Jian Xian

Cancer Research UK Cambridge Institute, Cambridge, England, United Kingdom

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Publications (7)62.68 Total impact

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    ABSTRACT: BRCA2 mutations are significantly associated with early onset breast cancer, and the tumour suppressing function of BRCA2 has been attributed to its involvement in homologous recombination (HR)-mediated DNA repair. In order to identify additional functions of BRCA2, we generated BRCA2-knockout HCT116 human colorectal carcinoma cells. Using genome-wide microarray analyses, we have discovered a link between the loss of BRCA2 and the up-regulation of a subset of interferon (IFN)-related genes, including APOBEC3F and APOBEC3G. The over-expression of IFN-related genes was confirmed in different human BRCA2−/− and mouse Brca2−/− tumour cell lines, and was independent of senescence and apoptosis. In isogenic wild type BRCA2 cells, we observed over-expression of IFN-related genes after treatment with DNA-damaging agents, and following ionizing radiation. Cells with endogenous DNA damage because of defective BRCA1 or RAD51 also exhibited over-expression of IFN-related genes. Transcriptional activity of the IFN-stimulated response element (ISRE) was increased in BRCA2 knockout cells, and the expression of BRCA2 greatly decreased IFN-α stimulated ISRE reporter activity, suggesting that BRCA2 directly represses the expression of IFN-related genes through the ISRE. Finally, the colony forming capacity of BRCA2 knockout cells was significantly reduced in the presence of either IFN-β or IFN-γ, suggesting that IFNs may have potential as therapeutic agents in cancer cells with BRCA2 mutations.
    The Journal of Pathology 07/2014; · 7.59 Impact Factor
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    ABSTRACT: Synthetic lethality is a genetic concept in which cell death is induced by the combination of mutations in two sensitive genes, while mutation of either gene alone is not sufficient to affect cell survival. Synthetic lethality can be also achieved "chemically" by combination of drug-like molecules targeting distinct but cooperative pathways. Previously, we reported that the small molecule pyridostatin (PDS) stabilizes G-quadruplexes in cells and elicits a DNA damage response (DDR) by causing the formation of DNA double strand breaks (DSB). We hypothesize that cell death mediated by ligand-induced G-quadruplex stabilization could be potentiated in cells deficient in DNA damage repair genes. Here, we demonstrated that PDS acts synergistically both with NU7441, an inhibitor of the DNA-PK kinase crucial for non-homologous end joining (NHEJ) repair of DNA DSBs, and BRCA2-deficient cells that are genetically impaired in homologous recombination-mediated DSB repair (HR). G-quadruplex targeting ligands have potential as cancer therapeutic agents, acting synergistically with inhibition or mutation of the DNA damage repair machinery.
    Journal of the American Chemical Society 06/2013; · 10.68 Impact Factor
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    ABSTRACT: Tgfbi, a fasciclin family extracellular matrix protein, has various roles in human diseases from corneal dystrophies tocancer. However, the molecular mechanisms that underlie its functions are poorly understood. Here, we studied the role of Tgfbi during Xenopus embryogenesis. During gastrulation and immediately after, Xtgfbi is expressed at developmentally important signaling centres including the dorsal marginal zone, notochord and floorplate.Xtgfbi knockdown by anti-sense morpholinos causesdefective organizer induction, patterning and differentiation of muscle, neuron and neural crests, similar to suppression of canonical Wnt signaling. In Xenopus embryos and animal caps as well as DLD-1 cells, we show that Tgfbi is strongly required for the full activation of the canonical Wnt pathway by promoting phosphorylation of GSK3β and consequently enhancing stabilization and nuclear localization of β-catenin. Further analysis shows that Tgfbi is likely to promote GSK3β phosphorylation through integrin-linked kinase.
    Developmental Biology 12/2012; · 3.87 Impact Factor
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    ABSTRACT: Complex stiffness gradient substrates for the study of mechanotactic cell migration are developed by Easan Sivaniah, Kristian Franze, and co-workers on page 6059. Polyacrylamide gels are cast upon a stiff support with controlled topography, resulting in a thin gel layer of variable height. The topographical profiles project a stiffness map onto the gel, resulting in controlled linear and non-linear 2D stiffness gradients. Fibroblasts, which migrate towards stiffer substrates, accumulate in areas with a gel thickness below 15 μm.
    Advanced Materials 11/2012; 24(45):6058. · 14.83 Impact Factor
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    ABSTRACT: Polyacrylamide gels are cast upon a stiff support with controlled topography, resulting in a thin gel layer of variable height. The topographical profiles project a stiffness map onto the gel, resulting in controlled linear and non-linear 2D stiffness gradients. Fibroblasts, which migrate towards stiffer substrates, accumulate in areas with a gel thickness below 15 μm.
    Advanced Materials 09/2012; · 14.83 Impact Factor
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    ABSTRACT: The combretastatins have been investigated for their antimitotic and antivascular properties, and it is widely postulated that a 3,4,5-trimethoxyaryl A-ring is essential to maintain potent activity. We have synthesized new tetrazole analogues (32-34), demonstrating that 3,5-dihalogenation can consistently increase potency by up to 5-fold when compared to the equivalent trimethoxy compound on human umbilical vein endothelial cells (HUVECs) and a range of cancer cells. Moreover, this increased potency offsets that lost by installing the tetrazole bridge into combretastatin A-4 (1), giving crystalline, soluble compounds that have low nanomolar activity, arrest cells in G2/M phase, and retain microtubule inhibitory activity. Molecular modeling has shown that optimized packing within the binding site resulting in increased Coulombic interaction may be responsible for this improved activity.
    ACS Medicinal Chemistry Letters 03/2012; 3(3):177-81. · 3.31 Impact Factor
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    ABSTRACT: High-grade serous ovarian carcinoma (HGSOC) is characterized by genomic instability, ubiquitous TP53 loss, and frequent development of platinum resistance. Loss of homologous recombination (HR) is a mutator phenotype present in 50% of HGSOCs and confers hypersensitivity to platinum treatment. We asked which other mutator phenotypes are present in HGSOC and how they drive the emergence of platinum resistance. We performed whole-genome paired-end sequencing on a model of two HGSOC cases, each consisting of a pair of cell lines established before and after clinical resistance emerged, to describe their structural variants (SVs) and to infer their ancestral genomes as the SVs present within each pair. The first case (PEO1/PEO4), with HR deficiency, acquired translocations and small deletions through its early evolution, but a revertant BRCA2 mutation restoring HR function in the resistant lineage re-stabilized its genome and reduced platinum sensitivity. The second case (PEO14/PEO23) had 216 tandem duplications and did not show evidence of HR or mismatch repair deficiency. By comparing the cell lines to the tissues from which they originated, we showed that the tandem duplicator mutator phenotype arose early in progression in vivo and persisted throughout evolution in vivo and in vitro, which may have enabled continual evolution. From the analysis of SNP array data from 454 HGSOC cases in The Cancer Genome Atlas series, we estimate that 12.8% of cases show patterns of aberrations similar to the tandem duplicator, and this phenotype is mutually exclusive with BRCA1/2 carrier mutations.
    The Journal of Pathology 12/2011; 226(5):703-12. · 7.59 Impact Factor