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1.  Structure and Function of SET and MYND Domain-Containing Proteins 
SET (Suppressor of variegation, Enhancer of Zeste, Trithorax) and MYND (Myeloid-Nervy-DEAF1) domain-containing proteins (SMYD) have been found to methylate a variety of histone and non-histone targets which contribute to their various roles in cell regulation including chromatin remodeling, transcription, signal transduction, and cell cycle control. During early development, SMYD proteins are believed to act as an epigenetic regulator for myogenesis and cardiomyocyte differentiation as they are abundantly expressed in cardiac and skeletal muscle. SMYD proteins are also of therapeutic interest due to the growing list of carcinomas and cardiovascular diseases linked to SMYD overexpression or dysfunction making them a putative target for drug intervention. This review will examine the biological relevance and gather all of the current structural data of SMYD proteins.
doi:10.3390/ijms16011406
PMCID: PMC4307310  PMID: 25580534
SMYD (SET and MYND domain-containing proteins); structure and function; SET (Suppressor of variegation, Enhancer of Zeste, Trithorax); MYND (Myeloid-Nervy-DEAF1)
2.  Long non-coding RNA PVT1 is associated with tumor progression and predicts recurrence in hepatocellular carcinoma patients 
Oncology Letters  2014;9(2):955-963.
PVT1, which maps to chromosome 8q24, is a copy number amplification-associated long non-coding RNA. Overexpression of PVT1 is a powerful predictor of tumor progression and patient survival in a diverse range of cancer types. However, the association between PVT1 and hepatocellular carcinoma (HCC) remains unclear. The aim of the present study was to examine the expression pattern of PVT1, and its clinical significance in HCC. Between 2003 and 2012, reverse transcription-quantitative polymerase chain reaction was used to determine the expression levels of PVT1 in two independent cohorts: Cohort one, 58 HCC resection samples; and cohort 2, 214 HCC transplant samples. Additionally, the correlation between PVT1 expression levels and clinical parameters and outcomes was analyzed. The relative expression levels of PVT1 were significantly higher in cancerous tissues compared with the corresponding non-cancerous tissues (cohort one, P=0.0016; cohort two, P=0.0274). Furthermore, overexpression of PVT1 was associated with a higher serum α-fetoprotein expression level (P=0.011) and a higher recurrence rate (P=0.004). Kaplan-Meier analysis indicated that the patients with high PVT1 expression exhibited poor recurrence-free survival (P=0.021), and multivariate analysis demonstrated that high levels of PVT1 expression are an independent predictor for HCC recurrence (P=0.042; hazard ratio, 1.653). Thus, the high expression levels of PVT1 in HCC may serve as a novel biomarker for predicting tumor recurrence in HCC patients, and as a potential therapeutic target.
doi:10.3892/ol.2014.2730
PMCID: PMC4301564  PMID: 25624916
hepatocellular carcinoma; long non-coding RNA; PVT1; recurrence; progression
3.  Role of PDGFR-β/PI3K/AKT signaling pathway in PDGF-BB induced myocardial fibrosis in rats 
Objective: To investigate the role of PDGFR-β/PI3K/AKT signaling pathway in the myocardial fibrosis. Methods: CFs were divided into following 4 groups: control group (CON), PDGF-BB group (P), PDGF-BB+IMA group (IMA), and PDGF-BB+LY294002 (LY). Results: Immunofluorescence staining showed about 90% of cells were positive for vimentin and 10% for α-SMA. After incubation for 7 days, fluorescence microscopy revealed more than 90% of cells were positive for α-SMA, which was significantly higher than that in CON group (P < 0.01), but markedly lower than that in IMA group and LY group (P < 0.01). The mRNA and protein expression of PDGFR-β, Col I, Col III, PI3K and Akt increased dramatically at 48 h after PDGF-BB treatment when compared with CON group (P < 0.01). However, IMA and LY294002 significantly inhibited the expression of PDGFR-β and p-PI3K (P < 0.05). In addition, the mRNA expression of PDGFR-β, PI3K and Akt in IMA group and LY group was also markedly lower than those in P group (P < 0.01), and the mRNA and protein expression of Col I and Col III reduced remarkably when compared with P group (P < 0.01). Of note, the mRNA expression of PDGFR-α was comparable among 4 groups, and PDGFR-β expression after PDGF-BB treatment increased significantly when compared with PDGFR-α expression (P < 0.01). Conclusion: PDGF-BB may induce CF proliferation and their transformation into myofibroblasts, which leads to increased synthesis of collagen, resulting in myocardial fibrosis. This is closely associated with PDGFR-β, but not PDGFR-α. PDGFR-β/PI3K/Akt signaling pathway is involved in the PDGF-BB induced myocardial fibrosis.
PMCID: PMC4297339  PMID: 25628782
Myocardial fibrosis; myofibroblasts; platelet-derived growth factor; signaling pathway
4.  ''Minimizing tacrolimus'' strategy and long-term survival after liver transplantation 
World Journal of Gastroenterology : WJG  2014;20(32):11363-11369.
AIM: To investigate the effect of the ‘‘minimizing tacrolimus’’ strategy on long-term survival of patients after liver transplantation (LT).
METHODS: We conducted a retrospective study of 319 patients who received LT between January 2009 and December 2011 at the First Affiliated Hospital of Zhejiang University School of Medicine. Following elimination of ineligible patients, 235 patients were included in the study. The relationship between early tacrolimus (TAC) exposure and survival period was analyzed by Kaplan Meier curves. Adverse effects related to TAC were evaluated by the χ2 test. Routine monitoring of blood TAC concentration (TC) was performed using the PRO-TracTM II Tacrolimus Elisa Kit (Diasorin, United States).
RESULTS: Of 235 subjects enrolled in the study, 124 (52.8%) experienced adverse effects due to TAC. When evaluating mean TC, the survival time of patients with a mean TC < 5 ng/mL was significantly shorter than that in the other groups (911.3 ± 131.6 d vs 1381.1 ± 66.1 d, 911.3 ± 131.6 d vs 1327.3 ± 47.8 d, 911.3 ± 131.6 d vs 1343.2 ± 83.1 d, P < 0.05), while the survival times of patients with a mean TC of 5-7, 7-10 and 10-15 ng/mL were comparable. Adverse effects due to TAC in all four groups were not significantly different. When comparing the standard deviation (SD) of TC among the groups, the survival time of patients with a SD of 2-4 was significantly longer than that in the other groups (1388.8 ± 45.4 d vs 1029.6 ± 131.3 d, 1388.8 ± 45.4 d vs 1274.9 ± 57.0 d, P < 0.05), while in patients with a SD < 2 and SD > 4, the survival time was not statistically different. Adverse effects experienced in all three groups were not statistically different. In Cox regression analysis, male patients and those with a primary diagnosis of benign disease, mean TC > 5 ng/mL and TC SD 2-4 had better outcomes.
CONCLUSION: The early ‘‘minimizing tacrolimus’’ strategy with a mean TC of 5-10 ng/mL and SD of 2-4 was beneficial in terms of long-term survival after LT.
doi:10.3748/wjg.v20.i32.11363
PMCID: PMC4145777  PMID: 25170223
Tacrolimus; Liver transplantation; Outcome; Minimizing tacrolimus; Immunosuppressive drug
5.  Rhesus monkey is a new model of secondary lymphedema in the upper limb 
Objective: This study is to establish the rhesus monkey model of lymphedema in the upper limbs, and assess the suitability of this model. Methods: An animal model of lymphedema was established by the combined irradiation and surgical techniques in the upper limbs of these rhesus monkeys. Physical examination, high-resolution MR lymphangiography, bioelectrical impedance analysis (BIA), and immunohistochemical staining were performed to determine the severity of the edema in the upper limbs of the animal model. Results: Our results from physical examination indicated that the rhesus monkey model present with typical appearance and features of lymphedema. MR lymphangiography further demonstrated pathologically modified lymphatic vessels in our rhesus monkey model. BIA revealed increased water content in the upper limb in these rhesus monkeys, which was in line with the pathology of lymphedema. Immunohistochemical staining showed the curvature of the lymphatic vessels in the rhesus monkey model, typical pathological changes in lymphedema. Conclusion: Rhesus monkey lymphedema model provides a more consistent background to elucidate the pathophysiology of the disease. This new model would help to increase our understanding of acquired upper limb lymphedema, and promote the development of new treatments for this intractable disorder.
PMCID: PMC4203178  PMID: 25337207
Secondary lymphedema; rhesus monkeys; upper extremity; breast cancer; animal model
6.  ISL-1 is overexpressed in non-Hodgkin lymphoma and promotes lymphoma cell proliferation by forming a p-STAT3/p-c-Jun/ISL-1 complex 
Molecular Cancer  2014;13:181.
Background
Insulin enhancer binding protein-1 (ISL-1), a LIM-homeodomain transcription factor, is essential for the heart, motor neuron and pancreas development. Recently, ISL-1 has been found in some types of human cancers. However, how ISL-1 exerts the role in tumor development is not clear.
Methods and results
The expression of ISL-1 was assessed in 211 human lymphoma samples and 23 normal lymph node samples. Immunohistochemistry results demonstrated a markedly higher expression of ISL-1 in 75% of non-Hodgkin lymphoma (NHL) samples compared with that in normal lymph nodes or Hodgkin lymphoma (HL) samples. CCK-8 analysis, cell cycle assay and xenograft model were performed to characterize the association between ISL-1 expression level and biological functions in NHL. The results showed that ISL-1 overexpression obviously promoted NHL cells proliferation, changed the cell cycle distribution in vitro and significantly enhanced xenografted lymphoma development in vivo. Real-time PCR, Western blot, luciferase assay and ChIP assay were used to explore the potential regulatory targets of ISL-1 and the results demonstrated that ISL-1 activated the c-Myc expression in NHL by direct binding to a conserved binding site on the c-Myc enhancer. Further results revealed that ISL-1 could be positively regulated by the c-Jun N-terminal kinase (JNK) and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways. Both the JNK and JAK/STAT signaling inhibitors could significantly suppressed the growth of NHL cells through the down-regulation of ISL-1 as demonstrated by CCK-8 and Western blot assays. Bioinformatic analysis and luciferase assay exhibited that ISL-1 was a novel target of p-STAT3 and p-c-jun. ChIP, Co-IP and ChIP-re-IP analysis revealed that ISL-1 could participate with p-STAT3 and p-c-Jun to form a p-STAT3/p-c-Jun/ISL-1 transcriptional complex that binds directly on the ISL-1 promoter, demonstrating a positive feedback regulatory mechanism for ISL-1 expression in NHL.
Conclusions
Our results provide the first evidence that ISL-1 is tightly linked to NHL proliferation and development by promoting c-Myc transcription, and its aberrant expression was regulated by p-STAT3/p-c-Jun/ISL-1 complex activation.
doi:10.1186/1476-4598-13-181
PMCID: PMC4125377  PMID: 25070240
ISL-1; Lymphomagenesis; Signal transduction; Transcriptional complex
7.  Investigation of Data Representation Issues in Computerizing Clinical Practice Guidelines in China 
Healthcare Informatics Research  2014;20(3):236-242.
Objectives
From the point of view of clinical data representation, this study attempted to identify obstacles in translating clinical narrative guidelines into computer interpretable format and integrating the guidelines with data in Electronic Health Records in China.
Methods
Based on SAGE and K4CARE formulism, a Chinese clinical practice guideline for hypertension was modeled in Protégé by building an ontology that had three components: flowchart, node, and vMR. Meanwhile, data items imperative in Electronic Health Records for patients with hypertension were reviewed and compared with those from the ontology so as to identify conflicts and gaps between.
Results
A set of flowcharts was built. A flowchart comprises three kinds of node: State, Decision, and Act, each has a set of attributes, including data input/output that exports data items, which then were specified following ClinicalStatement of HL7 vMR. A total of 140 data items were extracted from the ontology. In modeling the guideline, some narratives were found too inexplicit to formulate, and encoding data was quite difficult. Additionally, it was found in the healthcare records that there were 8 data items left out, and 10 data items defined differently compared to the extracted data items.
Conclusions
The obstacles in modeling a clinical guideline and integrating with data in Electronic Health Records include narrative ambiguity of the guideline, gaps and inconsistencies in representing some data items between the guideline and the patient' records, and unavailability of a unified medical coding system. Therefore, collaborations among various participants in developing guidelines and Electronic Health Record specifications is needed in China.
doi:10.4258/hir.2014.20.3.236
PMCID: PMC4141139  PMID: 25152838
Clinical Practice Guideline; Standardization; Knowledge Representation; Clinical Decision Support Systems
8.  Structure of the bacteriophage T4 DNA adenine methyltransferase 
Nature structural biology  2003;10(10):849-855.
DNA-adenine methylation at certain GATC sites plays a pivotal role in bacterial and phage gene expression as well as bacterial virulence. We report here the crystal structures of the bacteriophage T4Dam DNA adenine methyltransferase (MTase) in a binary complex with the methyl-donor product S-adenosyl-L-homocysteine (AdoHcy) and in a ternary complex with a synthetic 12-bp DNA duplex and AdoHcy. T4Dam contains two domains: a seven-stranded catalytic domain that harbors the binding site for AdoHcy and a DNA binding domain consisting of a five-helix bundle and a β-hairpin that is conserved in the family of GATC-related MTase orthologs. Unexpectedly, the sequence-specific T4Dam bound to DNA in a nonspecific mode that contained two Dam monomers per synthetic duplex, even though the DNA contains a single GATC site. The ternary structure provides a rare snapshot of an enzyme poised for linear diffusion along the DNA.
doi:10.1038/nsb973
PMCID: PMC4030375  PMID: 12937411
9.  Histological complete response to a combined docetaxel/cisplatin/fluorouracil neoadjuvant chemotherapy for T4 stage gastric adenocarcinoma 
Local advanced gastric carcinoma has a very poor prognosis. When a T4 gastric carcinoma has invaded the surrounding tissues and organs, curative resection is unlikely. We present here a case of a 63-year-old woman with a T4 unresectable gastric adenocarcinoma. She underwent two 3-week cycles of docetaxel/cisplatin/fluorouracil chemotherapy, followed by radical gastric resection. Each cycle consisted of 75 mg/m2 docetaxel and 75 mg/m2 cisplatin on day 1, and 200 mg/m2 leucovorin and 500 mg/m2 fluorouracil on days 1 through 5. The patient exhibited a complete histologic response. Our results indicate that docetaxel/cisplatin/fluorouracil neoadjuvant chemotherapy is a promising method of treatment for advanced gastric cancer.
doi:10.1186/1477-7819-12-150
PMCID: PMC4032865  PMID: 24885421
Gastric cancer; neoadjuvant chemotherapy; docetaxel; cisplatin; fluorouracil
10.  High throughput immunosenor based on multi-label strategy and a novel array electrode 
Scientific Reports  2014;4:4747.
Accurate prediction of a particular cancer can be achieved by measuring multiplex biomarkers. Traditional methods for multi-biomarkers detection are either multi-spots assay with chip or multi-label assay with one detection spot. However, the detection throughput of these two approaches is limited by the substrate area and the numbers of available label respectively. To solve this problem, in the present study, an immunoassay was firstly prepared by combining multi-label strategy and multi-spot assay with a novel array electrode for simultaneous detection of six biomarkers for hepatocellular carcinoma (HCC). The detection throughput of the proposed method was doubled in comparison with traditional multi-spots assay (one target protein was detected on each analytic spot), which could greatly enhance the sensitivity and specificity of HCC diagnosis. This detection model may serve as the starting point for high throughput of multianalyte assay.
doi:10.1038/srep04747
PMCID: PMC3996466  PMID: 24756073
11.  Long Non-Coding RNA HOTAIR Promotes Cell Migration and Invasion via Down-Regulation of RNA Binding Motif Protein 38 in Hepatocellular Carcinoma Cells 
Long non-coding RNA HOTAIR exerts regulatory functions in various biological processes in cancer cells, such as proliferation, apoptosis, mobility, and invasion. We previously found that HOX transcript antisense RNA (HOTAIR) is a negative prognostic factor and exhibits oncogenic activity in hepatocellular carcinoma (HCC). In this study, we aimed to investigate the role and molecular mechanism of HOTAIR in promoting HCC cell migration and invasion. Firstly, we profiled its gene expression pattern by microarray analysis of HOTAIR loss in Bel-7402 HCC cell line. The results showed that 129 genes were significantly down-regulated, while 167 genes were significantly up-regulated (fold change >2, p < 0.05). Bioinformatics analysis indicated that RNA binding proteins were involved in this biological process. HOTAIR suppression using RNAi strategy with HepG2 and Bel-7402 cells increased the mRNA and protein expression levels of RNA binding motif protein 38 (RBM38). Moreover, the expression levels of RBM38 in HCC specimens were significantly lower than paired adjacent noncancerous tissues. In addition, knockdown of HOTAIR resulted in a decrease of cell migration and invasion, which could be specifically rescued by down-regulation of RBM38. Taken together, HOTAIR could promote migration and invasion of HCC cells by inhibiting RBM38, which indicated critical roles of HOTAIR and RBM38 in HCC progression.
doi:10.3390/ijms15034060
PMCID: PMC3975384  PMID: 24663081
RNA binding motif protein 38; HOX transcript antisense RNA; hepatocellular carcinoma; long non-coding RNA
12.  Single Nucleotide Polymorphisms in the Metastasis-associated in Colon Cancer-1 Gene Predict the Recurrence of Hepatocellular Carcinoma after Transplantation 
Background: The newly identified metastasis-associated in colon cancer-1 (MACC1) gene is involved in angiogenesis, epithelial-to-mesenchymal transition (EMT), invasiveness, and metastasis in a variety of malignancies. Overexpression of MACC1 gene is a prognostic marker for poor outcome of hepatocellular carcinoma (HCC) patients. However, the association between genetic polymorphisms of MACC1 gene and poor outcome in HCC has been not been performed. We therefore investigated the correlation of MACC1 single nucleotide polymorphisms (SNPs) with tumor recurrence and overall survival in HCC patients undergoing liver transplantation (LT). Methods: The study included 187 HCC patients treated with LT. Five polymorphisms in the MACC1 gene (rs1990172, rs3735615, rs4721888, rs2241056, rs975263) were genotyped in 183 cases of tumorous tissue sample and 117 cases of adjacent normal tissue sample using SNaP-Shot assays. The association of SNPs with tumor recurrence and overall survival was then analyzed by additive, dominant, recessive, and overdominant models in a cohort of 156 HCC patients. Results: In terms of tumor recurrence, heterozygous of SNP rs1990172 and SNP rs975263 showed a significant high risk of relapse using univariate and multivariate analysis (overdominant, HR(95%CI)=2.27 [1.41-3.66], P=0.001; HR(95%CI)=2.16 [1.37-3.39], P=0.001). But the difference between heterozygous of these two SNPs and overall survival did not reach a significance in all models. The other three investigated SNPs were not significantly associated with tumor recurrence and overall survival (P>0.05). In addition, we found no significant difference in genotype frequencies between HCC and controls. Conclusions: Our data suggest that SNP rs1990172 and SNP rs975263 in the MACC1 gene may be potential genetic markers for HCC recurrence in LT patients.
doi:10.7150/ijms.7142
PMCID: PMC3894398  PMID: 24465159
metastasis-associated in colon cancer-1; epithelial-to-mesenchymal transition
13.  Role of overexpression of MACC1 and/or FAK in predicting prognosis of hepatocellular carcinoma after liver transplantation 
Background: Metastasis-associated in colon cancer-1 (MACC1) acts as a promoter of tumor metastasis; however, the predictive value of MACC1 for hepatocellular carcinoma (HCC) after liver transplantation (LT) remains unclear.
Methods: We examined the expression of MACC1 and its target genes MET and FAK by quantitative PCR in 160 patients with HCC that was undergone LT.
Results: The patients with MACC1high or FAKhigh in HCCs showed a significantly shorter overall survival and higher cumulative recurrence rates after liver transplantation (LT), compared with MACC1low or FAKlow group. Multivariate analysis indicated that MACC1 alone or combination of MACC1/FAK was an independent prognostic factor for overall survival and cumulative recurrence.
Conclusions: MACC1 or combination of MACC1/FAK could serve as a novel biomarker in predicting the prognosis of HCC after LT.
doi:10.7150/ijms.7769
PMCID: PMC3917116  PMID: 24516351
hepatocellular carcinoma; metastasis-associated in colon cancer-1; metastasis; prognosis; liver transplantation
14.  New Conformational State of NHERF1-CXCR2 Signaling Complex Captured by Crystal Lattice Trapping 
PLoS ONE  2013;8(12):e81904.
NHERF1 is a PDZ adaptor protein that scaffolds the assembly of diverse signaling complexes and has been implicated in many cancers. However, little is known about the mechanism responsible for its scaffolding promiscuity or its ability to bind to multiple targets. Computational studies have indicated that PDZ promiscuity may be attributed to its conformational dynamics, but experimental evidence for this relationship remains very limited. Here we examine the conformational flexibility of the NHERF1 PDZ1 domain using crystal lattice trapping via solving PDZ1 structure of a new crystal form. The structure, together with prior PDZ1 structures of a different space group, reveals that 4 of 11 ligand-interacting residues undergo significant crystal packing-induced structural changes. Most of these residues correspond to the residues involved in allosteric transition when a peptide ligand binds. In addition, a subtle difference in ligand conformations causes the same peptide to bind in slightly different modes in different crystal forms. These findings indicate that substantial structural flexibility is present in the PDZ1 peptide-binding pocket, and the structural substate trapped in the present crystal form can be utilized to represent the conformational space accessible to the protein. Such knowledge will be critical for drug design against the NHERF1 PDZ1 domain, highlighting the continued need for experimentally determined PDZ1-ligand complexes.
doi:10.1371/journal.pone.0081904
PMCID: PMC3858284  PMID: 24339979
15.  Effects of Exopolysaccharide Production on Liquid Vegetative Growth, Stress Survival and Stationary Phase Recovery in Myxococcus xanthus 
Journal of microbiology (Seoul, Korea)  2012;50(2):10.1007/s12275-012-1349-5.
Exopolysaccharide (EPS) of Myxococcus xanthus is a well-regulated cell surface component. In addition to its known functions for social motility and fruiting body formation on solid surfaces, EPS has also been proposed to play a role in multi-cellular clumping in liquid medium, though this phenomenon has not been well studied. In this report, we confirmed that M. xanthus clumps formed in liquid were correlated with EPS levels and demonstrated that the EPS encased cell clumps exhibited biofilm-like structures. The clumps protected the cells at physiologically relevant EPS concentrations, while cells lacking EPS exhibited significant reduction in long-term viability and resistance to stressful conditions. However, excess EPS production was counterproductive to vegetative growth and viable cell recovery declined in extended late stationary phase as cells became trapped in the matrix of clumps. Therefore, optimal EPS production by M. xanthus is important for normal physiological functions in liquid.
doi:10.1007/s12275-012-1349-5
PMCID: PMC3819231  PMID: 22538652
Myxococcus xanthus; exopolysaccharide; vegetative growth; stress survival; stationary phase recovery
16.  Structural Insights into Neutrophilic Migration Revealed by the Crystal Structure of the Chemokine Receptor CXCR2 in Complex with the First PDZ Domain of NHERF1 
PLoS ONE  2013;8(10):e76219.
Neutrophil plays an essential role in host defense against infection, but uncontrolled neutrophilic infiltration can cause inflammation and severe epithelial damage. We recently showed that CXCR2 formed a signaling complex with NHERF1 and PLC-2, and that the formation of this complex was required for intracellular calcium mobilization and neutrophilic transepithelial migration. To uncover the structural basis of the complex formation, we report here the crystal structure of the NHERF1 PDZ1 domain in complex with the C-terminal sequence of CXCR2 at 1.16 Å resolution. The structure reveals that the CXCR2 peptide binds to PDZ1 in an extended conformation with the last four residues making specific side chain interactions. Remarkably, comparison of the structure to previously studied PDZ1 domains has allowed the identification of PDZ1 ligand-specific interactions and the mechanisms that govern PDZ1 target selection diversities. In addition, we show that CXCR2 can bind both NHERF1 PDZ1 and PDZ2 in pulldown experiments, consistent with the observation that the peptide binding pockets of these two PDZ domains are highly structurally conserved. The results of this study therefore provide structural basis for the CXCR2-mediated neutrophilic migration and could have important clinical applications in the prevention and treatment of numerous neutrophil-dependent inflammatory disorders.
doi:10.1371/journal.pone.0076219
PMCID: PMC3788737  PMID: 24098448
18.  Reduced expression of DACT2 promotes hepatocellular carcinoma progression: involvement of methylation-mediated gene silencing 
Background
Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies in humans, and its prognosis is generally poor even after surgery. Many advances have been made to understand the pathogenesis of HCC; however, the molecular mechanisms that lead to hepatocarcinogenesis and progression are still not clearly understood.
Methods
The expression of DACT2 in specimens from 30 paired HCCs and an additional 61 HCC patients after liver transplantation was evaluated by quantitative RT-PCR and immunohistochemical analysis. We investigated the methylation status of the DACT2 promoter region. We also analyzed the alterations of the cell cycle, migration and invasion after DACT2 knockdown.
Results
The expression level of DACT2 was significantly lower in HCC tissues than in non-cancerous tissues. Reduced DACT2 expression was associated with large tumor size. DACT2 transcripts were at low levels in hypermethylated liver cancer cells and were restored by exposure to a demethylating agent. Reduced expression of DACT2 in MHCC97L cells induced G1/S arrest, increased cell proliferation, and promoted cell invasion.
Conclusions
Our study suggests that DACT2 is silenced by promoter hypermethylation, and reduced DACT2 can promote liver cancer progression. DACT2 may serve as a novel tumor suppressor gene in HCC.
doi:10.1186/1477-7819-11-57
PMCID: PMC3605395  PMID: 23496880
DACT2; Hepatocellular carcinoma; Methylation; Progression
19.  A WAVE2–Arp2/3 actin nucleator apparatus supports junctional tension at the epithelial zonula adherens 
Molecular Biology of the Cell  2012;23(23):4601-4610.
WAVE2–Arp2/3 is a major nucleator of actin assembly at the zonula adherens and likely acts in response to junctional Rac signaling. It supports myosin II recruitment to, and tension generation at, the junction.
The epithelial zonula adherens (ZA) is a specialized adhesive junction where actin dynamics and myosin-driven contractility coincide. The junctional cytoskeleton is enriched in myosin II, which generates contractile force to support junctional tension. It is also enriched in dynamic actin filaments, which are replenished by ongoing actin assembly. In this study we sought to pursue the relationship between actin assembly and junctional contractility. We demonstrate that WAVE2–Arp2/3 is a major nucleator of actin assembly at the ZA and likely acts in response to junctional Rac signaling. Furthermore, WAVE2–Arp2/3 is necessary for junctional integrity and contractile tension at the ZA. Maneuvers that disrupt the function of either WAVE2 or Arp2/3 reduced junctional tension and compromised the ability of cells to buffer side-to-side forces acting on the ZA. WAVE2–Arp2/3 disruption depleted junctions of both myosin IIA and IIB, suggesting that dynamic actin assembly may support junctional tension by facilitating the local recruitment of myosin.
doi:10.1091/mbc.E12-08-0574
PMCID: PMC3510021  PMID: 23051739
20.  6-Nitro-1,3-benzothia­zole-2(3H)-thione 
In the title mol­ecule, C7H4N2O2S2, the nitro group is twisted by 5.5 (1)° from the plane of the attached benzene ring. In the crystal, N—H⋯S hydrogen bonds link pairs of mol­ecules into inversion dimers, which are linked by weak C—H⋯O inter­actions into sheets parallel to (101). The crystal packing exhibits short inter­molecular S⋯O contacts of 3.054 (4) Å and π–π inter­actions of 3.588 (5) Å between the centroids of the five- and six-membered rings of neighbouring mol­ecules.
doi:10.1107/S1600536812049719
PMCID: PMC3569234  PMID: 23424457
21.  Direct visualization of the interaction between pilin and exopolysaccharides of Myxococcus xanthus with eGFP fused PilA protein 
FEMS microbiology letters  2011;326(1):23-30.
Type IV pili (TFP) and exopolysaccharides (EPS) are important components for social behaviors in Myxococcus xanthus, including gliding motility and fruiting body formation. Although specific interactions between TFP and EPS have been proposed, direct observations of these interactions under native condition have not yet been made. In this study, we found that a truncated PilA protein (PilACt) which only contains the C-terminal domain (amino acids 32-208) is sufficient for EPS binding in vitro. Furthermore, an enhanced green fluorescent protein (eGFP) and PilACt fusion protein was constructed and used to label the native EPS in M. xanthus. Under confocal laser scanning microscope, the eGFP-PilACt-bound fruiting bodies, trail structures and biofilms exhibited similar patterns as the wheat germ agglutinin lectin (WGA)-labeled EPS structures. This study showed that eGFP-PilACt fusion protein was able to efficiently label the EPS of M. xanthus and for the first time provided evidence for the direct interaction between the PilA protein and EPS under native conditions.
doi:10.1111/j.1574-6968.2011.02430.x
PMCID: PMC3454480  PMID: 22092602
Type IV Pilin; Exopolysaccharides; Biofilm; Fruiting body; Confocal laser scanning microscopy; eGFP
22.  Prognostic Role of C-Reactive Protein in Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis 
Background: C-reactive protein (CRP) which used to be a prototypical inflammatory cytokine has been identified involving in the progression of tumor-promoting inflammation. Several studies have indicated that CRP is a predictor for hepatocellular carcinoma (HCC), but the results are controversial. Methods: We conducted a systematic review of ten studies (1885 patients) to examine the association of high serum CRP expression with overall survival (OS) and recurrence-free survival (RFS) in HCC patients by meta-analysis. Moreover, the correlation between high serum CRP and tumor clinicopathological parameters was also assessed. Hazard ratio (HR) or odds ratio (OR) with its 95% confidence interval (CI) was used as the effect size estimate. Results: Our pooled results showed that high expression level of serum CRP (≥10 mg/L) was associated with poor OS (HR: 2.15, 95% CI: 1.76-2.63) and RFS (HR: 2.66, 95% CI: 1.54-4.58) in HCC. Serum CRP overexpression (≥10 mg/L) was also significantly associated with the presence of tumor vascular invasion (OR: 3.05, 95% CI: 1.79-5.23), multiple tumor (OR: 2.36, 95% CI: 1.36-4.10), larger tumor size (OR: 3.41, 95% CI: 1.04-11.18), and advanced TNM stage (OR: 3.23, 95% CI: 2.29-4.57). In addition, serum CRP overexpression (≥10 mg/L) tended to be correlated with poor differentiation (OR: 1.58, 95% CI: 0.74-3.39), though not significantly. Conclusion: The present systematic review and meta-analysis demonstrate that high serum level of CRP (≥10 mg/L) denotes a poor prognosis of patients with HCC.
doi:10.7150/ijms.6050
PMCID: PMC3619114  PMID: 23569429
C-reactive protein; hepatocellular carcinoma; prognosis; survival.
23.  DNA Builds and Strengthens the Extracellular Matrix in Myxococcus xanthus Biofilms by Interacting with Exopolysaccharides 
PLoS ONE  2012;7(12):e51905.
One intriguing discovery in modern microbiology is the extensive presence of extracellular DNA (eDNA) within biofilms of various bacterial species. Although several biological functions have been suggested for eDNA, including involvement in biofilm formation, the detailed mechanism of eDNA integration into biofilm architecture is still poorly understood. In the biofilms formed by Myxococcus xanthus, a Gram-negative soil bacterium with complex morphogenesis and social behaviors, DNA was found within both extracted and native extracellular matrices (ECM). Further examination revealed that these eDNA molecules formed well organized structures that were similar in appearance to the organization of exopolysaccharides (EPS) in ECM. Biochemical and image analyses confirmed that eDNA bound to and colocalized with EPS within the ECM of starvation biofilms and fruiting bodies. In addition, ECM containing eDNA exhibited greater physical strength and biological stress resistance compared to DNase I treated ECM. Taken together, these findings demonstrate that DNA interacts with EPS and strengthens biofilm structures in M. xanthus.
doi:10.1371/journal.pone.0051905
PMCID: PMC3530553  PMID: 23300576
24.  Neuroendocrine carcinoma of the pancreas with soft tissue metastasis 
Neuroendocrine carcinoma (NEC) of the pancreas is rare. We report the case of a 34-year-old man with pancreatic NEC with soft tissue metastasis. The patient presented with right upper abdominal discomfort. Computed tomography revealed a low-density heterogeneous mass in the tail and body of the pancreas that encroached on the greater curvature of the stomach and spleen. We performed exploratory laparotomy and total pancreatectomy with splenectomy and total gastrectomy. Histopathological analysis showed spindle-shaped cells with scanty cytoplasm and hyperchromatic nuclei, confirming a primary pancreatic NEC. One month after the surgery, the patient experienced leg swelling. Positron emission tomography-computed tomography revealed high uptake of fludeoxyglucose in the left leg, and the leg was amputated. Histopathological analysis confirmed metastasis of pancreatic NEC. The patient was followed up and received chemotherapy (etoposide and cisplatin). One month after amputation, the level of tumor marker neuron-specific enolase was 142.70 μg/L and computed tomography scan revealed an aggravated metastatic lesion. The patient suffered from unbearable pain and we treated him with odynolysis. Four months postoperatively, the patient died of respiratory failure.
doi:10.3748/wjg.v18.i45.6682
PMCID: PMC3516215  PMID: 23236246
Neuroendocrine carcinoma; Pancreas; Soft tissue metastasis; Neuron-specific enolase; Positron emission tomography-computed tomography
25.  Alanine 32 in PilA is important for PilA stability and type IV pili function in Myxococcus xanthus 
Microbiology  2011;157(Pt 7):1920-1928.
Type IV pili (TFP) are membrane-anchored filaments with a number of important biological functions. In the model organism Myxococcus xanthus, TFP act as molecular engines that power social (S) motility through cycles of extension and retraction. TFP filaments consist of several thousand copies of a protein called PilA or pilin. PilA contains an N-terminal α-helix essential for TFP assembly and a C-terminal globular domain important for its activity. The role of the PilA sequence and its structure–function relationship in TFP-dependent S motility remain active areas of research. In this study, we identified an M. xanthus PilA mutant carrying an alanine to valine substitution at position 32 in the α-helix, which produced structurally intact but retraction-defective TFP. Characterization of this mutant and additional single-residue variants at this position in PilA demonstrated the critical role of alanine 32 in PilA stability, TFP assembly and retraction.
doi:10.1099/mic.0.049684-0
PMCID: PMC3167889  PMID: 21493683

Results 1-25 (48)