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1.  An Analysis of HLA-A, -B, and -DRB1 Allele and Haplotype Frequencies of 21,918 Residents Living in Liaoning, China 
PLoS ONE  2014;9(4):e93082.
HLA-A, -B and -DRB1 allele frequencies and their haplotype frequencies in 21,918 Chinese residents living in Liaoning Province, who were registered as volunteer donors of China Marrow Donor Registry, were investigated. They are composed of 93.37% Han Chinese, 5.1% Manchus, 0.57% Mongols, 0.46% Hui persons, 0.29% Koreans and 0.14% Xibe ethnic group. In total eighteen different HLA-A alleles, forty-eight different HLA-B alleles and fourteen different HLA-DRB1 alleles have been identified. Their frequencies are in agreement with the Hardy-Weinberg equilibrium. For Han Chinese in Liaoning, 1,534 different HLA-A-B-DRB1 haplotypes were identified, with a frequency of higher than 0.01%. A*30-B*13-DRB1*07, A*02-B*46-DRB1*09 and A*02-B*13-DRB1*12 are the most frequent haplotypes among Liaoning Han. While Liaoning Han, Liaoning Manchu, Liaoning Mongol, Liaoning Hui and Liaoning Korean share the northern Han characteristic haplotypes, all minority ethnic groups with the exception of Liaoning Manchu have developed their own unique HLA profiles. This dataset characterizes the HLA allele and haplotype frequencies in the Liaoning area and suggests that it is different from those in other parts of China and ethnic groups, which implicates transplant donor searching strategies and studies on population genetics.
doi:10.1371/journal.pone.0093082
PMCID: PMC3972227  PMID: 24691290
2.  Revisiting the Al/Al2O3 Interface: Coherent Interfaces and Misfit Accommodation 
Scientific Reports  2014;4:4485.
We study the coherent and semi-coherent Al/α-Al2O3 interfaces using molecular dynamics simulations with a mixed, metallic-ionic atomistic model. For the coherent interfaces, both Al-terminated and O-terminated nonstoichiometric interfaces have been studied and their relative stability has been established. To understand the misfit accommodation at the semi-coherent interface, a 1-dimensional (1D) misfit dislocation model and a 2-dimensional (2D) dislocation network model have been studied. For the latter case, our analysis reveals an interface dislocation structure with a network of three sets of parallel dislocations, each with pure-edge character, giving rise to a pattern of coherent and stacking-fault-like regions at the interface. Structural relaxation at elevated temperatures leads to a further change of the dislocation pattern, which can be understood in terms of a competition between the stacking fault energy and the dislocation interaction energy at the interface. Our results are expected to serve as an input for the subsequent dislocation dynamics models to understand and predict the macroscopic mechanical behavior of Al/α-Al2O3 composite heterostructures.
doi:10.1038/srep04485
PMCID: PMC3967201  PMID: 24670940
3.  Comparative Proteomic Analysis of Differential Responses of Pinus massoniana and Taxus wallichiana var. mairei to Simulated Acid Rain 
Acid rain (AR), a serious environmental issue, severely affects plant growth and development. As the gymnosperms of conifer woody plants, Pinus massoniana (AR-sensitive) and Taxus wallichiana var. mairei (AR-resistant) are widely distributed in southern China. Under AR stress, significant necrosis and collapsed lesions were found in P. massoniana needles with remarkable yellowing and wilting tips, whereas T. wallichiana var. mairei did not exhibit chlorosis and visible damage. Due to the activation of a large number of stress-related genes and the synthesis of various functional proteins to counteract AR stress, it is important to study the differences in AR-tolerance mechanisms by comparative proteomic analysis of tolerant and sensitive species. This study revealed a total of 65 and 26 differentially expressed proteins that were identified in P. massoniana and T. wallichiana var. mairei, respectively. Among them, proteins involved in metabolism, photosynthesis, signal transduction and transcription were drastically down-regulated in P. massoniana, whereas most of the proteins participating in metabolism, cell structure, photosynthesis and transcription were increased in T. wallichiana var. mairei. These results suggest the distinct patterns of protein expression in the two woody species in response to AR, allowing a deeper understanding of diversity on AR tolerance in forest tree species.
doi:10.3390/ijms15034333
PMCID: PMC3975401  PMID: 24625662
acid rain tolerance; proteomic; Pinus massoniana; stress response; Taxus wallichiana var. mairei; woody plant
4.  Cellular RNA helicases and HIV-1: Insights from genome-wide, proteomic, and molecular studies 
Virus research  2012;171(2):357-365.
RNA helicases are ubiquitous in plants and animals and function in many cellular processes. Retroviruses, such as human immunodeficiency virus (HIV-1), encode no RNA helicases in their genomes and utilize host cellular RNA helicases at various stages of their life cycle. Here, we briefly summarize the roles RNA helicases play in HIV-1 replication that have been identified recently, in part, through genome-wide screenings, proteomics, and molecular studies. Some of these helicases augment virus propagation while others apparently participate in antiviral defenses against viral replication.
doi:10.1016/j.virusres.2012.06.022
PMCID: PMC3493675  PMID: 22814432
RNA helicases; Human Immunodeficiency virus type 1 (HIV-1); DEAD-Box domain; antiviral
5.  Hard Tick Factors Implicated in Pathogen Transmission 
Ticks are the most common arthropod vector, after mosquitoes, and are capable of transmitting the greatest variety of pathogens. For both humans and animals, the worldwide emergence or re-emergence of tick-borne disease is becoming increasingly problematic. Despite being such an important issue, our knowledge of pathogen transmission by ticks is incomplete. Several recent studies, reviewed here, have reported that the expression of some tick factors can be modulated in response to pathogen infection, and that some of these factors can impact on the pathogenic life cycle. Delineating the specific tick factors required for tick-borne pathogen transmission should lead to new strategies in the disruption of pathogen life cycles to combat emerging tick-borne disease.
doi:10.1371/journal.pntd.0002566
PMCID: PMC3907338  PMID: 24498444
6.  Identification of RNA silencing components in soybean and sorghum 
BMC Bioinformatics  2014;15:4.
Background
RNA silencing is a process triggered by 21–24 small RNAs to repress gene expression. Many organisms including plants use RNA silencing to regulate development and physiology, and to maintain genome stability. Plants possess two classes of small RNAs: microRNAs (miRNAs) and small interfering RNAs (siRNAs). The frameworks of miRNA and siRNA pathways have been established in the model plant, Arabidopsis thaliana (Arabidopsis).
Results
Here we report the identification of putative genes that are required for the generation and function of miRNAs and siRNAs in soybean and sorghum, based on knowledge obtained from Arabidopsis. The gene families, including DCL, HEN1, SE, HYL1, HST, RDR, NRPD1, NRPD2/NRPE2, NRPE1, and AGO, were analyzed for gene structures, phylogenetic relationships, and protein motifs. The gene expression was validated using RNA-seq, expressed sequence tags (EST), and reverse transcription PCR (RT-PCR).
Conclusions
The identification of these components could provide not only insight into RNA silencing mechanism in soybean and sorghum but also basis for further investigation. All data are available at http://sysbio.unl.edu/.
doi:10.1186/1471-2105-15-4
PMCID: PMC3882329  PMID: 24387046
7.  Elevated MicroRNA-31 Expression Regulates Colorectal Cancer Progression by Repressing Its Target Gene SATB2 
PLoS ONE  2013;8(12):e85353.
Several studies have brought about increasing evidence to support the hypothesis that miRNAs play a pivotal role in multiple processes of carcinogenesis, including cell growth, apoptosis, differentiation, and metastasis. In this study, we investigated the potential role of miR-31 in colorectal cancer (CRC) aggressiveness and its underlying mechanisms. We found that miR-31 increased in CRC cells originated from metastatic foci and human primary CRC tissues with lymph node metastases. Furthermore, the high-level expression of miR-31 was significantly associated with a more aggressive and poor prognostic phenotype of patients with CRC (p < 0.05). The stable over-expression of miR-31 in CRC cells was sufficient to promote cell proliferation, invasion, and migration in vitro. It facilitated tumor growth and metastasis in vivo too. Further studies showed that miR-31 can directly bind to the 3’untranslated region (3’UTR) of SATB2 mRNA and subsequently repress both the mRNA and protein expressions of SATB2. Ectopic expression of SATB2 by transiently transfected with pCAG-SATB2 vector encoding the entire SATB2 coding sequence could reverse the effects of miR-31 on CRC tumorigenesis and progression. In addition, ectopic over-expression of miR-31 in CRC cells induced epithelial-mesenchymal transition (EMT). Our results illustrated that the up-regulation of miR-31 played an important role in CRC cell proliferation, invasion, and metastasis in vitro and in vivo through direct repressing SATB2, suggesting a potential application of miR-31 in prognosis prediction and therapeutic application in CRC.
doi:10.1371/journal.pone.0085353
PMCID: PMC3875556  PMID: 24386467
8.  De novo Sequencing, Characterization, and Comparison of Inflorescence Transcriptomes of Cornus canadensis and C. florida (Cornaceae) 
PLoS ONE  2013;8(12):e82674.
Background
Transcriptome sequencing analysis is a powerful tool in molecular genetics and evolutionary biology. Here we report the results of de novo 454 sequencing, characterization, and comparison of inflorescence transcriptomes of two closely related dogwood species, Cornus canadensis and C. florida (Cornaceae). Our goals were to build a preliminary source of genome sequence data, and to identify genes potentially expressed differentially between the inflorescence transcriptomes for these important horticultural species.
Results
The sequencing of cDNAs from inflorescence buds of C. canadensis (cc) and C. florida (cf), and normalized cDNAs from leaves of C. canadensis resulted in 251799 (ccBud), 96245 (ccLeaf) and 114648 (cfBud) raw reads, respectively. The de novo assembly of the high quality (HQ) reads resulted in 36088, 17802 and 21210 unigenes for ccBud, ccLeaf and cfBud. A reference transcriptome for C. canadensis was built by assembling HQ reads of ccBud and ccLeaf, containing 40884 unigenes. Reference mapping and comparative analyses found 10926 sequences were putatively specific to ccBud, and 6979 putatively specific to cfBud. Putative differentially expressed genes between ccBud and cfBud that are related to flower development and/or stress response were identified among 7718 shared sequences by ccBud and cfBud. Bi-directional BLAST found 87 (41.83% of 208) of Arabidopsis genes related to inflorescence development had putative orthologs in the dogwood transcriptomes. Comparisons of the shared sequences by ccBud and cfBud yielded 65931 high quality SNPs between two species. The twenty unigenes with the most SNPs are listed as potential genetic markers for evolutionary studies.
Conclusions
The data provide an important, although preliminary, information platform for functional genomics and evolutionary developmental biology in Cornus. The study identified putative candidates potentially involved in the genetic regulation of inflorescence evolution and/or disease resistance in dogwoods for future analyses. Results of the study also provide markers useful for dogwood phylogenomic studies.
doi:10.1371/journal.pone.0082674
PMCID: PMC3873919  PMID: 24386108
9.  Structure-Guided Engineering of Lactococcus lactis Alcohol Dehydrogenase LlAdhA for Improved Conversion of Isobutyraldehyde to Isobutanol 
Journal of biotechnology  2012;164(2):188-195.
We have determined the X-ray crystal structures of the NADH-dependent alcohol dehydrogenase LlAdhA from Lactococcus lactis and its laboratory-evolved variant LlAdhARE1 at 1.9 Å and 2.5 Å resolution, respectively. LlAdhARE1, which contains three amino acid mutations (Y50F, I212T, and L264V), was engineered to increase the microbial production of isobutanol (2-methylpropan-1-ol) from isobutyraldehyde (2-methylpropanal). Structural comparison of LlAdhA and LlAdhARE1 indicates that the enhanced activity on isobutyraldehyde stems from increases in the protein’s active site size, hydrophobicity, and substrate access. Further structure-guided mutagenesis generated a quadruple mutant (Y50F/N110S/I212T/L264V), whose KM for isobutyraldehyde is ~17-fold lower and catalytic efficiency (kcat/KM) is ~160-fold higher than wild-type LlAdhA. Combining detailed structural information and directed evolution, we have achieved significant improvements in non-native alcohol dehydrogenase activity that will facilitate the production of next-generation fuels such as isobutanol from renewable resources.
doi:10.1016/j.jbiotec.2012.08.008
PMCID: PMC3542407  PMID: 22974724
Alcohol dehydrogenase; Crystal structure; Site-saturation mutagenesis; Directed evolution; Isobutyraldehyde; Biofuel
10.  Detection of Foot-and-mouth Disease Serotype O by ELISA Using a Monoclonal Antibody 
Hybridoma  2012;31(6):462-464.
An ELISA assay with monoclonal antibody (MELISA) was used to type serotype O of foot-and-mouth disease virus (FMDV). All FMDV serotype O reference strains were positive by MELISA, while other viruses such as FMDV serotypes Asia 1, C, A and classical swine fever virus, swine vesicular disease virus, and porcine reproductive and respiratory syndrome virus remained negative. Further, FMDV serotype O positive samples were able to be detected by MELISA. This assay may be particularly suitable for diagnosis of FMDV serotype O infection in field stations.
doi:10.1089/hyb.2012.0081
PMCID: PMC3526892  PMID: 23244327
11.  Polymorphisms of Genes in Neurotransmitter Systems Were Associated with Alcohol Use Disorders in a Tibetan Population 
PLoS ONE  2013;8(11):e80206.
Studies of linkage and association in various ethnic populations have revealed many predisposing genes of multiple neurotransmitter systems for alcohol use disorders (AUD). However, evidence often is contradictory regarding the contribution of most candidate genes to the susceptibility of AUD. We, therefore, performed a case-control study to investigate the possible associations of genes selected from multiple neurotransmitter systems with AUD in a homogeneous Tibetan community population in China. AUD cases (N = 281) with an alcohol use disorder identification test (AUDIT) score ≥10, as well as healthy controls (N = 277) with an AUDIT score ≤5, were recruited. All participants were genotyped for 366 single nucleotide polymorphisms (SNPs) of 34 genes selected from those involved in neurotransmitter systems. Association analyses were performed using PLINK version 1.07 software. Allelic analyses before adjustment for multiple tests showed that 15 polymorphisms within seven genes were associated with AUD (p<0.05). After adjustment for the number of SNPs genotyped within each gene, only the association of a single marker (rs10044881) in HTR4 remained statistically significant. Haplotype analysis for two SNPs in HTR4 (rs17777298 and rs10044881) showed that the haplotype AG was significantly associated with the protective effect for AUD. In conclusion, the present study discovered that the HTR4 gene may play a marked role in the pathogenesis of AUD. In addition, this Tibetan population sample marginally replicated previous evidence regarding the associations of six genes in AUD.
doi:10.1371/journal.pone.0080206
PMCID: PMC3842251  PMID: 24312204
12.  Association between GRIN3A Gene Polymorphism in Kawasaki Disease and Coronary Artery Aneurysms in Taiwanese Children 
PLoS ONE  2013;8(11):e81384.
Kawasaki disease (KD) is pediatric systemic vasculitis with the classic complication of coronary artery aneurysm (CAA). It is the leading cause of acquired cardiovascular diseases in children. Some severe cases present with multi-organ involvement or neurological dysfunction. To identify the role of the glutamate receptor, ionotropic, N-methyl-d-aspartate 3A (GRIN3A) in KD, we investigated genetic variations in GRIN3A in a Taiwanese cohort of 262 KD patients (76 with and 186 without CAA complications). We used univariate and multivariate regression analyses to identify the associations between clinical characteristics and GRIN3A genetic variations in KD. According to univariate regression analysis, CAA formation in KD was significantly associated with fever duration (p < 0.0001), first Intravenous immunoglobulin (IVIG) used (days after day one of fever) (p < 0.0001), and the GRIN3A (rs7849782) genetic variant (p < 0.001). KD patients with GG+GC genotype showed a lower rate of developing CAA (GG+GC genotype: odds ratio = 0.26; 95% CI = 0.14–0.46). Significant associations were identified between KD with CAA complication and the GRIN3A (rs7849782) genetic variant by using multivariate regression analysis. Specifically, significant correlations were observed between KD with CAA complications and the presence of GG+GC genotypes for the GRIN3A rs7849782 single-nucleotide polymorphism (full model: odds ratio = 0.25; 95% CI = 0.14–0.46). Our results suggest that a polymorphism of the GRIN3A gene may play a role in KD pathogenesis.
doi:10.1371/journal.pone.0081384
PMCID: PMC3838481  PMID: 24278430
13.  Aphid Feeding Activates Expression of a Transcriptome of Oxylipin-Based Defense Signals in Wheat Involved in Resistance to Herbivory 
Journal of chemical ecology  2010;36(3):10.1007/s10886-010-9756-8.
Damage by the Russian wheat aphid (RWA), Diuraphis noxia, significantly reduces wheat and barley yields worldwide. In compatible interactions, virulent RWA populations flourish and susceptible plants suffer extensive leaf chlorophyll loss. In incompatible interactions, RWA reproduction and population growth are significantly reduced and RWA-related chlorophyll loss in resistant plants is minor. The objectives of this study were to develop an understanding of the molecular and phytochemical bases of RWA resistance in plants containing the Dnx resistance gene. Microarray, real-time polymerase chain reaction, and phytohormone assays were conducted to identify transcriptome components unique to RWA-infested Dnx plants and susceptible (Dn0) plants, and to identify and characterize putative genes involved in Dnx plant defense responses. We found that RWA-infested Dnx plants upregulated > 180 genes related to reactive oxygen species, signaling, pathogen defense, and arthropod allelochemical and physical defense. The expression of several of these genes in RWA-infested Dnx plants increased significantly from 6- to 24-h post infestation (hpi), but their expression in Dn0 plants, when present, was delayed until 48- to 96 hpi. Concentrations of 16- and 18-carbon fatty acids, trans-methyl-12-oxophytodienoic acid, and abscisic acid were significantly greater in Dnx foliage than in Dn0 foliage after RWA infestation, suggesting that Dnx RWA defense and resistance genes may be regulated via the oxylipin pathway. These findings provide a foundation for the elucidation of the molecular basis for compatible- and incompatible plant-aphid interactions.
doi:10.1007/s10886-010-9756-8
PMCID: PMC3831272  PMID: 20229216
Diuraphis noxia; Insect; Microarray; Northern blot; Oxylipin signaling; Plant defense; Real-time polymerase chain reaction (PCR); Russian wheat aphid; Triticum aestivum; Wheat
14.  Acid ceramidase-mediated production of sphingosine 1-phosphate promotes prostate cancer invasion through up-regulation of cathepsin B 
Invasiveness is one of the key features of aggressive prostate cancer, however our understanding of the precise mechanisms effecting invasion remains limited. The ceramide hydrolyzing enzyme acid ceramidase (AC), overexpressed in most prostate tumors, causes an aggressive and invasive phenotype through downstream effectors that have not yet been well characterized. Here we demonstrate that AC, through generation of sphingosine-1-phosphate (S1P), promotes Ets1 nuclear expression and binding to the promoter region of matrix-degrading protease cathepsin B. Through confocal microscopy and flow cytometry, we found that AC overexpression promotes pericellular localization of cathepsin B and its translocation to the outer leaflet of the cell membrane. AC overexpressing cells have an increased abundance of cathepsin B-enriched invasive structures and enhanced ability to invade through a collagen matrix, but not in the presence of an inhibitor of cathepsin B. In human prostate tissues, AC and cathepsin B overexpression were strongly associated and may relate to poor cancer outcome. These results demonstrate a novel pathway by which AC, through S1P, promotes an invasive phenotype in prostate cancer by causing overexpression and secretion of cathepsin B through activation and nuclear expression of Ets1. As prostate cancer prognosis is dramatically worse when invasion has occurred, this study provides critical insight into the progression towards lethal prostate cancer.
doi:10.1002/ijc.27480
PMCID: PMC3384773  PMID: 22322590
Prostate cancer; acid ceramidase; cathepsin B; invasion; tumor metastasis
15.  Crystallization and preliminary X-ray study of the deaminase AmnE from Pseudomonas sp. AP-3. Corrigendum 
A correction is made to the article by Yu et al. (2013). Acta Cryst. F69, 812–814.
The article by Yu et al. (2013, Acta Cryst. F69, 812–814) is corrected.
doi:10.1107/S1744309113029321
PMCID: PMC3818065
AmnE; Pseudomonas sp. AP-3; corrigendum
16.  Fibroblast Growth Factor-1 (FGF-1) Loaded Microbeads Enhance Local Capillary Neovascularization 
The Journal of surgical research  2009;160(2):10.1016/j.jss.2009.06.003.
Background
Growth of new blood vessels (neovascularization) occurs naturally in the body, but the slow rate of the process may not be sufficient for survival of engineered tissues and transplanted cells, such as pancreatic islets. For transplanted islets, it is crucial that the transplantation site has sufficient vasculature to support the needs of the islets. Therefore, the specific aim of this research was quantify the effect of FGF-1 incorporation into alginate microbeads on neovascularization of such capsules in an in vivo rat transplant model.
Materials and Methods
Microbeads loaded with FGF-1 or control beads (beads without FGF-1) were implanted in the rat omental pouch model. Animals were sacrificed 7 d post-implantation.
Results
Microbeads loaded with FGF-1 stimulated a significant increase in vascular density compared with control rats implanted with control beads.
Conclusions
These results indicate that alginate microbeads loaded with FGF-1 enhance local neovascularization around implanted microbeads. These data provide a compelling impetus for experimental pursuit of FGF-loaded alginate microcapsules for vascularization of transplanted islets.
doi:10.1016/j.jss.2009.06.003
PMCID: PMC3810356  PMID: 19959194
alginate; FGF-1; protein delivery; neovascularization; microcapsules; cellular transplant
17.  MUC1 Regulates Expression of Multiple microRNAs Involved in Pancreatic Tumor Progression, Including the miR-200c/141 Cluster 
PLoS ONE  2013;8(10):e73306.
MUC1 is a transmembrane glycoprotein that modulates transcription via its cytoplasmic domain. We evaluated the capacity of MUC1 to regulate the global transcription of microRNAs in pancreatic cancer cells expressing MUC1. Results indicated that MUC1 regulated expression of at least 103 microRNAs. We evaluated further regulation of the microRNA transcript cluster miR-200c/141, which was among the most highly regulated microRNAs. We found that MUC1 directly interacted with ZEB1, a known transcriptional repressor of the miR-200c/141 cluster, at the promoter of miR-200c/141, and further reduced transcript production. These data indicate that signaling through MUC1 influences cancer progression by regulating transcription of microRNAs that are associated with the process of metastasis.
doi:10.1371/journal.pone.0073306
PMCID: PMC3797065  PMID: 24143167
18.  The long non-coding RNA HOTAIR indicates a poor prognosis and promotes metastasis in non-small cell lung cancer 
BMC Cancer  2013;13:464.
Background
The identification of cancer-associated long non-coding RNAs and the investigation of their molecular and biological functions are important for understanding the molecular biology and progression of cancer. HOTAIR (HOX transcript antisense intergenic RNA) has been implicated in several cancers; however, its role in non-small cell lung cancer (NSCLC) is unknown. The aim of the present study was to examine the expression pattern of HOTAIR in NSCLC and to evaluate its biological role and clinical significance in tumor progression.
Methods
Expression of HOTAIR was analyzed in 42 NSCLC tissues and four NSCLC cell lines by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Over-expression and RNA interference (RNAi) approaches were used to investigate the biological functions of HOTAIR. The effect of HOTAIR on proliferation was evaluated by MTT and colony formation assays, and cell migration and invasion were evaluated by transwell assays. Tail vein injection of cells was used to study metastasis in nude mice. Protein levels of HOTAIR targets were determined by western blot analysis. Differences between groups were tested for significance using Student’s t-test (two-tailed).
Results
HOTAIR was highly expressed both in NSCLC samples and cell lines compared with corresponding normal counterparts. HOTAIR upregulation was correlated with NSCLC advanced pathological stage and lymph-node metastasis. Moreover, patients with high levels of HOTAIR expression had a relatively poor prognosis. Inhibition of HOTAIR by RNAi decreased the migration and invasion of NSCLC cells in vitro and impeded cell metastasis in vivo. HOXA5 levels were affected by HOTAIR knockdown or over-expression in vitro.
Conclusions
Our findings indicate that HOTAIR is significantly up-regulated in NSCLC tissues, and regulates NSCLC cell invasion and metastasis, partially via the down-regulation of HOXA5. Thus, HOTAIR may represent a new marker of poor prognosis and is a potential therapeutic target for NSCLC intervention.
doi:10.1186/1471-2407-13-464
PMCID: PMC3851855  PMID: 24103700
Long non-coding RNA; HOTAIR; Non-small cell lung cancer; Prognosis; Metastasis
19.  Long non-coding RNA MEG3 inhibits NSCLC cells proliferation and induces apoptosis by affecting p53 expression 
BMC Cancer  2013;13:461.
Background
Long non-coding RNAs play an important role in tumorigenesis, hence, identification of cancer-associated lncRNAs and investigation of their biological functions and molecular mechanisms are important for understanding the development and progression of cancer. Recently, the downregulation of lncRNA MEG3 has been observed in various human cancers. However, its role in non-small cell lung cancer (NSCLC) is unknown. The aim of this study was to examine the expression pattern of MEG3 in NSCLC and to evaluate its biological role and clinical significance in tumor progression.
Methods
Expression of MEG3 was analyzed in 44 NSCLC tissues and 7 NSCLC cell lines by qRT-PCR. Over-expression approaches were used to investigate the biological functions of MEG3 in NSCLC cells. Bisulfite sequencing was used to investigate DNA methylation on MEG3 expression. The effect of MEG3 on proliferation was evaluated by MTT and colony formation assays, and cell apoptosis was evaluated by Hoechst staining and Flow-cytometric analysis. NSCLC cells transfected with pCDNA-MEG3 were injection into nude mice to study the effect of MEG3 on tumorigenesis in vivo . Protein levels of MEG3 targets were determined by western blot analysis. Differences between groups were tested for significance using Student’s t-test (two-tailed).
Results
MEG3 expression was decreased in non-small cell lung cancer (NSCLC) tumor tissues compared with normal tissues, and associated with advanced pathologic stage, and tumor size. Moreover, patients with lower levels of MEG3 expression had a relatively poor prognosis. Overexpression of MEG3 decreased NSCLC cells proliferation and induced apoptosis in vitro and impeded tumorigenesis in vivo. MDM2 and p53 protein levels were affected by MEG3 over-expression in vitro.
Conclusions
Our findings indicate that MEG3 is significantly down-regulated in NSCLC tissues that could be affected by DNA methylation, and regulates NSCLC cell proliferation and apoptosis, partially via the activition of p53. Thus, MEG3 may represent a new marker of poor prognosis and is a potential therapeutic target for NSCLC intervention.
doi:10.1186/1471-2407-13-461
PMCID: PMC3851462  PMID: 24098911
Long non-coding RNA; MEG3; NSCLC; Proliferation; p53
20.  Acid Ceramidase Promotes Nuclear Export of PTEN through Sphingosine 1-Phosphate Mediated Akt Signaling 
PLoS ONE  2013;8(10):e76593.
The tumor suppressor PTEN is now understood to regulate cellular processes at the cytoplasmic membrane, where it classically regulates PI3K signaling, as well as in the nucleus where multiple roles in controlling cell cycle and genome stability have been elucidated. Mechanisms that dictate nuclear import and, less extensively, nuclear export of PTEN have been described, however the relevance of these processes in disease states, particularly cancer, remain largely unknown. We investigated the impact of acid ceramidase on the nuclear-cytoplasmic trafficking of PTEN. Immunohistochemical analysis of a human prostate tissue microarray revealed that nuclear PTEN was lost in patients whose tumors had elevated acid ceramidase. We found that acid ceramidase promotes a reduction in nuclear PTEN that is dependent upon sphingosine 1-phosphate-mediated activation of Akt. We were further able to show that sphingosine 1-phosphate promotes formation of a complex between Crm1 and PTEN, and that leptomycin B prevents acid ceramidase and sphingosine 1-phosphate mediated loss of nuclear PTEN, suggesting an active exportin-mediated event. To investigate whether the tumor promoting aspects of acid ceramidase in prostate cancer depend upon its ability to export PTEN from the nucleus, we used enforced nuclear expression of PTEN to study docetaxel-induced apoptosis and cell killing, proliferation, and xenoengraftment. Interestingly, while acid ceramidase was able to protect cells expressing wild type PTEN from docetaxel, promote proliferation and xenoengraftment, acid ceramidase had no impact in cells expressing PTEN-NLS. These findings suggest that acid ceramidase, through sphingosine 1-phosphate, promotes nuclear export of PTEN as a means of promoting tumor formation, cell proliferation, and resistance to therapy.
doi:10.1371/journal.pone.0076593
PMCID: PMC3788144  PMID: 24098536
21.  Radiation-induced acid ceramidase confers prostate cancer resistance and tumor relapse 
The Journal of Clinical Investigation  2013;123(10):4344-4358.
Escape of prostate cancer (PCa) cells from ionizing radiation–induced (IR-induced) killing leads to disease progression and cancer relapse. The influence of sphingolipids, such as ceramide and its metabolite sphingosine 1-phosphate, on signal transduction pathways under cell stress is important to survival adaptation responses. In this study, we demonstrate that ceramide-deacylating enzyme acid ceramidase (AC) was preferentially upregulated in irradiated PCa cells. Radiation-induced AC gene transactivation by activator protein 1 (AP-1) binding on the proximal promoter was sensitive to inhibition of de novo ceramide biosynthesis, as demonstrated by promoter reporter and ChIP-qPCR analyses. Our data indicate that a protective feedback mechanism mitigates the apoptotic effect of IR-induced ceramide generation. We found that deregulation of c-Jun induced marked radiosensitization in vivo and in vitro, which was rescued by ectopic AC overexpression. AC overexpression in PCa clonogens that survived a fractionated 80-Gy IR course was associated with increased radioresistance and proliferation, suggesting a role for AC in radiotherapy failure and relapse. Immunohistochemical analysis of human PCa tissues revealed higher levels of AC after radiotherapy failure than those in therapy-naive PCa, prostatic intraepithelial neoplasia, or benign tissues. Addition of an AC inhibitor to an animal model of xenograft irradiation produced radiosensitization and prevention of relapse. These data indicate that AC is a potentially tractable target for adjuvant radiotherapy.
doi:10.1172/JCI64791
PMCID: PMC3784522  PMID: 24091326
22.  Analysis on genetic diversification and heterosis in autotetraploid rice 
SpringerPlus  2013;2:439.
Polyploidization has played an important role in plant evolution and is a pathway for plants to increase genetic diversification and to get higher heterosis comparing with that of diploid does. This study was undertaken to assess the genetic variation and relationships among 40 autotetraploid rice genotypes and their counterpart diploid cultivars with 99 SSR markers screened from published rice genome. The 99 SSR markers detected polymorphism among autotetraploid genotypes and revealed a total of 291 alleles with an average of 2.949 alleles per locus. Autotetraploid lines showed higher genetic diversity and significant variation in agronomic traits than diploid cultivars. Phylogenetic analysis revealed that most of autotetraploid lines were genetically different from their diploid parents, and inter-subspecific hybrids were prepared on the basis of genetic distance between parents. Inter-subspecific autotetraploid hybrids showed a higher and positive heterobeltiosis and competitive heterosis than diploid hybrids, especially for grain yield. Genetic distance appeared not to predict heterosis in diploid rice for all traits; however, it showed a significant correlation with grain yield, grain length and grain length to width ratio in autotetraploid rice. This extensive research on autotetraploid heterosis and genetic diversity will be useful for the development of autotetraploid rice hybrids.
doi:10.1186/2193-1801-2-439
PMCID: PMC3773102  PMID: 24046812
Genetic distance; Genetic variation; Heterobeltiosis; Inter-subspecific hybrids; Polyploidy
23.  Nitric Oxide Mediates Root K+/Na+ Balance in a Mangrove Plant, Kandelia obovata, by Enhancing the Expression of AKT1-Type K+ Channel and Na+/H+ Antiporter under High Salinity 
PLoS ONE  2013;8(8):e71543.
It is well known that nitric oxide (NO) enhances salt tolerance of glycophytes. However, the effect of NO on modulating ionic balance in halophytes is not very clear. This study focuses on the role of NO in mediating K+/Na+ balance in a mangrove species, Kandelia obovata Sheue, Liu and Yong. We first analyzed the effects of sodium nitroprusside (SNP), an NO donor, on ion content and ion flux in the roots of K. obovata under high salinity. The results showed that 100 μM SNP significantly increased K+ content and Na+ efflux, but decreased Na+ content and K+ efflux. These effects of NO were reversed by specific NO synthesis inhibitor and scavenger, which confirmed the role of NO in retaining K+ and reducing Na+ in K. obovata roots. Using western-blot analysis, we found that NO increased the protein expression of plasma membrane (PM) H+-ATPase and vacuolar Na+/H+ antiporter, which were crucial proteins for ionic balance. To further clarify the molecular mechanism of NO-modulated K+/Na+ balance, partial cDNA fragments of inward-rectifying K+ channel, PM Na+/H+ antiporter, PM H+-ATPase, vacuolar Na+/H+ antiporter and vacuolar H+-ATPase subunit c were isolated. Results of quantitative real-time PCR showed that NO increased the relative expression levels of these genes, while this increase was blocked by NO synthesis inhibitors and scavenger. Above results indicate that NO greatly contribute to K+/Na+ balance in high salinity-treated K. obovata roots, by activating AKT1-type K+ channel and Na+/H+ antiporter, which are the critical components in K+/Na+ transport system.
doi:10.1371/journal.pone.0071543
PMCID: PMC3747234  PMID: 23977070
24.  Preferential apelin-13 production by the proprotein convertase PCSK3 is implicated in obesity☆ 
FEBS Open Bio  2013;3:328-333.
The peptide hormone apelin is translated as a 77-residue preproprotein, truncated to the 55-residue proapelin and, subsequently, to 13–36-residue bioactive isoforms named apelin-13 to -36. Proapelin is hypothesized to be cleaved to apelin-36 and then to the shorter isoforms. However, neither the mechanism of proapelin processing nor the endoproteases involved have been determined. We show direct cleavage of proapelin to apelin-13 by proprotein convertase subtilisin/kexin 3 (PCSK3, or furin) in vitro, with no production of longer isoforms. Conversely, neither PCSK1 nor PCSK7 has appreciable proapelin cleavage activity. Furthermore, we show that both proapelin and PCSK3 transcript expression levels are increased in adipose tissue with obesity and during adipogenesis, suggesting that PCSK3 is responsible for proapelin processing in adipose tissue.
Graphical abstract
Highlights
•No prohormone processing mechanisms have yet been shown for apelin.•Proapelin is cleaved into apelin-13 both specifically and preferentially by PCSK3.•Conversely, PCSK1 and PCSK7 do not cleave proapelin.•PCSK3 and apelin expression increase with adipocyte differentiation and obesity.•We show the first evidence of and propose a new theory for apelin bioactivation.
doi:10.1016/j.fob.2013.08.001
PMCID: PMC3821026  PMID: 24251091
Proprotein convertase/subtisilin kexin 3; Furin; Prohormone processing; Adipocyte differentiation; Proapelin; MALDI-MS, matrix assisted laser desorption ionization mass spectrometry; PCSK, proprotein convertase subtilisin/kexin; RP-HPLC, reverse phase high performance liquid chromatography; (q)PCR, (quantitative) polymerase chain reaction; RT-PCR, reverse transcription-PCR; TEV, tobacco etch virus
25.  WT1 Promotes Cell Proliferation in Non-Small Cell Lung Cancer Cell Lines through Up-Regulating Cyclin D1 and p-pRb In Vitro and In Vivo 
PLoS ONE  2013;8(8):e68837.
The Wilms’ tumor suppressor gene (WT1) has been identified as an oncogene in many malignant diseases such as leukaemia, breast cancer, mesothelioma and lung cancer. However, the role of WT1 in non-small-cell lung cancer (NSCLC) carcinogenesis remains unclear. In this study, we compared WT1 mRNA levels in NSCLC tissues with paired corresponding adjacent tissues and identified significantly higher expression in NSCLC specimens. Cell proliferation of three NSCLC cell lines positively correlated with WT1 expression; moreover, these associations were identified in both cell lines and a xenograft mouse model. Furthermore, we demonstrated that up-regulation of Cyclin D1 and the phosphorylated retinoblastoma protein (p-pRb) was mechanistically related to WT1 accelerating cells to S-phase. In conclusion, our findings demonstrated that WT1 is an oncogene and promotes NSCLC cell proliferation by up-regulating Cyclin D1 and p-pRb expression.
doi:10.1371/journal.pone.0068837
PMCID: PMC3731304  PMID: 23936312

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