Stefanska B.,McGill University |
Huang J.,Chinese National Human Genome Center at Shanghai |
Bhattacharyya B.,McGill University |
Suderman M.,McGill University |
And 3 more authors.
Cancer Research | Year: 2011
We use hepatic cellular carcinoma (HCC), one of the most common human cancers, as a model to delineate the landscape of promoter hypomethylation in cancer. Using a combination of methylated DNA immunoprecipitation and hybridization with comprehensive promoter arrays, we have identified approximately 3,700 promoters that are hypomethylated in tumor samples. The hypomethylated promoters appeared in clusters across the genome suggesting that a high-level organization underlies the epigenomic changes in cancer. In normal liver, most hypomethylated promoters showed an intermediate level of methylation and expression, however, high-CpG dense promoters showed the most profound increase in gene expression. The demethylated genes are mainly involved in cell growth, cell adhesion and communication, signal transduction, mobility, and invasion; functions that are essential for cancer progression and metastasis. The DNA methylation inhibitor, 5- aza-2′-deoxycytidine, activated several of the genes that are demethylated and induced in tumors, supporting a causal role for demethylation in activation of these genes. Previous studies suggested that MBD2 was involved in demethylation of specific human breast and prostate cancer genes. Whereas MBD2 depletion in normal liver cells had little or no effect, we found that its depletion in human HCC and adenocarcinoma cells resulted in suppression of cell growth, anchorage-independent growth and invasiveness as well as an increase in promoter methylation and silencing of several of the genes that are hypomethylated in tumors. Taken together, the findings define the potential functional role of hypomethylation in cancer. ©2011 AACR.
Han Z.-G.,Shanghai JiaoTong University |
Han Z.-G.,Chinese National Human Genome Center at Shanghai
Annual Review of Genomics and Human Genetics | Year: 2012
Liver cancer is the sixth-most-common cancer overall but the third-most-frequent cause of cancer death. Among primary liver cancers, hepatocellular carcinoma (HCC), the major histological subtype, is associated with multiple risk factors, including hepatitis B and C virus infection, alcohol consumption, obesity, and diet contamination. Although previous studies have revealed that certain genetic and epigenetic changes, such as TP53 and β-catenin mutations, occur in HCC cells, the pathogenesis of this cancer remains obscure. Functional genomic approaches-including genome-wide association studies, whole-genome and whole-exome sequencing, array-based comparative genomic hybridization, global DNA methylome mapping, and gene or noncoding RNA expression profiling-have recently been applied to HCC patients with different clinical features to uncover the genetic risk factors and underlying molecular mechanisms involved in this cancer's initiation and progression. The genome-wide analysis of germline and somatic genetic and epigenetic events facilitates understanding of the pathogenesis and molecular classification of liver cancer as well as the identification of novel diagnostic biomarkers and therapeutic targets for cancer. © 2012 by Annual Reviews. All rights reserved.
Zhang J.,Shanghai JiaoTong University |
Zhang J.,Shanghai Key Laboratory of Stomatology |
Sun Q.,Shanghai JiaoTong University |
Zhang Z.,Shanghai JiaoTong University |
And 6 more authors.
Oncogene | Year: 2013
Dysregulated microRNAs (miRNAs) have an important role in many malignant tumors. However, elucidating the roles of miRNAs in cancer biology, especially in epithelial cancers, remains an ongoing process. In this study, we show that both miR-143 and miR-145, which belong to the same miRNA cluster, can negatively modulate expression of their target gene, MDM2. The miR-143 and miR-145 is posttranscriptionally activated by upregulated p53, thereby generating a short miRNAs-MDM2-p53 feedback loop. Re-expression of these miRNAs suppresses cellular growth and triggers the apoptosis of epithelial cancer, in vitro and in vivo, by enhancing p53 activity via MDM2 turnover. Moreover, the miRNA-dependent MDM2 turnover contributes to the equilibrium of repeated p53 pulses in response to DNA damage stress. These findings suggest that MDM2 dysregulation caused by downregulation of miR-143 and miR-145 contributes to epithelial cancer development and has a key role in regulating cellular proliferation and apoptosis. Re-expression of miR-143 and miR-145 may be a reasonable strategy for treatment of epithelial cancers. © 2013 Macmillan Publishers Limited.
Chen W.-H.,CAS Institute of Plant Physiology and Ecology |
Chen W.-H.,Chinese National Human Genome Center at Shanghai |
Chen W.-H.,Shanghai JiaoTong University |
Qin Z.-J.,CAS Institute of Plant Physiology and Ecology |
And 4 more authors.
Nucleic Acids Research | Year: 2013
Techniques for assembly of designed DNA sequences are important for synthetic biology. So far, a few methods have been developed towards high-throughput seamless DNA assembly in vitro, including both the homologous sequences-based system and the type IIS-mediated system. Here, we describe a novel method designated 'MASTER Ligation', by which multiple DNA sequences can be seamlessly assembled through a simple and sequence-independent hierarchical procedure. The key restriction endonuclease used, MspJI, shares both type IIM and type IIS properties; thus, it only recognizes the methylation-specific 4-bp sites, mCNNR (R = A or G), and cuts DNA outside of the recognition sequences. This method was tested via successful assembly of either multiple polymerase chain reaction amplicons or restriction fragments of the actinorhodin biosynthetic cluster of Streptomyces coelicolor (∼29 kb), which was further heterologously expressed in a fast-growing and moderately thermophilic strain, Streptomyces sp. 4F. © 2013 The Author(s).
Cheng N.,Shanghai JiaoTong University |
Cheng N.,Chinese National Human Genome Center at Shanghai |
Li Y.,Chinese National Human Genome Center at Shanghai |
Han Z.-G.,Shanghai JiaoTong University |
Han Z.-G.,Chinese National Human Genome Center at Shanghai
Hepatology | Year: 2013
Hepatocellular carcinoma (HCC) is one of the most common cancers and shows a propensity to metastasize and infiltrate adjacent and more distant tissues. However, the mechanisms that contribute to tumor metastasis remain unclear. Here we evaluate the effect of Argonaute2 (Ago2), a member of the Ago gene family that plays a role in short interfering RNA-mediated gene silencing, on HCC tumorigenesis, and metastasis. We found that Ago2 was frequently up-regulated in HCC specimens compared to that in corresponding adjacent nontumor liver. Interestingly, Ago2 overexpression can promote proliferation, colony formation in an anchor-independent manner, migration, tumorigenicity, and metastasis of HCC cells in vivo; in contrast, Ago2 knockdown can restrict anchor-independent colony formation, migration, and tumor metastasis of HCC cells in vivo. However, known microRNAs related to tumor metastasis appeared not be deregulated with Ago2 overexpression in HCC cells; even the knockdown of Dicer, which is responsible for microRNA biosynthesis, did not abolish the actions of Ago2 in HCC cells. Significantly, focal adhesion kinase (FAK), a well-known molecule associated with tumor metastasis, was up-regulated as a result of Ago2 overexpression. Chromatin immunoprecipitation assay showed that Ago2 can bind to the FAK promoter and then trigger its transcription. Moreover, an increased DNA copy number of Ago2 on chromosome 8q24, one of the most frequent DNA amplified regions, was validated and shown by way of fluorescence in situ hybridization. Conclusion: Our data demonstrate that Ago2 overexpression, as a result of genomic DNA amplification, promotes HCC tumorigenesis and metastasis by way of up-regulation of FAK transcription, thereby providing new insight into HCC progression and Ago2 function. (HEPATOLOGY 2013) Copyright © 2012 American Association for the Study of Liver Diseases.
Chen N.,CAS Shanghai Institute of Applied Physics |
He Y.,Soochow University of China |
Su Y.,CAS Shanghai Institute of Applied Physics |
Su Y.,Soochow University of China |
And 6 more authors.
Biomaterials | Year: 2012
Semiconductor Quantum dots (QDs) have raised great attention because of their superior optical properties and wide utilization in biological and biomedical studies. More recently, there have been intense concerns on cytotoxicity assessment of QDs. Most QDs are made of heavy metal ions (e.g., Cd 2+), which may result in potential in vitro toxicity that hampers their practical applications. In this article, we aim to summarize recent progress on mechanistic studies of cytotoxicity of II-IV QDs. We have studied the cytotoxicity of a series of aqueous synthesized QDs (aqQDs), i.e. CdTe, CdTe/CdS core-shell structured and CdTe/CdS/ZnS core-shell-shell structured aqQDs. Our results suggested that released cadmium ions are responsible for the observed cytotoxicity of cadmium-based QDs. The fact that CdTe/CdS/ZnS core-shell-shell structured QDs are nearly nontoxic to cells further confirmed the role of released cadmium ions on cytotoxicity, and the effective protection of the ZnS shell. However, intracellular level of Cd 2+ ions cannot be the only reason since the comparison with CdCl 2-treated cells suggests there are other factors contributed to the cytotoxicity of aqQDs. Our studies on genome-wide gene expression profiling and subcellular localization of aqQDs with synchrotron-based scanning transmission X-ray microscopy (STXM) further suggest that the cytotoxicity of CdTe QDs not only comes from the release of Cd 2+ ions but also intracellular distribution of QD nanoparticles in cells and the associated nanoscale effects. © 2011 Elsevier Ltd.
Jin W.,Chinese Academy of Sciences |
Wang S.,Harvard University |
Wang H.,Chinese National Human Genome Center at Shanghai |
Jin L.,Fudan University |
Xu S.,Chinese Academy of Sciences
American Journal of Human Genetics | Year: 2012
The processes of genetic admixture determine the haplotype structure and linkage disequilibrium patterns of the admixed population, which is important for medical and evolutionary studies. However, most previous studies do not consider the inherent complexity of admixture processes. Here we proposed two approaches to explore population admixture dynamics, and we demonstrated, by analyzing genome-wide empirical and simulated data, that the approach based on the distribution of chromosomal segments of distinct ancestry (CSDAs) was more powerful than that based on the distribution of individual ancestry proportions. Analysis of 1,890 African Americans showed that a continuous gene flow model, in which the African American population continuously received gene flow from European populations over about 14 generations, best explained the admixture dynamics of African Americans among several putative models. Interestingly, we observed that some African Americans had much more European ancestry than the simulated samples, indicating substructures of local ancestries in African Americans that could have been caused by individuals from some particular lineages having repeatedly admixed with people of European ancestry. In contrast, the admixture dynamics of Mexicans could be explained by a gradual admixture model in which the Mexican population continuously received gene flow from both European and Amerindian populations over about 24 generations. Our results also indicated that recent gene flows from Sub-Saharan Africans have contributed to the gene pool of Middle Eastern populations such as Mozabite, Bedouin, and Palestinian. In summary, this study not only provides approaches to explore population admixture dynamics, but also advances our understanding on population history of African Americans, Mexicans, and Middle Eastern populations. © 2012 The American Society of Human Genetics.
Liu H.-S.,National Engineering Research Center for Biochip at Shanghai |
Liu H.-S.,Chinese National Human Genome Center at Shanghai |
Liu H.-S.,Tongji University |
Xiao H.-S.,National Engineering Research Center for Biochip at Shanghai |
Xiao H.-S.,Chinese National Human Genome Center at Shanghai
World Journal of Gastroenterology | Year: 2014
Gastric cancer is the fourth most common cancer in the world and the second leading cause of cancer-related death. More than 80% of diagnoses occur at the middle to late stage of the disease, highlighting an urgent need for novel biomarkers detectable at earlier stages. Recently, aberrantly expressed microRNAs (miRNAs) have received a great deal of attention as potential sensitive and accurate biomarkers for cancer diagnosis and prognosis. This review summarizes the current knowledge about potential miRNA biomarkers for gastric cancer that have been reported in the publicly available literature between 2008 and 2013. Available evidence indicates that aberrantly expressed miRNAs in gastric cancer correlate with tumorigenesis, tumor proliferation, distant metastasis and invasion. Furthermore, tissue and cancer types can be classified using miRNA expression profiles and next-generation sequencing. As miRNAs in plasma/serum are well protected from RNases, they remain stable under harsh conditions. Thus, potential functions of these circulating miRNAs can be deduced and may implicate their diagnostic value in cancer detection. Circulating miRNAs, as well as tissue miRNAs, may allow for the detection of gastric cancer at an early stage, prediction of prognosis, and monitoring of recurrence and/or lymph node metastasis. Taken together, the data suggest that the participation of miRNAs in biomarker development will enhance the sensitivity and specificity of diagnostic and prognostic tests for gastric cancer. © 2014 Baishideng Publishing Group Inc. All rights reserved.
Insights into hepatopancreatic functions for nutrition metabolism and ovarian development in the crab Portunus trituberculatus: Gene discovery in the comparative transcriptome of different hepatopancreas stages
Wang W.,Shanghai Ocean University |
Wu X.,Shanghai Ocean University |
Liu Z.,Shanghai Ocean University |
Zheng H.,Chinese National Human Genome Center at Shanghai |
Cheng Y.,Shanghai Ocean University
PLoS ONE | Year: 2014
The crustacean hepatopancreas has different functions including absorption, storage of nutrients and vitellogenesis during growth, and ovarian development. However, genetic information on the biological functions of the crustacean hepatopancreas during such processes is limited. The swimming crab, Portunus trituberculatus, is a commercially important species for both aquaculture and fisheries in the Asia-Pacific region. This study compared the transcriptome in the hepatopancreas of female P. trituberculatus during the growth and ovarian maturation stages by 454 high-throughput pyrosequencing and bioinformatics. The goal was to discover genes in the hepatopancreas involved in food digestion, nutrition metabolism and ovarian development, and to identify patterns of gene expression during growth and ovarian maturation. Our transcriptome produced 303,450 reads with an average length of 351 bp, and the high quality reads were assembled into 21,635 contigs and 31,844 singlets. Based on BLASTP searches of the deduced protein sequences, there were 7,762 contigs and 4,098 singlets with functional annotation. Further analysis revealed 33,427 unigenes with ORFs, including 17,388 contigs and 16,039 singlets in the hepatopancreas, while only 7,954 unigenes (5,691 contigs and 2,263 singlets) with the predicted protein sequences were annotated with biological functions. The deduced protein sequences were assigned to 3,734 GO terms, 25 COG categories and 294 specific pathways. Furthermore, there were 14, 534, and 22 identified unigenes involved in food digestion, nutrition metabolism and ovarian development, respectively. 212 differentially expressed genes (DEGs) were found between the growth and endogenous stage of the hepatopancreas, while there were 382 DEGs between the endogenous and exogenous stage hepatopancreas. Our results not only enhance the understanding of crustacean hepatopancreatic functions during growth and ovarian development, but also represent a basis for further research on new genes and functional genomics of P. trituberculatus or closely related species. © 2014 Wang et al.
Dong H.,Chinese National Human Genome Center at Shanghai |
Wang S.,Chinese National Human Genome Center at Shanghai
Frontiers of Medicine in China | Year: 2012
The emergence of next-generation sequencing technologies has led to dramatic advances in cancer genome studies. The increased efficiency and resolution of next-generation sequencing greatly facilitate the detection of genetic, genomic, and epigenomic alterations, such as single nucleotide mutations, small insertions and deletions, chromosomal rearrangements, copy number variations, and DNA methylation. Comprehensive analysis of cancer genomes through approaches of whole genome, exome, and transcriptome sequencing has significantly improved the understanding of cancer biology, diagnosis, and therapy. The present study briefly reviews the recent pioneering studies on cancer genome sequencing and provides an unprecedented insight into the landscape of genomic alterations in human sporadic cancers. © Higher Education Press and Springer-Verlag Berlin Heidelberg 2012.