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1.  Tom70 serves as a molecular switch to determine pathological cardiac hypertrophy 
Cell Research  2014;24(8):977-993.
Pathological cardiac hypertrophy is an inevitable forerunner of heart failure. Regardless of the etiology of cardiac hypertrophy, cardiomyocyte mitochondrial alterations are always observed in this context. The translocases of mitochondrial outer membrane (Tom) complex governs the import of mitochondrial precursor proteins to maintain mitochondrial function under pathophysiological conditions; however, its role in the development of pathological cardiac hypertrophy remains unclear. Here, we showed that Tom70 was downregulated in pathological hypertrophic hearts from humans and experimental animals. The reduction in Tom70 expression produced distinct pathological cardiomyocyte hypertrophy both in vivo and in vitro. The defective mitochondrial import of Tom70-targeted optic atrophy-1 triggered intracellular oxidative stress, which led to a pathological cellular response. Importantly, increased Tom70 levels provided cardiomyocytes with full resistance to diverse pro-hypertrophic insults. Together, these results reveal that Tom70 acts as a molecular switch that orchestrates hypertrophic stresses and mitochondrial responses to determine pathological cardiac hypertrophy.
doi:10.1038/cr.2014.94
PMCID: PMC4123302  PMID: 25022898
pathological cardiac hypertrophy; translocases of mitochondrial outer membrane; optic atrophy-1; oxidative stress
2.  Integrative Analysis of Prognosis Data on Multiple Cancer Subtypes 
Biometrics  2014;70(3):480-488.
Summary
In cancer research, profiling studies have been extensively conducted, searching for genes/SNPs associated with prognosis. Cancer is diverse. Examining the similarity and difference in the genetic basis of multiple subtypes of the same cancer can lead to a better understanding of their connections and distinctions. Classic meta-analysis methods analyze each subtype separately and then compare analysis results across subtypes. Integrative analysis methods, in contrast, analyze the raw data on multiple subtypes simultaneously and can outperform meta-analysis methods. In this study, prognosis data on multiple subtypes of the same cancer are analyzed. An AFT (accelerated failure time) model is adopted to describe survival. The genetic basis of multiple subtypes is described using the heterogeneity model, which allows a gene/SNP to be associated with prognosis of some subtypes but not others. A compound penalization method is developed to identify genes that contain important SNPs associated with prognosis. The proposed method has an intuitive formulation and is realized using an iterative algorithm. Asymptotic properties are rigorously established. Simulation shows that the proposed method has satisfactory performance and outperforms a penalization-based meta-analysis method and a regularized thresholding method. An NHL (non-Hodgkin lymphoma) prognosis study with SNP measurements is analyzed. Genes associated with the three major subtypes, namely DLBCL, FL, and CLL/SLL, are identified. The proposed method identifies genes that are different from alternatives and have important implications and satisfactory prediction performance.
doi:10.1111/biom.12177
PMCID: PMC4209207  PMID: 24766212
Cancer prognosis; Integrative analysis; Genetic association; Marker identification; Penalization
3.  Identification of ULK1 as a novel biomarker involved in miR-4487 and miR-595 regulation in neuroblastoma SH-SY5Y cell autophagy 
Scientific Reports  2015;5:11035.
Autophagy, referring to an evolutionarily conserved, multi-step lysosomal degradation process, has been well-known to be initiated by Unc-51 like kinase 1 (ULK1) with some links to Parkinson’s disease (PD). MicroRNAs (miRNAs), small and non-coding endogenous RNAs 22 ~ 24 nucleotides (nt) in length, have been demonstrated to play an essential role for modulating autophagy. Recently, the relationships between miRNAs and autophagy have been widely reported in PD; however, how microRNAs regulate autophagy still remains in its infancy. Thus, in this study, we computationally constructed the ULK1-regulated autophagic kinase subnetwork in PD and further identified ULK1 able to negatively regulate p70S6K in starvation-induced autophagy of neuroblastoma SH-SY5Y cells. Combination of in silico prediction and microarray analyses, we identified that miR-4487 and miR-595 could target ULK1 and experimentally verified they could negatively or positively regulate ULK1-mediated autophagy. In conclusion, these results may uncover the novel ULK1-p70S6K autophagic pathway, as well as miR-4487 and miR-595 as new ULK1 target miRNAs. Thus, these findings would provide a clue to explore ULK1 and its target miRNAs as potential biomarkers in the future PD therapy.
doi:10.1038/srep11035
PMCID: PMC4505320  PMID: 26183158
4.  Rice_Phospho 1.0: a new rice-specific SVM predictor for protein phosphorylation sites 
Scientific Reports  2015;5:11940.
Experimentally-determined or computationally-predicted protein phosphorylation sites for distinctive species are becoming increasingly common. In this paper, we compare the predictive performance of a novel classification algorithm with different encoding schemes to develop a rice-specific protein phosphorylation site predictor. Our results imply that the combination of Amino acid occurrence Frequency with Composition of K-Spaced Amino Acid Pairs (AF-CKSAAP) provides the best description of relevant sequence features that surround a phosphorylation site. A support vector machine (SVM) using AF-CKSAAP achieves the best performance in classifying rice protein phophorylation sites when compared to the other algorithms. We have used SVM with AF-CKSAAP to construct a rice-specific protein phosphorylation sites predictor, Rice_Phospho 1.0 (http://bioinformatics.fafu.edu.cn/rice_phospho1.0). We measure the Accuracy (ACC) and Matthews Correlation Coefficient (MCC) of Rice_Phospho 1.0 to be 82.0% and 0.64, significantly higher than those measures for other predictors such as Scansite, Musite, PlantPhos and PhosphoRice. Rice_Phospho 1.0 also successfully predicted the experimentally identified phosphorylation sites in LOC_Os03g51600.1, a protein sequence which did not appear in the training dataset. In summary, Rice_phospho 1.0 outputs reliable predictions of protein phosphorylation sites in rice, and will serve as a useful tool to the community.
doi:10.1038/srep11940
PMCID: PMC4493637  PMID: 26149854
5.  METTL21C is a potential pleiotropic gene for osteoporosis and sarcopenia acting through the modulation of the NFκB signaling pathway 
Sarcopenia and osteoporosis are important public health problems that occur concurrently. A bivariate genome-wide association study (GWAS) identified METTL21c as a suggestive pleiotropic gene for both bone and muscle. METTL21 family of proteins methylates chaperones involved in the etiology of both Inclusion Body Myositis with Paget's disease. To validate these GWAS results, Mettl21c mRNA expression was reduced with siRNA in a mouse myogenic C2C12 cell line and the mouse osteocyte-like cell line MLO-Y4. At day 3, as C2C12 myoblasts start to differentiate into myotubes, a significant reduction in the number of myocytes aligning/organizing for fusion was observed in the siRNA-treated cells. At day 5, both fewer and smaller myotubes were observed in the siRNA-treated cells as confirmed by histomorphometric analyses and immunostaining with Myosin Heavy Chain (MHC) antibody, which only stains myocytes/myotubes but not myoblasts. Intracellular calcium (Ca2+) measurements of the siRNA-treated myotubes showed a decrease in maximal amplitude peak response to caffeine suggesting that less Ca2+ is available for release due to the partial silencing of Mettl21c, correlating with impaired myogenesis. In siRNA-treated MLO-Y4 cells, 48 hours after treatment with dexamethasone, there was a significant increase in cell death, suggesting a role of Mettl21c in osteocyte survival. To investigate the molecular signaling machinery induced by the partial silencing of Mettl21c, we monitored with a real-time PCR gene array the activity of 10 signaling pathways. We discovered that Mettl21c knockdown modulated only the NFκB signaling pathway (i.e., Birc3, Ccl5 and Tnf). These results suggest that Mettl21c might exert its bone-muscle pleiotropic function via the regulation of the NFκB signaling pathway, which is critical for bone and muscle homeostasis. These studies also provide rationale for cellular and molecular validation of GWAS, and warrant additional in vitro and in vivo studies to advance our understanding of role of METTL21C in musculoskeletal biology.
doi:10.1002/jbmr.2200
PMCID: PMC4074268  PMID: 24677265
Genetic Research; Human Association Studies; Osteocytes; Skeletal Muscle; Bone-Muscle Interactions
6.  Recombinant ESAT-6-Like Proteins Provoke Protective Immune Responses against Invasive Staphylococcus aureus Disease in a Murine Model 
Infection and Immunity  2014;83(1):339-345.
Staphylococcus aureus is a common pathogen found in the community and in hospitals. Most notably, methicillin-resistant S. aureus is resistant to many antibiotics, which is a growing public health concern. The emergence of drug-resistant strains has prompted the search for alternative treatments, such as immunotherapeutic approaches. To date, most clinical trials of vaccines or of passive immunization against S. aureus have ended in failure. In this study, we investigated two ESAT-6-like proteins secreted by S. aureus, S. aureus EsxA (SaEsxA) and SaEsxB, as possible targets for a vaccine. Mice vaccinated with these purified proteins elicited high titers of anti-SaEsxA and anti-SaEsxB antibodies, but these antibodies could not prevent S. aureus infection. On the other hand, recombinant SaEsxA (rSaEsxA) and rSaEsxB could induce Th1- and Th17-biased immune responses in mice. Mice immunized with rSaEsxA and rSaEsxB had significantly improved survival rates when challenged with S. aureus compared with the controls. These findings indicate that SaEsxA and SaEsxB are two promising Th1 and Th17 candidate antigens which could be developed into multivalent and serotype-independent vaccines against S. aureus infection.
doi:10.1128/IAI.02498-14
PMCID: PMC4288882  PMID: 25368117
7.  PD-L1 and Survival in Solid Tumors: A Meta-Analysis 
PLoS ONE  2015;10(6):e0131403.
Background
Numerous agents targeting PD-L1/PD-1 check-point are in clinical development. However, the correlation between PD-L1expression and prognosis of solid tumor is still in controversial. Here, we elicit a systematic review and meta-analysis to investigate the potential value of PD-L1 in the prognostic prediction in human solid tumors.
Methods
Electronic databases were searched for studies evaluating the expression of PD-L1 and overall survival (OS) of patients with solid tumors. Odds ratios (ORs) from individual studies were calculated and pooled by using a random-effect model, and heterogeneity and publication bias analyses were also performed.
Results
A total of 3107 patients with solid tumor from 28 published studies were included in the meta-analysis. The median percentage of solid tumors with PD-L1 overexpression was 52.5%. PD-L1 overexpression was associated with worse OS at both 3 years (OR = 2.43, 95% confidence interval (CI) = 1.60 to 3.70, P < 0.0001) and 5 years (OR = 2.23, 95% CI = 1.40 to 3.55, P = 0.0008) of solid tumors. Among the tumor types, PD-L1 was associated with worse 3 year-OS of esophageal cancer, gastric cancer, hepatocellular carcinoma, and urothelial cancer, and 5 year-OS of esophageal cancer, gastric cancer and colorectal cancer.
Conclusions
These results suggest that expression of PD-L1 is associated with worse survival in solid tumors. However, the correlations between PD-L1 and prognosis are variant among different tumor types. More studies are needed to investigate the clinical value of PD-L1 expression in prognostic prediction and treatment option.
doi:10.1371/journal.pone.0131403
PMCID: PMC4483169  PMID: 26114883
8.  A phase II neoadjuvant trial of anastrozole, fulvestrant and gefitinib in patients with newly diagnosed estrogen receptor positive breast cancer 
Endocrine therapy in patients with breast cancer can be limited by the problem of resistance. Preclinical studies suggest that complete blockade of the estrogen receptor (ER) combined with inhibition of the epidermal growth factor receptor (EGFR) can overcome endocrine resistance. We tested this hypothesis in a phase II neoadjuvant trial of anastrozole and fulvestrant combined with gefitinib in postmenopausal women with newly diagnosed ER-positive breast cancer. After a baseline tumor core biopsy, patients were randomized to receive anastrozole and fulvestrant (AF) or anastrozole, fulvestrant, and gefitinib (AFG) for 3 weeks. After a second biopsy at 3 weeks, all patients received AFG for 4 months and surgery was done if the tumor was operable. The primary endpoint was best clinical response by RECIST criteria and secondary endpoints were toxicity and change in biomarkers. The study closed after 15 patients were enrolled because of slow accrual. Median patient age was 67 years and median clinical tumor size was 7 cm. Four patients had metastatic disease present. Three patients withdrew before response was assessed. In the remaining twelve patients, there were two complete clinical responses (17%), three partial responses (25%), five had stable disease (41%), and two (17%) had progressive disease. Most common adverse events were rash in four patients, diarrhea in four, joint symptoms in three, and abnormal liver function tests in three. There were no grade 4 toxicities and all toxicities were reversible. At 3 weeks, cell proliferation as measured by Ki-67 was significantly reduced in the AFG group (p value= 0.01) with a parallel reduction in the expression of the Cyclin D1 (p value=0.02). RNA microarray data showed a corresponding decrease in the expression of cell cycle genes. These results suggest that AFG was an effective neoadjuvant therapy and consistently reduced proliferation in ER-positive tumors.
doi:10.1007/s10549-011-1679-8
PMCID: PMC4477822  PMID: 21792626
breast cancer; estrogen receptor; endocrine resistance; EGFR; proliferation
9.  Autoantibodies against tumor-associated antigens for detection of hepatocellular carcinoma 
World Journal of Hepatology  2015;7(11):1581-1585.
Hepatocellular carcinoma (HCC) is one of the most common tumors worldwide. The survival rate after the onset of symptoms is generally less than one year for the late presentation of HCC, and reliable tools for early diagnosis are lacking. Therefore, novel biomarkers for the early detection of HCC are urgently required. Recent studies show that the abnormal release of proteins by tumor cells can elicit humoral immune responses to self-antigens called tumor-associated antigens (TAAs). The corresponding autoantibodies can be detected before the clinical diagnosis of cancer. Therefore, there is growing interest in using serum autoantibodies as cancer biomarkers. In this review, we focus on the advances in research on autoantibodies against TAAs as serum biomarker for detection of HCC, the mechanism of the production of TAAs, and the association of autoantibodies with patients’ clinical characteristics.
doi:10.4254/wjh.v7.i11.1581
PMCID: PMC4462696  PMID: 26085917
Hepatocellular carcinoma; Diagnosis; Serological marker; Autoantibody; Tumor associated antigen
10.  In silico Analysis and Experimental Validation of Lignan Extracts from Kadsura longipedunculata for Potential 5-HT1AR Agonists 
PLoS ONE  2015;10(6):e0130055.
Objectives
Kadsura longipedunculata (KL) has been widely used for the treatment of insomnia in traditional Chinese medicine. The aim of this study was to explore the mechanism of the sedative and hypnotic effects of KL.
Materials and Methods
The content of KL was evaluated by HPLC-TOF-MS, and a potential target was found and used to construct its 3D structure to screen for potential ligands among the compounds in KL by using bioinformatics analysis, including similarity ensemble approach (SEA) docking, homology modeling, molecular docking and ligand-based pharmacophore. The PCPA-induced insomnia rat model was then applied to confirm the potential targets related to the sedative effects of KL by performing the forced swimming test (FST), the tail suspension test (TST) and the measurement of target-related proteins using western blotting and immunofluorescence.
Results
Bioinformatics analysis showed that most of lignan compounds in KL were optimal ligands for the 5-HT1A receptor (5-HT1AR), and they were found to be potential targets related to sedative effects; the main lignan content of KL extracts was characterized by HPLC-TOF-MS, with 7 proposed lignans detected. Administration of KL could significantly reduce FST and TST immobility time in the PCPA-induced 5HT-depleted insomnia rat model. The expressions of proteins related to the 5-HT1AR pathway were regulated by extracts of KL in a concentration-dependent manner, indicating that extracts of KL had 5-HT1AR agonist-like effects.
Conclusion
In silico analysis and experimental validation together demonstrated that lignan extracts from KL can target 5-HT1AR in insomniac rats, which could shed light on its use as a potential 5-HT1AR agonist drug.
doi:10.1371/journal.pone.0130055
PMCID: PMC4468062  PMID: 26076134
11.  Using Historical Atlas Data to Develop High-Resolution Distribution Models of Freshwater Fishes 
PLoS ONE  2015;10(6):e0129995.
Understanding the spatial pattern of species distributions is fundamental in biogeography, and conservation and resource management applications. Most species distribution models (SDMs) require or prefer species presence and absence data for adequate estimation of model parameters. However, observations with unreliable or unreported species absences dominate and limit the implementation of SDMs. Presence-only models generally yield less accurate predictions of species distribution, and make it difficult to incorporate spatial autocorrelation. The availability of large amounts of historical presence records for freshwater fishes of the United States provides an opportunity for deriving reliable absences from data reported as presence-only, when sampling was predominantly community-based. In this study, we used boosted regression trees (BRT), logistic regression, and MaxEnt models to assess the performance of a historical metacommunity database with inferred absences, for modeling fish distributions, investigating the effect of model choice and data properties thereby. With models of the distribution of 76 native, non-game fish species of varied traits and rarity attributes in four river basins across the United States, we show that model accuracy depends on data quality (e.g., sample size, location precision), species’ rarity, statistical modeling technique, and consideration of spatial autocorrelation. The cross-validation area under the receiver-operating-characteristic curve (AUC) tended to be high in the spatial presence-absence models at the highest level of resolution for species with large geographic ranges and small local populations. Prevalence affected training but not validation AUC. The key habitat predictors identified and the fish-habitat relationships evaluated through partial dependence plots corroborated most previous studies. The community-based SDM framework broadens our capability to model species distributions by innovatively removing the constraint of lack of species absence data, thus providing a robust prediction of distribution for stream fishes in other regions where historical data exist, and for other taxa (e.g., benthic macroinvertebrates, birds) usually observed by community-based sampling designs.
doi:10.1371/journal.pone.0129995
PMCID: PMC4468192  PMID: 26075902
12.  The potential role of COX-2 in cancer stem cell-mediated canine mammary tumor initiation: an immunohistochemical study 
Journal of Veterinary Science  2015;16(2):225-231.
Increasing evidence suggests that cancer stem cells (CSCs) are responsible for tumor initiation and maintenance. Additionally, it is becoming apparent that cyclooxygenase (COX) signaling is associated with canine mammary tumor development. The goals of the present study were to investigate COX-2 expression patterns and their effect on CSC-mediated tumor initiation in primary canine mammary tissues and tumorsphere models using immunohistochemistry. Patterns of COX-2, CD44, octamer-binding transcription factor (Oct)-3/4, and epidermal growth factor receptor (EGFR) expression were examined in malignant mammary tumor (MMT) samples and analyzed in terms of clinicopathological characteristics. COX-2 and Oct-3/4 expression was higher in MMTs compared to other histological samples with heterogeneous patterns. In MMTs, COX-2 expression correlated with tumor malignancy features. Significant associations between COX-2, CD44, and EGFR were observed in low-differentiated MMTs. Comparative analysis showed that the levels of COX-2, CD44, and Oct-3/4 expression varied significantly among TSs of three histological grades. Enhanced COX-2 staining was consistently observed in TSs. Similar levels of staining intensity were found for CD44 and Oct-3/4, but EGFR expression was weak. Our findings indicate the potential role of COX-2 in CSC-mediated tumor initiation, and suggest that COX-2 inhibition may help treat canine mammary tumors by targeting CSCs.
doi:10.4142/jvs.2015.16.2.225
PMCID: PMC4483507  PMID: 26124697
cancer stem cells; canine mammary tumor; COX-2; tumor initiation
13.  Molecular Biogeography of Tribe Thermopsideae (Leguminosae): A Madrean-Tethyan Disjunction Pattern with an African Origin of Core Genistoides 
BioMed Research International  2015;2015:864804.
Thermopsideae has 45 species and exhibits a series of interesting biogeographical distribution patterns, such as Madrean-Tethyan disjunction and East Asia-North America disjunction, with a center of endemism in the Qinghai-Xizang Plateau (QTP) and Central Asia. Phylogenetic analysis in this paper employed maximum likelihood using ITS, rps16, psbA-trnH, and trnL-F sequence data; biogeographical approaches included BEAST molecular dating and Bayesian dispersal and vicariance analysis (S-DIVA). The results indicate that the core genistoides most likely originated in Africa during the Eocene to Oligocene, ca. 55-30 Ma, and dispersed eastward to Central Asia at ca. 33.47 Ma. The origin of Thermopsideae is inferred as Central Asian and dated to ca. 28.81 Ma. Ammopiptanthus is revealed to be a relic. Birth of the ancestor of Thermopsideae coincided with shrinkage of the Paratethys Sea at ca. 30 Ma in the Oligocene. The Himalayan motion of QTP uplift of ca. 20 Ma most likely drove the diversification between Central Asia and North America. Divergences in East Asia, Central Asia, the Mediterranean, and so forth, within Eurasia, except for Ammopiptanthus, are shown to be dispersals from the QTP. The onset of adaptive radiation at the center of the tribe, with diversification of most species in Thermopsis and Piptanthus at ca. 4-0.85 Ma in Tibet and adjacent regions, seems to have resulted from intense northern QTP uplift during the latter Miocene to Pleistocene.
doi:10.1155/2015/864804
PMCID: PMC4465657  PMID: 26114116
14.  Antiproliferative effects and molecular mechanisms of troglitazone in human cervical cancer in vitro 
OncoTargets and therapy  2015;8:1211-1218.
We investigated the effects of troglitazone on human cervical cancer SiHa cells and its mechanisms of action. SiHa cells were incubated with different concentrations of troglitazone (100, 200, or 400 μg/mL) for 24, 48, and 72 hours. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay; cell cycle and apoptosis were detected by flow cytometry; and morphology of SiHa cells was observed under an inverted microscope. pcDNA3.1 and pcDNA3.1-Skp2 plasmids were constructed and then transfected into SiHa cells. Protein expression was analyzed by Western blotting. Troglitazone inhibited the proliferation of SiHa cells in a time- and concentration-dependent manner. Troglitazone caused G0/1 phase arrest but failed to reduce apoptosis in SiHa cells. Troglitazone significantly increased expression of p27 but decreased Skp2 expression. Skp2 overexpression inhibited the role of troglitazone in increasing expression of p27, and the cell cycle inhibitory effect of troglitazone. Troglitazone can inhibit SiHa cell viability by affecting cell cycle distribution but not apoptosis, and Skp2 and p27 may play a critical role.
doi:10.2147/OTT.S79899
PMCID: PMC4454221  PMID: 26060406
SiHa cells; cell cycle; apoptosis
15.  Flavonoid Glycosides of Polygonum capitatum Protect against Inflammation Associated with Helicobacter pylori Infection 
PLoS ONE  2015;10(5):e0126584.
The antibacterial and anti-inflammatory activities, and protective effects of extracts (flavonoid glycosides) of Polygonum capitatum were investigated to detect the evidence for the utilization of the herb in the clinical therapy of gastritis caused by H. pylori. A mouse gastritis model was established using H. pylori. According to treating methods, model mice were random assigned into a model group (MG group), a triple antibiotics group (TG group, clarithromycin, omeprazole and amoxicillin), low/middle/high concentrations of flavonoid glycosides groups (LF, MF and HF groups) and low/middle/high concentrations of flavonoid glycosides and amoxicillin groups (LFA, MFA and HFA groups). A group with pathogen-free mice was regarded as a control group (CG group). The eradicate rates of H. pylori were 100%, 93%, 89% in TG, MFA and HF groups. The serum levels of IFN-gamma and gastrin were higher in a MG group than those from all other groups (P < 0.05). The serum levels of IFN-gamma and gastrin were reduced significantly in LF, MF and HF groups (P < 0.05) while little changes were observed in LFA, MFA and HFA groups. In contrast, the serum levels of IL-4 were lower and higher in MG and CG groups compared with other groups (P<0.05). The serum levels of IL-4 were increased significantly in LF, MF and HF groups (P < 0.05) while little changes were found in LFA, MFA and HFA groups. According to pathological scores, flavonoid glycosides therapy showed better protection for gastric injuries than the combination of flavonoid glycoside and amoxicillin (P < 0.05). The results suggested that flavonoid glycoside has repairing functions for gastric injuries. The results suggest that the plant can treat gastritis and protect against gastric injuries. The flavonoid glycosides from Polygonum capitatum should be developed as a potential drug for the therapy of gastritis caused by H. pylori.
doi:10.1371/journal.pone.0126584
PMCID: PMC4436306  PMID: 25993258
16.  Evaluating the microRNA-target gene regulatory network in renal cell carcinomas, identification for potential biomarkers and critical pathways 
Variant microRNA (miRNA) expression is a character of many cancer types. The combined analysis of miRNA and messenger RNA (mRNA) expression profiles is crucial to identifying links between deregulated miRNAs and oncogenic pathways. The aim of this study was to screen several novel genes associated with renal cell carcinoma (RCC), and analyze the gene functions and signal pathways which were critical to RCCs with DNA microarray. The gene expression profile of GSE6344 was downloaded from Gene Expression Omnibus database, including 10 RCC samples and 10 healthy controls. Compared with the control samples, differentially expressed genes (DEGs) of RCC was identified. The selected DEGs were further analyzed using bioinformatics methods. Gene ontology (GO) enrichment analysis was performed using Gene Set Analysis Toolkit and protein-protein interaction (PPI) network was constructed with prePPI. Then, pathway enrichment analysis to PPI network was performed using WebGestalt software. We found that a total of 521 DEGs were down-regulated and 473 DEGs were up-regulated in RCC samples compared to healthy controls. A total of 15 remarkable enhanced functions and 17 suppressed functions were identified. PPI nodes of high degrees, such as RHCG, RALYL, SLC4A1, UMOD and CA9, were obtained. The DEGs were classified and significantly enriched in cytokine and cytokine receptor pathway. The hub genes we find from RCC samples are not only biomarkers, but also may provide the groundwork for a combination therapy approach for RCCs.
PMCID: PMC4509205  PMID: 26221260
Microarray profiling; oncogenes; potential biomarkers; critical pathways; renal cell carcinoma
17.  A De Novo Floral Transcriptome Reveals Clues into Phalaenopsis Orchid Flower Development 
PLoS ONE  2015;10(5):e0123474.
Phalaenopsis has a zygomorphic floral structure, including three outer tepals, two lateral inner tepals and a highly modified inner median tepal called labellum or lip; however, the regulation of its organ development remains unelucidated. We generated RNA-seq reads with the Illumina platform for floral organs of the Phalaenopsis wild-type and peloric mutant with a lip-like petal. A total of 43,552 contigs were obtained after de novo assembly. We used differentially expressed gene profiling to compare the transcriptional changes in floral organs for both the wild-type and peloric mutant. Pair-wise comparison of sepals, petals and labellum between peloric mutant and its wild-type revealed 1,838, 758 and 1,147 contigs, respectively, with significant differential expression. PhAGL6a (CUFF.17763), PhAGL6b (CUFF.17763.1), PhMADS1 (CUFF.36625.1), PhMADS4 (CUFF.25909) and PhMADS5 (CUFF.39479.1) were significantly upregulated in the lip-like petal of the peloric mutant. We used real-time PCR analysis of lip-like petals, lip-like sepals and the big lip of peloric mutants to confirm the five genes’ expression patterns. PhAGL6a, PhAGL6b and PhMADS4 were strongly expressed in the labellum and significantly upregulated in lip-like petals and lip-like sepals of peloric-mutant flowers. In addition, PhAGL6b was significantly downregulated in the labellum of the big lip mutant, with no change in expression of PhAGL6a. We provide a comprehensive transcript profile and functional analysis of Phalaenopsis floral organs. PhAGL6a PhAGL6b, and PhMADS4 might play crucial roles in the development of the labellum in Phalaenopsis. Our study provides new insights into how the orchid labellum differs and why the petal or sepal converts to a labellum in Phalaenopsis floral mutants.
doi:10.1371/journal.pone.0123474
PMCID: PMC4430480  PMID: 25970572
18.  PSCA s2294008 C>T and rs2976392 G>A polymorphisms contribute to cancer susceptibility: evidence from published studies 
Genes & Cancer  2015;6(5-6):254-264.
PSCA gene plays an important role in cell adhesion, proliferation and survival. Increasing studies have focused on the association of PSCA gene rs2294008 C>T and rs2976392 G>A with cancer risk. However, the conclusions were inconsistent. Therefore, we performed a meta-analysis to elucidate whether there is a true association, or artifact. We systematically searched eligible studies from MEDLINE, EMBASE and CBM database. Odds ratios and 95% confidence intervals were used to evaluate the strength of the association. The final analysis included 32 studies consisting of 30028 cases and 38765 controls for the rs2294008 C>T polymorphism, and 14 studies with 8190 cases and 7176 controls for the rs2976392 G>A polymorphism. Consequently, the PSCA rs2294008 C>T polymorphism was significantly associated with increased overall cancer risk. Further stratifications indicated the increased risk was more pronounced for gastric (diffused type and non-gastric cardia adenocarcinoma) and bladder cancer. A similar association was observed for the rs2976392 G>A polymorphism. This meta-analysis demonstrated that both of the PSCA rs2294008 C>T and rs2976392 G>A polymorphisms are associated with increased cancer risk, especially for gastric cancer and bladder cancer. Further large-scale studies with different ethnicities and subtypes of gastric cancer are required to confirm the results from this meta-analysis.
PMCID: PMC4482246  PMID: 26124924
PSCA; GWAS; polymorphism; susceptibility; meta-analysis
19.  Genomic losses at 5q13.2 and 8p23.1 in dysplastic hepatocytes are common events in hepatitis B virus-related hepatocellular carcinoma 
Oncology Letters  2015;9(6):2839-2846.
Chromosomal loci with genomic imbalances are frequently identified in hepatocellular carcinoma (HCC). Greater than two-thirds of hepatitis B virus (HBV)-related HCCs originate from liver cirrhosis following a duration of up to two decades. However, it is unclear whether these genomic imbalances occur and accumulate in dysplastic hepatocytes of the cirrhotic liver during the progression from regenerated nodules to preneoplastic lesions, including dysplastic nodules (DN). In the present study, high-grade DNs (HGDNs) of HBV-related liver cirrhosis were screened to identify loci with genomic imbalances, and the frequency of the identified loci in a group of HCCs was analyzed in order to determine whether there may be a genetic link between liver cirrhosis and HCC. Genomic DNA was extracted from six HGDNs of two cases of HBV-related liver cirrhosis and subjected to array comparative genomic hybridization (CGH) analysis with a NimbleGen 720K microarray. Loci with the most frequently observed genomic imbalances in DNs were further analyzed in 83 cases of HCC by differential polymerase chain reaction (PCR) and quantitative PCR. The array CGH analysis revealed that the majority of genomic imbalances in the HGDNs were genomic losses of small segments, with loss of heterozygosity (LOH) at 5q13.2 and 8p23.1 identified most frequently. Of the 83 HCC cases, 30 (36.1%) cases were identified with LOH at 5q13.2, where known tumor-associated genes are located, including general transcription factor IIH subunit 2 (GTF2H2), baculoviral IAP repeat-containing protein 1 (BIRC1) and occludin (OCLN). LOH frequency at 8p23.1 in HCC was 61.29% (D8S1130) and 68.4% (D8S503) respectively, similar to the results obtained in previous studies. In conclusion, the results of the present study provided evidence that genomic losses at 5q13.2 and 8p23.1 identified in dysplastic hepatocytes of the cirrhotic liver are common events in HCC. HCC-associated chromosomal abnormalities may occur and accumulate in preneoplastic lesions of liver cirrhosis.
doi:10.3892/ol.2015.3140
PMCID: PMC4473700  PMID: 26137157
genomic imbalances; loss of heterozygosity; 5q13.2; dysplastic nodule; hepatocellular carcinoma
20.  Shp2 SUMOylation promotes ERK activation and hepatocellular carcinoma development 
Oncotarget  2015;6(11):9355-9369.
Shp2, an ubiquitously expressed protein tyrosine phosphatase, is essential for regulation of Ras/ERK signaling pathway and tumorigenesis. Here we report that Shp2 is modified by SUMO1 at lysine residue 590 (K590) in its C-terminus, which is reduced by SUMO1-specific protease SENP1. Analysis of wild-type Shp2 and SUMOylation-defective Shp2K590R mutant reveals that SUMOylation of Shp2 promotes EGF-stimulated ERK signaling pathway and increases anchorage-independent cell growth and xenografted tumor growth of hepatocellular carcinoma (HCC) cell lines. Furthermore, we find that mutant Shp2K590R reduces its binding with the scaffolding protein Gab1, and consistent with this, knockdown of SENP1 increased the interaction between Shp2 and Gab1. More surprisingly, we show that human Shp2 (hShp2) and mouse Shp2 (mShp2) have differential effects on ERK activation as a result of different SUMOylation level, which is due to the event of K590 at hShp2 substituted by R594 at mShp2. In summary, our data demonstrate that SUMOylation of Shp2 promotes ERK activation via facilitating the formation of Shp2-Gab1 complex and thereby accelerates HCC cell and tumor growth, which presents a novel regulatory mechanism underlying Shp2 in regulation of HCC development.
PMCID: PMC4496222  PMID: 25823821
Shp2; SUMOylation; Gab1; ERK activation; hepatocellular carcinoma (HCC)
21.  Analysis of Kif5b Expression during Mouse Kidney Development 
PLoS ONE  2015;10(4):e0126002.
Recent studies showed that kidney-specific inactivation of Kif3a produces kidney cysts and renal failure, suggesting that kinesin-mediated intracellular transportation is important for the establishement and maintenance of renal epithelial cell polarity and normal nephron functions. Kif5b, one of the most conserved kinesin heavy chain, is the mouse homologue of the human ubiquitous Kinesin Heavy Chain (uKHC). In order to elucidate the role of Kif5b in kidney development and function, it is essential to establish its expression profile within the organ. Therefore, in this study, we examined the expression pattern of Kif5b in mouse kidney. Kidneys from embryonic (E) 12.5-, 16.5-dpc (days post coitus) mouse fetuses, from postnatal (P) day 0, 10, 20 pups and from adult mice were collected. The distribution of Kif5b was analyzed by immunostaining. The possible involvement of Kif5b in kidney development was investigated in conditional mutant mice by using a Cre-LoxP strategy. This study showed that the distribution of Kif5b displayed spatiotemporal changes during postnatal kidney development. In kidneys of new born mice, Kif5b was strongly expressed in all developing tubules and in the ureteric bud, but not in the glomerulus or in other early-developing structures, such as the cap mesenchyme, the comma-shaped body, and the S-shaped body. In kidneys of postnatal day 20 or of older mice, however, Kif5b was localized selectively in the basolateral domain of epithelial cells of the thick ascending loop of Henle, as well as of the distal convoluted tubule, with little expression being observed in the proximal tubule or in the collecting duct. Conditional knock-down of Kif5b in mouse kidney did not result in detectable morphological defects, but it did lead to a decrease in cell proliferation rate and also to a mislocalization of Na+/K+/-ATPase, indicating that although Kif5b is non-essential for kidney morphogenesis, it is important for nephron maturation.
doi:10.1371/journal.pone.0126002
PMCID: PMC4401754  PMID: 25885434
22.  Comparison of antibacterial effects between antimicrobial peptide and bacteriocins isolated from Lactobacillus plantarum on three common pathogenic bacteria 
New strategies for the prevention or treatment of infections are required. The purpose of this study is to evaluate the effects of antimicrobial peptides and bacteriocins isolated from Lactobacillus plantarum on growth and biofilm formation of three common pathogenic microbes. The antibacterial properties of the antimicrobial peptide Tet213 and bacteriocins were tested by the disc diffusion method. Tet213 and bacteriocins showed inhibitory effects on biofilm formation for the three organisms, as observed by fluorescence microscopy. Furthermore, Tet213 and the bacteriocins all showed antimicrobial activity against the three bacterial species, with Tet213 having a greater inhibitory effect on S. aureus than the bacteriocins (P < 0.05), while the bacteriocins showed stronger antimicrobial activity against S. sanguis (P < 0.05).
PMCID: PMC4483923  PMID: 26131169
Antimicrobial activity; antimicrobial peptide; bacteriocin; biofilm
24.  Systems biology network-based discovery of a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing apoptosis in cervical cancer 
Oncotarget  2015;6(10):8071-8088.
The aim of this study was to discover a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing apoptosis in cervical cancer. In this study, we systematically constructed the global protein-protein interaction (PPI) network and predicted apoptosis-related protein connections by the Naïve Bayesian model. Then, we identified some classical apoptotic PPIs and other previously unrecognized PPIs between apoptotic kinases, such as AMPK and ZIPK. Subsequently, we screened a series of candidate compounds targeting AMPK/ZIPK, synthesized some compounds and eventually discovered a novel dual-target activator (BL-AD008). Moreover, we found BL-AD008 bear remarkable anti-proliferative activities toward cervical cancer cells and could induce apoptosis by death-receptor and mitochondrial pathways. Additionally, we found that BL-AD008-induced apoptosis was affected by the combination of AMPK and ZIPK. Then, we found that BL-AD008 bear its anti-tumor activities and induced apoptosis by targeting AMPK/ZIPK in vivo. In conclusion, these results demonstrate the ability of systems biology network to identify some key apoptotic kinase targets AMPK and ZIPK; thus providing a dual-target small molecule activator (BL-AD008) as a potential new apoptosis-modulating drug in future cervical cancer therapy.
PMCID: PMC4480736  PMID: 25797270
Systems biology network; Apoptosis; AMPK; ZIPK; Dual-target activator (BL-AD008)
25.  Prognostic Value, Clinicopathologic Features and Diagnostic Accuracy of Interleukin-8 in Colorectal Cancer: A Meta-Analysis 
PLoS ONE  2015;10(4):e0123484.
Background
The prognostic value and diagnostic accuracy of Interleukin-8 (IL-8) in colorectal cancer have been assessed with several studies, but the conclusions were inconclusive. Thus we performed a meta-analysis to evaluate the impact of IL-8 expression on colorectal cancer prognosis, clinicopathologic features and diagnostic accuracy.
Methods
Comprehensive search strategies were used to search relevant literature in the PubMed, EBSCO and the ISI Web of Science databases. The correlation between IL-8 expression and prognosis, clinicopathologic features and diagnostic accuracy was analyzed.
Results
A total of 18 articles met the inclusion criteria, including 1509 patients for clinicopathologic features or prognosis evaluation and 725 participants for diagnostic evaluation. The results suggested that overexpression of IL-8 was significantly associated with poor prognosis in colorectal cancer (HR = 1.54, 95%CI 1.03–2.32), especially in Union for International Cancer Control (UICC) stage IV patients (HR = 2.28, 95%CI 1.60–3.25). With further subgroup analysis, we found that high IL-8 level in serum was significantly correlated with poor prognosis (HR = 2.13, 95%CI 1.49–3.05). In addition, significant correlations were observed between high IL-8 expression and advanced stage (OR = 3.01, 95%CI 1.98–4.56), lymphatic metastasis (OR = 2.24, 95%CI 1.39–3.63), and liver metastasis (OR = 3.47, 95%CI 1.74–6.89). Moreover, IL-8 had high diagnostic accuracy, with pooled sensitivity 0.70(95%CI 0.66–0.74), specificity 0.91(95%CI 0.86–0.94), positive likelihood ratio (LR) 7.00(95%CI 2.48–19.73), negative LR 0.24(95%CI 0.09–0.64), diagnostic OR 24.00(95%CI 5.52–104.38).
Conclusions
This study showed that IL-8 could be a potential indicator for detecting colorectal cancer and predicting prognosis. In addition, high IL-8 level was significantly correlated with advanced stage, lymphatic metastasis, liver metastasis.
doi:10.1371/journal.pone.0123484
PMCID: PMC4391830  PMID: 25856316

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