Ting Zhang

National University of Singapore, Singapore, Singapore

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Publications (5)17.98 Total impact

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    ABSTRACT: We previously reported the identification and characteristics of hepaCAM, a new immunoglobulin-like adhesion molecule. Frequently lost in diverse tumors, hepaCAM exhibits antiproliferative effects on cancer cells and promotes cell-extracellular matrix (ECM) interactions when re-expressed. Herein, we demonstrate for the first time that hepaCAM is cleaved in the human breast carcinoma MCF7 cells, generating a fragment containing mainly the cytoplasmic domain. The phorbol ester phorbol 12-myristate 13-acetate (PMA) did not affect the cleavage of hepaCAM. However, calcium-influx promoted hepaCAM cleavage independent of PKC. In addition, inhibitors of proteasome and cysteine proteases strongly suppressed the cleavage of hepaCAM, indicating the involvement of proteasome, calpain-1 and cathepsin B. Furthermore, we showed that functions of hepaCAM were impaired when the cytoplasmic domain was cleaved. The truncation mutant of hepaCAM failed to promote cell-ECM adhesion and migration, and lost the inhibitory effects on cell growth, suggesting a regulatory role of the cleavage in hepaCAM functions.
    International Journal of Oncology 07/2010; 37(1):155-65. · 2.66 Impact Factor
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    ABSTRACT: Subsequent to our identification of a novel immunoglobulin-like cell adhesion molecule hepaCAM, we showed that hepaCAM is frequently lost in diverse human cancers and is capable of modulating cell motility and growth when re-expressed. Very recently, a molecule identical to hepaCAM (designated as GlialCAM) was found highly expressed in glial cells of the brain. Here, we demonstrate that hepaCAM is capable of inducing differentiation of the human glioblastoma U373-MG cells. Expression of hepaCAM resulted in a significant increase in the astrocyte differentiation marker glial fibrillary acid protein (GFAP), indicating that hepaCAM promotes glioblastoma cells to undergo differentiation. To determine the relationship between hepaCAM expression level and cell differentiation, we established two U373-MG cell lines expressing hepaCAM at different levels. The results revealed that high-level hepaCAM triggered a clear increase in GFAP expression as well as morphological changes characteristic of glioblastoma cell differentiation. Furthermore, high expression of hepaCAM significantly accelerated cell adhesion but inhibited cell proliferation and migration. Concomitantly, deregulation of cell cycle regulatory proteins was detected. Expectedly, the differentiation was noticeably less apparent in cells expressing low-level hepaCAM. Taken together, our findings suggest that hepaCAM induces differentiation of the glioblastoma U373-MG cells. The degree of cell differentiation is dependent on the expression level of hepaCAM.
    Journal of Cellular Biochemistry 07/2009; 107(6):1129-38. · 3.06 Impact Factor
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    ABSTRACT: Previously, we reported the identification of a novel immunoglobulin-like cell adhesion molecule hepaCAM that promotes cell-extracellular matrix (ECM) interactions including cell adhesion and motility. Cell-ECM interactions are known to be directed by the actin cytoskeleton. In this study, we examined the association of hepaCAM with the actin cytoskeleton. We found that hepaCAM was partially insoluble in Triton X-100 and colocalized with the actin cytoskeleton on the plasma membrane. Disruption of F-actin decreased the detergent insolubility and disturbed the subcellular localization of hepaCAM. Coimmunoprecipitation and F-actin cosedimentation assays revealed that hepaCAM directly bound to F-actin. In addition, we constructed three N- and C-terminal domain-deleted mutants of hepaCAM to determine the actin-binding region as well as to evaluate the effect of the domains on the biological function of hepaCAM. Detergent solubility assays showed that the cytoplasmic domain of hepaCAM might be required for actin association. However, deletion of either the extracellular or the cytoplasmic domain of hepaCAM abolished actin coprecipitation as well as delayed cell-ECM adhesion and cell motility. The data suggest that an intact hepaCAM protein is critical for establishing a stable physical association with the actin cytoskeleton; and such association is important for modulating hepaCAM-mediated cell adhesion and motility.
    Journal of Cellular Physiology 02/2009; 219(2):382-91. · 4.22 Impact Factor
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    ABSTRACT: Subsequent to our identification of the novel immunoglobulin-like cell adhesion molecule hepaCAM, we demonstrated that hepaCAM is capable of modulating cell growth and cell-extracellular matrix interactions. In this study, we examined the localization of hepaCAM in lipid rafts/caveolae as well as the interaction of hepaCAM with the caveolar structural protein caveolin-1 (Cav-1). Our results revealed that a portion of hepaCAM resided in detergent-resistant membranes and co-partitioned with Cav-1 to low buoyant density fractions characteristic of lipid rafts/caveolae. In addition, co-localization and coimmunoprecipitation assays confirmed the association of hepaCAM with Cav-1. Deletion analysis of hepaCAM showed that the extracellular first immunoglobulin domain of hepaCAM was required for binding Cav-1. Furthermore, when co-expressed, Cav-1 induced the expression of hepaCAM as well as distributed hepaCAM to intracellular Cav-1-positive caveolar structures. Taken together, our findings indicate that hepaCAM is partially localized in the lipid rafts/caveolae and interacts with Cav-1 through its first immunoglobulin domain.
    Biochemical and Biophysical Research Communications 01/2009; 378(4):755-60. · 2.41 Impact Factor
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    ABSTRACT: Previously, we reported the identification of a novel immunoglobulin-like cell adhesion molecule hepaCAM that is frequently downregulated and inhibits cell growth in hepatocellular carcinoma. In this study, we show that the expression of hepaCAM is suppressed in diverse human cancers. Aiming to evaluate the biological role of hepaCAM in breast cancer, we stably transfected the MCF7 cell line with either wild-type hepaCAM or its mutant hCAM-tailless that lacked the cytoplasmic domain. We found that hepaCAM inhibited colony formation and cell proliferation and arrested cells in the G(2)/M phase. Intriguingly, hepaCAM was capable of inducing cellular senescence as defined by the enlarged cell morphology and increased beta-galactosidase activity. Furthermore, hepaCAM elevated the expression levels of senescence-associated proteins including p53, p21 and p27. In contrast, cell growth inhibition and senescence were less apparent in cells overexpressing hCAM-tailless mutant. To determine if the p53-mediated pathway was involved in hepaCAM-induced senescence, we used the small-interfering RNA system to knock down endogenous p53 expression. In the presence of hepaCAM, downregulation of p53 resulted in a clear reduction of p21, insignificant change in p27 and alleviated senescence. Together, the results suggest that the expression of hepaCAM in MCF7 cells not only inhibits cell growth but also induces cellular senescence through the p53/21 pathway.
    Carcinogenesis 11/2008; 29(12):2298-305. · 5.64 Impact Factor