphisms in the DNA repair gene X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln (rs25487), Arg194Trp (rs1799782), Arg280His (rs25489) and X-ray repair cross-complementing group 3 (XRCC3) T241M (rs861539) have been implicated in colorectal cancer (CRC) risk, but the results are conflicting. Here, we performed a meta-analysis of 23 published case control datasets and assessed genetic heterogeneity between those datasets. All the case-control studies published from January 2000 to June 2012 on the association between those polymorphisms and CRC risk were identified by searching the electronic literature Medline. Statistical analysis was performed with the software programs Review Manager (version 4.2). For overall CRC, no significant association was observed, the pooled odds ratios for XRCC1 Arg399Gln, Arg194Trp, Arg280His, and XRCC3 T241M were 1.02 (95 % CI: 0.93, 1.12), 1.03 (95 % CI: 0.94, 1.14), 0.98 (95 % CI: 0.85, 1.13) and 1.03 (95 % CI: 0.85, 1.26), respectively. Furthermore, no significant association was observed in subgroup analyses based on ethnicity. The results suggested that these four SNPs evaluated are not associated with risk of CRC.
  Molecular Biology Reports 12/2012; · 2.93 Impact Factor
• Article: Genetic variations in the TGFβ signaling pathway, smoking, and risk of colorectal cancer in a Chinese population.

  Rong Zhong, Li Liu, Li Zou, Sheng Wei, Beibei Zhu, Hao Xiang, Wei Chen, Jigui Chen, Rui Rui, Xiawen Zheng, Jieyun Yin, Shengyu Duan, Beifang Yang, Jingwen Sun, Jiao Lou, Duoshuang Xie, Yihua Xu, Shaofa Nie, Xiaoping Miao
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  ABSTRACT: Recent genome-wide association studies (GWAS) have reported multiple risk loci associated with risk of colorectal cancer (CRC), some of which are involved in the TGFβ signaling pathway. We systematically examined associations of common genetic variations in the TGFβ signaling pathway and environmental factors with CRC risk using a two-staged case-control study in a Chinese population. A set of 77 single nucleotide polymorphisms (SNPs) in 10 candidate genes involved in the TGFβ signaling pathway and several environmental factors including sex, age, smoking and drinking were examined by random forest to capture the potential gene-gene and gene-environment interactions in stage 1 of the study with 443 CRC patients and 480 controls. Three promising SNPs (SMAD7 rs11874392, TGFBR1 rs10988706 and rs6478972) selected by the random forest method were genotyped in stage 2 comprising 351 cases and 360 controls for validation. SMAD7 rs11874392 presented consistently significant associations with a risk of CRC at both stages, with OR= 1.41(95% CI=1.21-1.63) using additive modes in combined analyses. Moreover, the potential interactions between SMAD7 rs11874392, TGFBR1 rs10988706 and rs6478972 were indicated consistently in both stages of the study by using pair-wise interaction and multi-locus genotype pattern analysis. Additionally, gene-smoking interactions for rs11874392, rs10988706, and rs6478972 were also found to enhance the risk of CRC at both stages, with P for multiplicative interaction equal to 1.162×10-6, 8.574×10-8, and 9.410×10-8 in combined analyses, respectively. The study emphasized the substantial role of the TGFβ signaling pathway in CRC, especially in interaction with smoking.
  Carcinogenesis 12/2012; · 5.70 Impact Factor
• Source

  Available from: Keitaro Matsuo

  Article: Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia.

  Qing Lan, Chao A Hsiung, Keitaro Matsuo, Yun-Chul Hong, Adeline Seow, Zhaoming Wang, H Dean Hosgood, Kexin Chen, Jiu-Cun Wang, Nilanjan Chatterjee, [......], Hsien-Chih Lin, Tangchun Wu, Yi-Long Wu, Pan-Chyr Yang, Baosen Zhou, Min-Ho Shin, Joseph F Fraumeni, Dongxin Lin, Stephen J Chanock, Nathaniel Rothman
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  ABSTRACT: To identify common genetic variants that contribute to lung cancer susceptibility, we conducted a multistage genome-wide association study of lung cancer in Asian women who never smoked. We scanned 5,510 never-smoking female lung cancer cases and 4,544 controls drawn from 14 studies from mainland China, South Korea, Japan, Singapore, Taiwan and Hong Kong. We genotyped the most promising variants (associated at P < 5 × 10(-6)) in an additional 1,099 cases and 2,913 controls. We identified three new susceptibility loci at 10q25.2 (rs7086803, P = 3.54 × 10(-18)), 6q22.2 (rs9387478, P = 4.14 × 10(-10)) and 6p21.32 (rs2395185, P = 9.51 × 10(-9)). We also confirmed associations reported for loci at 5p15.33 and 3q28 and a recently reported finding at 17q24.3. We observed no evidence of association for lung cancer at 15q25 in never-smoking women in Asia, providing strong evidence that this locus is not associated with lung cancer independent of smoking.
  Nature Genetics 11/2012; · 35.53 Impact Factor
• Article: The SLC4A7 variant rs4973768 is associated with breast cancer risk: evidence from a case-control study and a meta-analysis.

  Wei Chen, Rong Zhong, Jie Ming, Li Zou, Beibei Zhu, Xuzai Lu, Juntao Ke, Yu Zhang, Li Liu, Xiaoping Miao, Tao Huang
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  ABSTRACT: Recent genome-wide association study has identified a genetic variant rs4973768, located in 3'-UTR of solute carrier family 4, sodium bicarbonate cotransporter, member 7 (SLC4A7), was associated with increased risk of breast cancer (BC). However, several following replication studies cannot yield consistent results. We thus conducted a hospital-based case-control study including 485 patients and 514 controls, combined a meta-analysis including 108,632 cases and 135,818 controls to explore the relationship between this variant and BC risk. Our case-control study showed that rs4973768 was significantly associated with increased BC risk with the odds ratio (OR) of 1.29 (95 % confidence interval [CI]: 1.04-1.60) under the allelic model. In addition, the meta-analysis also indicated that the variant slightly increased the risk of BC with the pooled OR of the per-allele effect being 1.08 (95 % CI: 1.04-1.11) although with significant heterogeneity between studies. Stratified analyses showed that ethnicity, sample size, and study design may explain part of the heterogeneity. Moreover, the bioinformatics analysis suggested that this variant may influence the transcriptional capacity of SLC4A7. In summary, our results showed that the SLC4A7 variant, rs4973768, is associated with risk of BC although the underlying biologic mechanism warrants further studies.
  Breast Cancer Research and Treatment 11/2012; · 4.43 Impact Factor
• Article: A functional polymorphism, rs28493229, in ITPKC and risk of Kawasaki disease: an integrated meta-analysis.

  Jiao Lou, Sanqing Xu, Li Zou, Rong Zhong, Ti Zhang, Yu Sun, Xuzai Lu, Li Liu, Chuanqi Li, Li Wang, Guanglian Xiong, Wei Wang, Fangqi Gong, Jing Wu
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  ABSTRACT: Kawasaki disease (KD) is a multi-systemic vasculitis which preferentially affects infants and children. A single nucleotide polymorphism (rs28493229) in the inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) was identified to be associated with the increased risk of KD; however, in more recent studies associations have been controversial. Thus, we performed a meta-analysis, integrating case-control and transmission/disequilibrium test (TDT) studies, to investigate the relationship between this polymorphism and risk of KD. A total of ten case-control and two TDT studies, comprising 3,821 cases, 12,802 controls and 949 families, were included in this meta-analysis. There was a significant association between the C allele of rs28493229 and the increased risk of KD (OR = 1.53, 95 % CI = 1.34-1.74, P < 0.001), by the random-effects model because of heterogeneity (Q = 27.67, P (heterogeneity) = 0.004). Nevertheless, it was screened out by meta-regression analysis that the coronary artery lesions (CALs) status of KD could partly explain the heterogeneity, with consistently significant associations in both subgroups after stratification by CALs status. Moreover, estimates before and after the deletion of each study were similar in sensitivity analysis, indicating robust stability of the meta-analysis. This meta-analysis reveals that the functional polymorphism rs28493229 in ITPKC significantly contributes to the risk of KD.
  Molecular Biology Reports 10/2012; · 2.93 Impact Factor
• Article: Polyfluorene nanoparticles coated with folate-functionalized triblock copolymer: effective agents for targeted cell imaging.

  Li Liu, Abhijit Patra, Ullrich Scherf, Thomas Kissel
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  ABSTRACT: An ultra-bright fluorescence probe comprising conjugated polymer nanoparticles is developed for biological imaging. Highly blue fluorescent polyfluorene nanoparticles (PF-NPs) stabilized by sodium dodecylsulfate with an average diameter of 100 nm are prepared by a miniemulsion technique. A folate-conjugated cationic triblock copolymer is employed to coat negatively charged PF-NPs via electrostatic interaction for specific cell imaging of folate receptor over-expressing cancer cells. The coated PF-NPs show a similar size and morphology to the pristine PF-NPs, while the fluorescence intensity is enhanced. Such surface-functionalized PF-NPs are demonstrated to be suitable probes for efficient cell imaging of folate receptor over-expressing KB cells by CLSM and flow cytometry.
  Macromolecular Bioscience 08/2012; 12(10):1384-90. · 3.89 Impact Factor
• Article: Pharmacokinetic-pharmacodynamic modeling of diclofenac in normal and Freund's complete adjuvant-induced arthritic rats.

  Jing Zhang, Pei Li, Hai-Fang Guo, Li Liu, Xiao-Dong Liu
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  ABSTRACT: Aim:To characterize pharmacokinetic-pharmacodynamic modeling of diclofenac in Freund's complete adjuvant (FCA)-induced arthritic rats using prostaglandin E(2) (PGE(2)) as a biomarker.Methods:The pharmacokinetics of diclofenac was investigated using 20-day-old arthritic rats. PGE(2) level in the rats was measured using an enzyme immunoassay. A pharmacokinetic-pharmacodynamic (PK-PD) model was developed to illustrate the relationship between the plasma concentration of diclofenac and the inhibition of PGE(2) production. The inhibition of diclofenac on lipopolysaccharide (LPS)-induced PGE(2) production in blood cells was investigated in vitro.Results:Similar pharmacokinetic behavior of diclofenac was found both in normal and FCA-induced arthritic rats. Diclofenac significantly decreased the plasma levels of PGE(2) in both normal and arthritic rats. The inhibitory effect on PGE(2) levels in the plasma was in proportion to the plasma concentration of diclofenac. No delay in the onset of inhibition was observed, suggesting that the effect compartment was located in the central compartment. An inhibitory effect sigmoid I(max) model was selected to characterize the relationship between the plasma concentration of diclofenac and the inhibition of PGE(2) production in vivo. The I(max) model was also used to illustrate the inhibition of diclofenac on LPS-induced PGE(2) production in blood cells in vitro.Conclusion:Arthritis induced by FCA does not alter the pharmacokinetic behaviors of diclofenac in rats, but the pharmacodynamics of diclofenac is slightly affected. A PK-PD model characterizing an inhibitory effect sigmoid I(max) can be used to fit the relationship between the plasma PGE(2) and diclofenac levels in both normal rats and FCA-induced arthritic rats.
  Acta Pharmacologica Sinica 07/2012; · 1.95 Impact Factor
• Article: Multi-loci analysis reveals the importance of genetic variations in sensitivity of platinum-based chemotherapy in non-small-cell lung cancer.

  Li Liu, Jing Wu, Rong Zhong, Chen Wu, Li Zou, Beifang Yang, Wei Chen, Beibei Zhu, Shengyu Duan, Dianke Yu, Wen Tan, Shaofa Nie, Dongxin Lin, Xiaoping Miao
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  ABSTRACT: Polymorphisms in DNA repair and apoptotic pathways may cause variations in chemosensitivity of non-small-cell lung cancer (NSCLC) through complex gene-gene and gene-environment interactions. A total of 200 advanced NSCLC patients who received platinum-based chemotherapies were recruited. The short-term clinical outcomes were classified as chemosensitive group, including complete remission (CR) and partial remission (PR), and chemoresistant group, namely stable disease (SD) and progression disease (PD) at the end of treatment. We applied multifactor dimensionality reduction (MDR), classification and regression tree (CART) and traditional logistic regression (LR) to explore high-order gene-gene and gene-environment interactions among 11 functional single nucleotide polymorphisms (SNPs), smoking status, cancer stages and treatment regimens in the response to chemotherapy. Multi-loci analyses consistently indicated that interactions among XRCC1 Arg194Trp, XPC PAT, FAS G-1377A, and FASL T-844C were associated with sensitivity to platinum-based chemotherapy. In MDR analysis, the four-factor model yielded the highest test accuracy of 0.72 (permutation P = 0.001). In CART analysis, these four SNPs were the determinant nodes of the growth of regression tree. Patients carrying XRCC1 Arg194Arg, FAS-1377GG, and FASL-844T allele displayed completely no response to platinum, whereas patients with XRCC1 194Trp allele and XPC PAT +/+ had 68.8% response rate to platinum. In LR analysis, a significant gene-dosage effect was detected along with the increasing number of favorable genotypes of these four polymorphisms (P(trend)  = 0.00002). Multi-loci analysis reveals the importance of genetic variations involved in DNA repair and apoptotic pathways in sensitivity of platinum-based chemotherapy in NSCLC. © 2012 Wiley Periodicals, Inc.
  Molecular Carcinogenesis 07/2012; · 3.16 Impact Factor
• Article: Polymorphisms in TP53 and MDM2 contribute to higher risk of colorectal cancer in Chinese population: a hospital-based, case-control study.

  Yuxing Zhang, Li Liu, Yingchun Tang, Chao Chen, Qian Wang, Jun Xu, Chao Yang, Xiaoping Miao, Sheng Wei, Jigui Chen, Shaofa Nie
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  ABSTRACT: The murine double minute 2 protein (MDM2) and TP53 interact in regulating cell cycle, DNA repair and apoptosis process, which is crucial in carcinogenesis. Since functional variations in these two genes were shown to change gene expression and function, we hypothesized that potentially functional polymorphisms in these genes may contribute to colorectal cancer (CRC) susceptibility. A hospital-based case-control study consisting of 444 patients and 569 controls was conducted to explore the associations between TP53 Arg72Pro and MDM2 T309G and CRC risk in Chinese. The combined effect of TP53 Arg72Pro and MDM2 T309G was significant in a gene dose-response increasing CRC risk (trend test: P = 0.02). Individuals carrying 3 or more potential risk alleles had 1.78 times risk (95 % CI: 1.13-2.80) to develop CRC compared with individuals without potential risk allele. This increased cancer risk was more pronounced in smokers who carried 3-4 potential risk alleles (OR = 2.75, 95 % CI: 1.14-6.60) and in young subjects (OR = 2.05, 95 % CI: 1.08-3.88). The gene-gene interaction between TP53 Arg72Pro and MDM2 T309G may interact in carcinogenesis of CRC in Chinese, especially in smokers, and this kind of interaction is associated with onset age of CRC.
  Molecular Biology Reports 06/2012; 39(10):9661-8. · 2.93 Impact Factor
• Article: IL-23R polymorphisms, HBV infection, and risk of hepatocellular carcinoma in a high-risk Chinese population.

  Yan Xu, Yao Liu, Shandong Pan, Li Liu, Jibin Liu, Xiangjun Zhai, Hongbing Shen, Zhibin Hu
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  ABSTRACT: BACKGROUND: The interleukin-23 receptor (IL-23R) plays an important role in the T-helper 17 cell-mediated inflammatory process and is also involved in tumor immune surveillance, which may be linked to carcinogenesis in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). In this study, we hypothesized that potentially functional genetic variants of the IL-23R gene may modify HCC risk. METHODS: We genotyped two single-nucleotide polymorphisms (SNPs) of IL-23R, rs6682925 and rs1884444, in a case-control study of 837 HCC cases, 899 HBV surface antigen (HBsAg)-positive controls, and 743 HBsAg-negative controls. A reporter gene assay was performed to evaluate the functional relevance of the rs6682925 SNP located at the promoter region of the IL-23R gene. RESULTS: We found that the two SNPs were associated with the risk of HCC when compared with both the HBsAg-positive and -negative controls. When compared with all controls, IL-23R rs6682925 and rs1884444 both increased the HCC risk in a recessive genetic model [rs6682925 CC vs. TT/TC: odds ratio (OR) 1.35, 95 % confidence interval (CI) 1.07-1.70; rs1884444 GG vs. TT/TG: OR 1.36, 95 % CI 1.05-1.77]. Furthermore, the variant C allele of rs6682925 in the promoter region of IL-23R was associated with increased reporter gene activity. CONCLUSIONS: These findings indicate that genetic variants in IL-23R may contribute to HCC development.
  Journal of Gastroenterology 06/2012; · 4.16 Impact Factor
• Article: Modular Synthesis of Folate Conjugated Ternary Copolymers: Polyethylenimine-graft-Polycaprolactone-block-Poly(ethylene glycol)-Folate for Targeted Gene Delivery.

  Li Liu, Mengyao Zheng, Thomas Renette, Thomas Kissel
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  ABSTRACT: Folate receptor (FR) is overexpressed in a variety of human cancers. Gene delivery vectors conjugated with folate as a ligand could possibly deliver gene materials into target tumor cells via FR-mediated endocytosis. This study addresses novel folate-conjugated ternary copolymers based on polyethylenimine-graft-polycaprolactone-block-poly(ethylene glycol) (PEI-g-PCL-b-PEG-Fol) as targeted gene delivery system using a modular synthesis approach including "click" conjugation of folate moieties with heterobifunctional PEG-b-PCL at PEG terminus and subsequently the introduction of PEI by a Michael addition between folate-PEG-b-PCL and PEI via active PCL terminus. This well-controlled synthetic procedure avoids tedious separation of byproduct. The structure of PEI-g-PCL-b-PEG-Fol was confirmed by (1)H NMR and UV spectra. DNA condensation of PEI-g-PCL-b-PEG-Fol was tested using a SYBR Gold quenching assay and agarose gel electrophoresis upon heparin competition assay. Although PEI-g-PCL-b-PEG-Fol could condense DNA completely at N/P ratio >2, polyplexes of N/P ratio 10 with sizes of about 120 nm and positive zeta potentials were selected for further biological evaluations due to polyplex stability. An enhancement of cellular uptake of PEI-g-PCL-b-PEG-Fol/pDNA polyplexes was observed in FR overexpressing KB cells in comparison to unmodified PEI-g-PCL-b-PEG, through flow cytometry analysis and confocal laser scanning imaging. Importantly, this enhanced cellular uptake could be inhibited by free folic acid and did not occur in FR-negative A549 cells, demonstrating specific cell uptake by FR-mediated endocytosis. Furthermore, the transfection efficiency of PEI-g-PCL-b-PEG-Fol/pDNA polyplexes was increased approximately 14-fold in comparison to folate-negative polyplexes. Therefore, the PEI-g-PCL-b-PEG-Fol merits further investigation under in vivo conditions for targeting FR overexpressing tumors.
  Bioconjugate Chemistry 05/2012; · 4.93 Impact Factor
• Article: Biphasic regulation of P-glycoprotein function and expression by NO donors in Caco-2 cells.

  Ru Duan, Nan Hu, Hai-yan Liu, Jia Li, Hai-fang Guo, Can Liu, Li Liu, Xiao-dong Liu
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  ABSTRACT: To investigate the effects of nitric oxide (NO) donors on the function and expression of P-glycoprotein (P-gp) in Caco-2 cells. Caco-2 cells were exposed to NO donors for designated times. P-gp function and expression were assessed using Rhodamine123 uptake assay and Western blotting, respectively. Intracellular reactive oxygen species (iROS) and intracellular reactive nitrogen species (iRNS) levels were measured using ROS and RNS assay kits, respectively. Exposure of Caco-2 cells to 0.1 or 2 mmol/L of sodium nitroprusside (SNP) affected the function and expression of P-gp in concentration- and time-dependent manners. A short-term (4 h) exposure reduced P-gp function and expression accompanied with significantly increased levels of iROS and iRNS. In contrast, a long-term (24 h) exposure stimulated the P-gp function and expression. The stimulatory effects of 2 mmol/L SNP was less profound as compared to those caused by 0.1 mmol/L SNP. The other NO donors SIN-1 and SNAP showed similar effects. Neither the NO scavenger PTIO (2 mmol/L) nor soluble guanylate cyclase inhibitor ODQ (50 μmol/L) reversed the SNP-induced alteration of P-gp function. On the other hand, free radical scavengers ascorbate, glutathione and uric acid (2 mmol/L for each), PKC inhibitor chelerythrine (5 μmol/L), PI3K/Akt inhibitor wortmannin (1 μmol/L) and p38 MAPK inhibitor SB203580 (10 μmol/L) reversed the upregulation of P-gp function by the long-term exposure to SNP, but these agents had no effect on the impaired P-gp function following the short-term exposure to SNP. NO donors time-dependently regulate P-gp function and expression in Caco-2 cells: short-term exposure impairs P-gp function and expression, whereas long-term exposure stimulates P-gp function and expression. The regulation occurs via a NO-independent mechanism.
  Acta Pharmacologica Sinica 04/2012; 33(6):767-74. · 1.95 Impact Factor
• Article: Phases of the infinite U Hubbard model on square lattices.

  Li Liu, Hong Yao, Erez Berg, Steven R White, Steven A Kivelson
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  ABSTRACT: We apply the density matrix renormalization group to study the phase diagram of the infinite U Hubbard model on 2- to 6-leg ladders. Where the results are largely insensitive to the ladder width, we consider the results representative of the 2D square lattice. We find a fully polarized ferromagnetic Fermi liquid phase when n, the density of electrons per site, is in the range 1>n≳0.800. For n=3/4 we find an unexpected insulating checkerboard phase with coexisting bond-density order with 4 sites per unit cell and block-spin antiferromagnetic order with 8 sites per unit cell. For 3/4>n, all ladders with width >2 have unpolarized ground states.
  Physical Review Letters 03/2012; 108(12):126406. · 7.37 Impact Factor
• Article: A genetic variant in 3'-untranslated region of cyclooxygenases-2 gene is associated with risk of gastric cancer in a Chinese population.

  Huizhang Li, Chuanli Ren, Zhining Fan, Guangfu Jin, Jiangbo Du, Li Liu, Chen Zhu, Feng Lu, Yanbing Ding, Bin Deng, Zhibin Hu, Yaochu Xu, Hongbing Shen
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  ABSTRACT: Cyclooxygenase-2 (COX-2) involves in multiple processes in carcinogenesis, including inflammation, apoptosis inhibition, immune response suppression, tumor cell invasion, and angiogenesis. COX-2 is overexpressed in various cancers, including gastric cancer. COX-2 is encoded by prostaglandin endoperoxide synthase 2 (PTGS2) gene. We hypothesized that potentially functional polymorphisms in PTGS2 may contribute to gastric cancer risk. To assess this hypothesis, we conducted a case-control study with 1681 gastric cancer cases and 1916 control subjects in a Chinese population to evaluate the association between a polymorphism in 3'-untranslated region of PTGS2, rs5275, and the risk of gastric cancer. Logistic regression analysis revealed that variant allele (C) of rs5275 was significantly associated with an increased risk of gastric cancer (per allele odds ratio [OR] = 1.14, 95% confidence interval [CI] = 1.01-1.29, p = 0.030). This association was more prominent in females (per allele OR = 1.42, 95% CI = 1.11-1.81, p = 0.005) and nonsmokers (per allele OR = 1.35, 95% CI = 1.14-1.59, p = 0.001). Interestingly, we detected a negative interaction between rs5275 and smoking on the gastric cancer risk (p = 0.007). Our findings indicate that PTGS2 rs5275T/C may be a candidate genetic marker for gastric cancer susceptibility.
  DNA and cell biology 03/2012; 31(7):1252-7. · 2.28 Impact Factor
• Article: Excess body mass index and risk of liver cancer: a nonlinear dose-response meta-analysis of prospective studies.

  Rui Rui, Jiao Lou, Li Zou, Rong Zhong, Ji Wang, Ding Xia, Qi Wang, Heng Li, Jing Wu, Xuzai Lu, Chuanqi Li, Li Liu, Jiahong Xia, Hua Xu
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  ABSTRACT: Excess body weight measured as body mass index (BMI) has a positive association with risk of common cancers. However, previous meta-analyses related to BMI and liver cancer had inconsistent results. The purpose of the current study is to establish a nonlinear dose-response relationship between BMI and incidence risk of liver cancer. A systematic literature search for relevant articles published from 1966 to November 2011 was conducted in PUBMED and EMBASE digital databases. Additional articles were manually searched by using the reference lists of identified papers. Restricted cubic splines and generalized least-squares regression methods were used to model a potential curvilinear relationship and to make a dose-response meta-analysis. Stratified analysis, sensitivity analysis and assessment of bias were performed in our meta-analysis. 8 articles including 1,779,471 cohort individuals were brought into meta-analysis. A non-linear dose-response association between BMI and risk of liver cancer was visually significant (P for nonlinearity<0.001), besides, the point value of BMI also enhanced the results quantitatively, where relative risks were 1.02 (95%CI = 1.02-1.03), 1.35 (95%CI = 1.24-1.47) and 2.22-fold (95%CI = 1.74-2.83) when BMI was at the point of 25, 30 and 35 kg/m(2) compared with reference (the median value of the lowest category), respectively. The ethnicity of the population was found as the main source of heterogeneity. In subsequent stratified analysis, no evidence of heterogeneity was showed in Asian and White populations (P for heterogeneity>0.1), and all value of BMI still presented significantly increased risk of cancer. The findings from meta-analysis provided that excess BMI had significant increased association with risk of liver cancer, although the biological mechanisms underlying the obesity-cancer link still need to be clarified.
  PLoS ONE 01/2012; 7(9):e44522. · 4.09 Impact Factor
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  Available from: PubMed Central

  Article: A genetic variant in the promoter region of miR-106b-25 cluster and risk of HBV infection and hepatocellular carcinoma.

  Yao Liu, Yixin Zhang, Juan Wen, Li Liu, Xiangjun Zhai, Jibin Liu, Shandong Pan, Jianguo Chen, Hongbing Shen, Zhibin Hu
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  ABSTRACT: MiR-106b-25 cluster, hosted in intron 13 of MCM7, may play integral roles in diverse processes including immune response and tumorigenesis. A single nucleotide polymorphism (SNP), rs999885, is located in the promoter region of MCM7. We performed a case-control study including 1300 HBV-positive hepatocellular carcinoma (HCC) cases, 1344 HBV persistent carriers and 1344 subjects with HBV natural clearance to test the association between rs999885 and the risk of HBV persistent infection and HCC. We also investigated the genotype-expression correlation between rs999885 and miR-106b-25 cluster in 25 pairs of HCC and adjacent non-tumor liver tissues. Compared with the HBV natural clearance subjects carrying rs999885 AA genotype, those with AG/GG genotypes had a decreased risk of chronic HBV infection with an adjusted odds ratio (OR) of 0.79 [95% confidence intervals (CIs) = 0.67-0.93]. However, the AG/GG genotypes were significantly associated with an increased HCC risk in HBV persistent carriers (adjusted OR = 1.25, 95% CIs = 1.06-1.47). Expression analysis revealed that the expression level of miR-106b-25 cluster was significantly higher in AG/GG carriers than those in AA carriers in non-tumor liver tissues. These findings indicate that the A to G base change of rs999885 may provide a protective effect against chronic HBV infection but an increased risk for HCC in HBV persistent carriers by altering the expression of the miR-106b-25 cluster.
  PLoS ONE 01/2012; 7(2):e32230. · 4.09 Impact Factor