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Articles by Z Hu
Total Records ( 12 ) for Z Hu
  H Fu , Z Hu , J Wen , K Wang and Y. Liu
 

Transforming growth factor-β (TGF-β) is involved in actin cytoskeleton reorganization and tumor progression. Fascin1, an actin-binding protein, increases cell invasiveness and motility in various transformed cells. To determine whether fascin1 is an important mediator of the tumor response to TGF-β, we applied the small interfering RNA (siRNA) technique to silence fascin1 in gastric cancer (GC) cells MKN45. Results showed that the effects of TGF-β1 on GC cells invasion and metastasis were mediated by tumor production of fascin1; furthermore, it was found that TGF-β1-induced fascin1 expression was suppressed by the specific inhibitors of JNK and ERK pathways, SP6001125 and PD98059, respectively, but not by transient transfection of Smad2 and Smad4 siRNA. Our data for the first time demonstrated that fascin1 is an important mediator of TGF-β1-induced invasion and metastasis of GC cells, which involves JNK and ERK signaling pathways.

  L Zhang , Z Hu , C Zhu , Q Liu , Y Zhou and Y. Zhang
 

Carboxylesterases (CEs) represent a multigene family of serine-dependent enzymes. Male-dependent CEs are over-expressed in the male reproductive tract of different animal species (bivalve mollusks, fruit-flies, and mammals). Here, a novel rat epididymis-specific gene named Ces7 was cloned and characterized. It was a novel member of CE family, which was mainly expressed and secreted to the lumens of the corpus and cauda epididymis. CES7 protein was highly glycosylated as other mammalian CEs. Furthermore, Ces7 increased with age growth until sex maturation and then maintained at high level. CES7 might be one of the major CEs in male reproductive tract and contribute to the sperm fertilization.

  Z Hu , D. A Follmann and J. Qin
 

Model misspecification can be a concern for high-dimensional data. Nonparametric regression obviates model specification but is impeded by the curse of dimensionality. This paper focuses on the estimation of the marginal mean response when there is missingness in the response and multiple covariates are available. We propose estimating the mean response through nonparametric functional estimation, where the dimension is reduced by a parametric working index. The proposed semiparametric estimator is robust to model misspecification: it is consistent for any working index if the missing mechanism of the response is known or correctly specified up to unknown parameters; even with misspecification in the missing mechanism, it is consistent so long as the working index can recover E(Y | X), the conditional mean response given the covariates. In addition, when the missing mechanism is correctly specified, the semiparametric estimator attains the optimal efficiency if E(Y | X) is recoverable through the working index. Robustness and efficiency of the proposed estimator is further investigated by simulations. We apply the proposed method to a clinical trial for HIV.

  C Wu , Z Hu , D Yu , L Huang , G Jin , J Liang , H Guo , W Tan , M Zhang , J Qian , D Lu , T Wu , D Lin and H. Shen
 

Recent three genome-wide association studies have mapped a lung cancer susceptibility locus to chromosome 15q25 in Caucasians. However, the reported risk single nucleotide polymorphisms (SNPs) are extremely rare in Asians, arguing against any of these being causative variants. This study sought to identify other variants on 15q25 associated with lung cancer susceptibility in Chinese. Two-stage case-control studies were conducted in subjects derived from both Northern and Southern China. The first-stage, consisting of 576 cases and 576 controls, was to discover novel risk variants using a haplotype-tagging SNP approach, and these variants were then replicated in the second-stage, consisting of 2,989 cases and 2,880 controls. Associations were estimated by logistic regression models, and function of the variants was examined by biochemical assays. We found that the three risk SNPs reported in Caucasians were not associated with lung cancer risk in Chinese. However, we identified four novel SNPs (rs2036534C>T, rs667282C>T, rs12910984G>A, and rs6495309T>C) that were associated with significantly increased lung cancer risk and smoking behavior, which were all confirmed in the replication analyses [odds ratios (95% confidence intervals) in the dominant model: 1.39 (1.23–1.57; P = 2.3 x 10–7), 1.52 (1.35–1.71; P = 2.0 x 10–12), 1.44 (1.28–1.63; P = 2.7 x 10–9), and 1.43 (1.27–1.61; P = 2.6 x 10–9), respectively]. We characterized the rs6495309T>C change in the CHRNA3 promoter as a functional variant because it affected the Oct-1 binding ability, resulting in increased CHRNA3 expression. These results support 15q25 as a susceptibility region for lung cancer in Chinese but underscore the difference in genetic markers among different ethnic populations. [Cancer Res 2009;69(12):5065–72]

  G Jin , L Xu , Y Shu , T Tian , J Liang , Y Xu , F Wang , J Chen , J Dai , Z Hu and H. Shen
 

Chromosome 5p15.33, containing TERT and CLPTM1L genes, was recently identified as one of the susceptible regions for lung cancer in Caucasian populations. We hypothesized that single-nucleotide polymorphisms (SNPs) identified in this region in Caucasians are also important in the development of lung cancer in Chinese population. To test this hypothesis, we genotyped two most significant SNPs reported in Caucasians, rs2736100A/C and rs402710C/T at 5p15.33, in a case–control study with 1221 non-small cell lung cancer (NSCLC) cases and 1344 cancer-free controls in a Chinese population. We found that rs2736100C allele in TERT gene was associated with a significantly increased risk of NSCLC with adjusted odds ratios of 1.26 [95% confidence interval (CI) = 1.05–1.51] and 1.31 (95% CI = 1.04–1.66) for one or two copies of the variant C allele, respectively. This significant association was more prominent among female (P for heterogeneity: 0.044), non-smokers (P for heterogeneity: 0.054) and/or the subjects with adenocarcinoma (P for heterogeneity: 0.058). However, no significant association was found between rs402710C/T and NSCLC risk. These results suggest that genetic variants in 5p15.33, especially in TERT gene, may also predispose the susceptibility of lung cancer, especially adenocarcinoma, in Chinese population.

  J Lu , Z Hu , S Wei , L. E Wang , A. K El Naggar , E. M Sturgis and Q. Wei
 

PIN1, a new peptidyl-prolyl cis/trans isomerase, regulates the conformation of Pro-directed phosphorylation sites, revealing a new postphosphorylation regulatory mechanism. PIN1-induced conformational changes potentiate multiple oncogenic signaling pathways, and PIN1 overexpression is reported as a prevalent and specific event in human cancers. In this study, we tested the hypothesis that common polymorphisms in the coding and promoter regions of PIN1 are associated with risk of squamous cell carcinoma of the head and neck (SCCHN). We genotyped three selected PIN1 polymorphisms (–842G>C, –667T>C and Gln33Gln) in a hospital-based case–control study of 1006 patients with SCCHN and 1007 cancer-free control subjects. We found that the –842C variant genotypes were associated with decreased risk for SCCHN [Odds Ratio (OR) = 0.74; 95% confidence interval (CI) = 0.59–0.93 for the CG genotype, OR = 0.82; 95% CI = 0.34–2.01 for the CC genotype and OR = 0.74; 95% CI = 0.59–0.93 for CG+CC genotypes, compared with the GG genotype]. However, no altered risks were observed for –667T>C and Gln33Gln polymorphisms. Further experiments of the reporter gene expression driven by the allelic PIN1 promoter showed that the –842G allele had a higher activity than that driven by the –842C allele, suggesting that the –842C allele was associated with a reduced transcriptional activity, a finding consistent with a reduced risk observed in the case–control analysis. Large prospective studies of diverse ethnic groups and diverse cancer sites are warranted to validate our findings.

  Z Hu , X Li , X Qu , Y He , B. Z Ring , E Song and L. Su
 

A few genetic polymorphisms of TP53 are known to have a significant effect on cancer susceptibility. Intron 3 16 bp duplication polymorphism of TP53 has been reported to be associated with breast cancer, colorectal cancer, lung cancer and other cancers, but the reported results remain inconclusive. The present study, a meta-analysis including a total of 9801 cases and 10 391 controls from 26 studies, revealed that the 16 bp insertion (Ins) allele is significantly associated with an increased cancer risk in overall analysis [Ins/Ins + deletion (Del)/Ins versus Del/Del: odds ratio (OR) = 1.14, 95% confidence interval (CI) = 1.02–1.27, P = 0.02; Ins/Ins versus Del/Del: OR = 1.35, 95% CI = 1.11–1.63, P = 0.002; Del/Ins versus Del/Del: OR = 1.10, 95% CI = 0.98–1.23, P = 0.11.), particularly in breast cancer subgroup (Ins/Ins + Del/Ins versus Del/Del: OR = 1.16, 95% CI = 1.03–1.31, P = 0.02; Ins/Ins versus Del/Del: OR = 1.81, 95% CI = 1.30–2.52, P < 0.001; Del/Ins versus Del/Del: OR = 1.10, 95% CI = 0.97–1.25, P = 0.13). The relative risks to the colorectal and lung cancers increased but their association power was relatively weak, which may result from a limited number of studies of these two cancer types. These results suggest that intron 3 16 bp duplication polymorphism of TP53 is potentially an important and clinically relevant genetic marker contributing to cancer susceptibility.

  S Zhang , J Lu , X Zhao , W Wu , H Wang , Q Wu , X Chen , W Fan , H Chen , F Wang , Z Hu , L Jin , Q Wei , H Shen , W Huang and D. Lu
 

Checkpoint kinase (CHEK) 2, a tumor suppressor gene, plays an essential role in the DNA damage checkpoint response cascade. We first investigated two polymorphisms in the proximal promoter of the CHEK2 gene and evaluated their associations with the risk of lung cancer in a case–control study using 500 incident lung cancer cases and 517 cancer-free controls. We found that CHEK2 rs2236141 –48 G > A was significantly associated with lung cancer risk (P = 0.0018). Similar results were obtained in a follow-up replication study in 575 lung cancer patients and 589 controls (P = 0.042). Quantitative polymerase chain reaction showed that individuals with the G allele had lower levels of CHEK2 transcripts in peripheral blood mononuclear cells and normal lung tissues. The –48 G->A variant eliminated a methylation site and thereby relieve the transcriptional repression of CHEK2. Therefore, this polymorphism affected downstream transcription through genetic and epigenetic modifications. Luciferase reporter assays demonstrated that the major G allele significantly attenuated reporter gene expression when methylated. Electrophoretic Mobility shift assays and surface plasmon resonance revealed that the methylated G allele increased transcription factor accessibility. We used in vivo chromatin immunoprecipitation to confirm that the relevant transcription factor was Sp1. Using lung tissue heterozygous for the G/A single-nucleotide polymorphism, we found that Sp1 acted as a repressor and had a stronger binding affinity for the G allele. These results support our hypothesis that the CHEK2 rs2236141 variant modifies lung cancer susceptibility in the Chinese population by affecting CHEK2 expression.

  X. M Li , Z Hu , M. L Jorgenson and W. B. Slayton
 

Background— The bone marrow contains a variety of blood vessels that have different functions in bone marrow maintenance and hematopoiesis. Arterioles control the flow of blood into bone marrow compartments, and sinusoids serve as a conduit to the bloodstream and as niches for megakaryocyte development. Most studies of bone marrow vasculature, including studies quantifying changes in the marrow vascular by microvascular density, do not differentiate between different types of marrow vessels. Recognizing changes in different types of blood vessels after chemotherapy exposure or during leukemia development has important physiological implications. We hypothesized that the functional heterogeneity of marrow vasculature could be recognized through the use of functional markers such as tyrosine kinase with immunoglobulin and epidermal growth factor homology domains-2 (Tie2) expression or 1,1-dioctadecyl -3,3,3,3-tetramethyl-indocarbocyanine perchlorate with acetylated low-density lipoprotein (DiI-Ac-LDL) uptake.

Methods and Results— When transgenic mice with green fluorescent protein (GFP) expressed downstream of the Tie2 promoter were injected with Ac-LDL, Ac-LDL was specifically endocytosed by sinusoids, and Tie2 expression was more pronounced in the arteries, arterioles, and transitional capillaries. Combining these 2 functional endothelial markers and using confocal microscopy to obtain 3-dimensional images, we identified transitional zones where arterioles emptied into the sinusoids. Alternatively, coinjection of lectin with DiI-Ac-LDL has a similar result in normal mice, as seen in Tie2/GFP mice, and can be used to differentiate vessel types in nontransgenic mice.

Conclusions— These results demonstrate that bone marrow vasculature is functionally heterogeneous. Methods to study changes in the marrow vasculature using microvascular density or quantifying changes in the vascular niche need to take this heterogeneity into account.

  C Zhang , C Wang , X Chen , C Yang , K Li , J Wang , J Dai , Z Hu , X Zhou , L Chen , Y Zhang , Y Li , H Qiu , J Xing , Z Liang , B Ren , K Zen and C. Y. Zhang
  BACKGROUND:

Sensitive and specific biomarkers for the early detection of esophageal squamous cell carcinoma (ESCC) are urgently needed to reduce the high morbidity and mortality of the disease. The discovery of serum microRNAs (miRNAs) and their unique concentration profiles in patients with various diseases makes them attractive, novel noninvasive biomarkers for tumor diagnosis. In this study, we investigated the serum miRNA profile in ESCC patients to develop a novel diagnostic ESCC biomarker.

METHODS:

Serum samples were taken from 290 ESCC patients and 140 age- and sex-matched controls. Solexa sequencing technology was used for an initial screen of miRNAs in serum samples from 141 patients and 40 controls. A hydrolysis probe–based stem–loop quantitative reverse-transcription PCR (RT-qPCR) assay was conducted in the training and verification phases to confirm the concentrations of selected miRNAs in serum samples from 149 patients and 100 controls.

RESULTS:

The Solexa sequencing results demonstrated marked upregulation of 25 serum miRNAs in ESCC patients compared with controls. RT-qPCR analysis identified a profile of 7 serum miRNAs (miR-10a, miR-22, miR-100, miR-148b, miR-223, miR-133a, and miR-127-3p) as ESCC biomarkers. The area under the ROC curve for the selected miRNAs ranged from 0.817 to 0.949, significantly higher than for carcinoembryonic antigen (0.549; P < 0.0005). More importantly, this panel of 7 miRNAs clearly distinguished stage I/II ESCC patients from controls.

CONCLUSIONS:

This panel of 7 serum miRNAs holds promise as a novel blood-based biomarker for the diagnosis of ESCC.

  Z Hu , D Dandekar , P. J O'Shaughnessy , K De Gendt , G Verhoeven and M. F. Wilkinson
 

Rhox5, the founding member of the reproductive homeobox on the X chromosome (Rhox) gene cluster, encodes a homeodomain-containing transcription factor that is selectively expressed in Sertoli cells, where it promotes the survival of male germ cells. To identify Rhox5-regulated genes, we generated 15P-1 Sertoli cell clones expressing physiological levels of Rhox5 from a stably transfected expression vector. Microarray analysis identified many genes altered in expression in response to Rhox5, including those encoding proteins controlling cell cycle regulation, apoptosis, metabolism, and cell-cell interactions. Fifteen of these Rhox5-regulated genes were chosen for further analysis. Analysis of Rhox5-null male mice indicated that at least nine of these are Rhox5-regulated in the testes in vivo. Many of them have distinct postnatal expression patterns and are regulated by Rhox5 at different postnatal time points. Most of them are expressed in Sertoli cells, indicating that they are candidates to be directly regulated by Rhox5. Transfection analysis with expression vectors encoding different mouse and human Rhox family members revealed that the regulatory response of a subset of these Rhox5-regulated genes is both conserved and redundant. Given that Rhox5 depends on androgen receptor (AR) for expression in Sertoli cells, we examined whether some Rhox5-regulated genes are also regulated by AR. We provide several lines of evidence that this is the case, leading us to propose that RHOX5 serves as a key intermediate transcription factor that directs some of the actions of AR in the testes.

  Z Hu , S Gulec and J. F. Collins
 

Molecular mechanisms mediating the induction of metal ion homeostasis-related genes in the mammalian intestine during iron deficiency remain unknown. To elucidate relevant regulatory pathways, genomewide gene expression profiles were determined in fully differentiated human intestinal epithelial (Caco-2) cells. Cells were deprived of iron (or not) for 6 or 18 h, and Gene Chip analyses were subsequently performed (Affymetrix). More than 2,000 genes were differentially expressed; genes related to monosaccharide metabolism, regulation of gene expression, hypoxia, and cell death were upregulated, while those related to mitotic cell cycle were downregulated. A large proportion of induced genes are hypoxia responsive, and promoter enrichment analyses revealed a statistical overrepresentation of hypoxia response elements (HREs). Immunoblot experiments demonstrated a >60-fold increase in HIF2 protein abundance in iron-deprived cells; HIF1 levels were unchanged. Furthermore, comparison of the Caco-2 cell data set with a Gene Chip data set from iron-deficient rat intestine revealed 29 common upregulated genes; the majority are hypoxia responsive, and their promoters are enriched for HREs. We conclude that the compensatory response of the intestinal epithelium to iron deprivation relates to hypoxia and that stabilization of HIF2 may be the primary event mediating metabolic and morphological changes observed during iron deficiency.

 
 
 
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