Ming Shi

Government of the People's Republic of China, Peping, Beijing, China

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Publications (46)158.59 Total impact

  • D Liu · Z Yang · T Wang · H Chen · Y Hu · C Hu · L Guo · Q Deng · Y Liu · M Yu · M Shi · N Du · N Guo
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    ABSTRACT: Currently, trastuzumab resistance is a major clinical problem in the treatment of Her2-overexpressing breast cancer. The underlying molecular mechanisms are not fully understood. Our previous study demonstrates that β2-adrenergic receptor (β2-AR) and Her2 comprise a positive feedback loop in human breast cancer cells and that crosstalk between Her2 and β2-AR affects the bio-behaviors of breast cancer cells, suggesting that the β2-AR activation may be involved in trastuzumab resistance. In this study, we show that the expression of β2-AR, which mediates most catecholamine-induced effects, negatively correlates with trastuzumab response in the patients with Her2-overexpressing breast cancer. Catecholamines potently antagonize the anti-proliferative effects of trastuzumab both in vitro and in vivo. Catecholamine stimulation upregulates the expression of miR-21 and MUC-1 by activating Her2 and STAT3, leading to deficiency of phosphatase and tensin homolog and activation of phosphatidylinositol-3-kinase (PI3K) and Akt. Through inhibition of miR-199a/b-3p, catecholamines induce the mammalian target of rapamycin (mTOR) activation. Thus, trastuzumab resistance-dependent PI3K/Akt/mTOR pathway is controlled by catecholamine-induced β2-AR activation. The data indicate that β2-AR is a reliable molecular marker for prediction of response probability to trastuzumab-based therapy in breast cancer. We also demonstrate that β-blocker propranolol not only enhances the antitumor activities of trastuzumab but also re-sensitizes the resistant cells to trastuzumab. Our retrospective study shows that concurrent treatment of β-blocker and trastuzumab significantly improved progression-free survival and overall survival in the patients with Her2-overexpressing metastatic breast cancer, implicating the possibility for combination therapy with trastuzumab plus β-blocker in Her2-overexpressing breast cancer.Oncogene advance online publication, 23 March 2015; doi:10.1038/onc.2015.58.
    Oncogene 03/2015; DOI:10.1038/onc.2015.58 · 8.56 Impact Factor
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    ABSTRACT: In the present study, we demonstrate that prolonged treatment by trastuzumab induced resistance of NCI-N87 gastric cancer cells to trastuzumab. The resistant cells possessed typical characteristics of epithelial to mesenchymal transition (EMT)/cancer stem cells and acquired more invasive and metastatic potentials both in vitro and in vivo. Long term treatment with trastuzumab dramatically inhibited the phosphorylation of Akt, but triggered the activation of STAT3. The level of IL-6 was remarkably increased, implicating that the release of IL-6 that drives the STAT3 activation initiates the survival signaling transition. Furthermore, the Notch activities were significantly enhanced in the resistant cells, companied by upregulation of the Notch ligand Jagged-1 and the Notch responsive genes Hey1 and Hey2. Inhibiting the endogenous Notch pathway reduced the IL-6 expression and restored the sensitivities of the resistant cells to trastuzumab. Blocking of the STAT3 signaling abrogated IL-6-induced Jagged-1 expression, effectively inhibited the growth of the trastuzumab resistant cells, and enhanced the anti-tumor activities of trastuzumab in the resistant cells. These findings implicate that the IL-6/STAT3/Jagged-1/Notch axis may be a useful target and that combination of the Notch or STAT3 inhibitors with trastuzumab may prevent or delay clinical resistance and improve the efficacy of trastuzumab in gastric cancer.
    Oncotarget 12/2014; · 6.63 Impact Factor
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    ABSTRACT: Angiogenesis is an important factor in invasive tumor growth, progression, and metastasis. Multiple proangiogenic mechanisms are involved in tumor angiogenesis. In this study, we showed that the neurotransmitter norepinephrine upregulated VEGF (VEGFA) expression in breast cancer cells and that the culture supernatant from norepinephrine-treated breast cancer cells promoted the formation of the capillary-like network of endothelial cells. However, the effects of norepinephrine were further enhanced when the endothelial cells were cocultured with breast cancer cells, indicating a critical role of tumor cell-endothelial cell contacts in norepinephrine-induced tumor angiogenesis. Interestingly, norepinephrine dramatically induced the activation of the Notch pathway, which is a cell-contact-mediated intercellular signaling pathway and tightly linked to tumor cell-stromal cell interaction and angiogenesis, in the endothelial cells that had been cocultured with breast cancer cells. Furthermore, the expression of the Notch ligand Jagged 1 was significantly upregulated by norepinephrine at both mRNA and protein levels in breast cancer cells. Inhibitors of β2-adrenergic receptor (β2-AR), protein kinase A (PKA), and mTOR could reverse norepinephrine-induced Jagged 1 upregulation, indicating that the β2-AR-PKA-mTOR pathway participates in this process. Knockdown of Jagged 1 expression in breast cancer cells not only repressed norepinephrine-induced activation of the Notch pathway in cocultured endothelial cells but also evidently impaired the effects of norepinephrine on capillary-like sprout formation. These data demonstrate that tumor angiogenesis mediated by the Jagged 1/Notch intercellular signaling is governed by the norepinephrine-activated β2-AR-PKA-mTOR pathway.
    Endocrine Related Cancer 10/2014; 21(5):783-795. DOI:10.1530/ERC-14-0236 · 4.91 Impact Factor
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    Y Hu · H Chen · C Duan · D Liu · L Qian · Z Yang · L Guo · L Song · M Yu · M Hu · M Shi · N Guo
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    ABSTRACT: Epithelial cell polarization and integration are essential to their function and loss of epithelial polarity and tissue architecture correlates with the development of aggressive tumors. Erbin is a basolateral membrane-associated protein. The roles of Erbin in establishing cell polarization and regulating cell adhesion have been suggested. Erbin is also a negative regulator in Ras-Raf-ERK (extracellular signal-regulated kinase) signaling pathway. However, the potential functions of Erbin in human cancer are basically unknown. In the present study, we show, for the first time, that loss of Erbin endows cervical cancer cells with resistance to anoikis both in vitro and in vivo and promotes the growth and metastasis of human cervical cancer xenografts in nude mice. We found that knockdown of Erbin induced the phosphorylation, nuclear translocation and transcriptional activities of signal transducer and activator of transcription factor 3 (STAT3) in cervical cancer cells. Overexpression of STAT3C or induction of endogenous STAT3 activation by interleukin (IL)-6 evidently inhibited anoikis of cervical cancer cells, whereas WP1066, a potent inhibitor of Janus-activated kinase 2 (Jak2)/STAT3, effectively blocked the effect of Erbin knockdown on cell survival under anchorage-independent conditions, indicating that loss of Erbin confers resistance of cervical cancer cells to anoikis in a STAT3-dependent manner. Interestingly, IL-6 induced STAT3 activation and Erbin expression simultaneously. Overexpression of STAT3C also significantly upregulated the level of Erbin, whereas the Jak2 inhibitor AG490 remarkably blocked not only STAT3 phosphorylation but also IL-6-induced Erbin expression. Knockdown of Erbin augmented the effects of IL-6 on STAT3 activation and anoikis resistance. In addition, by immunohistochemical analysis of Erbin expression, we demonstrate that the expression of Erbin is significantly decreased or even lost in cervical cancer tissues. These data reveal that Erbin is a novel negative regulator of STAT3, and the IL-6/STAT3/Erbin loop has a crucial role in cervical cancer progression and metastasis.
    Oncogenesis 06/2013; 2(6):e52. DOI:10.1038/oncsis.2013.18
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    ABSTRACT: Erbin is ubiquitously expressed in normal epithelial tissues and constitutively associates with Her2 at the basolateral membranes in epithelial cells. The inhibitory role of Erbin in ERK signaling has been demonstrated. However, whether the expression of Erbin is altered in Her2-overexpressing breast cancer is unclear. There is little information regarding the function of Erbin in cancer progression. In the present study, we demonstrate that the level of Erbin is significantly downregulated or lost in breast cancer tissues. Erbin deficiency resulted in a dramatic enhancement in heregulin-induced AKT activation and overexpression of Erbin not only significantly decreased the intensity of heregulin-induced AKT phosphorylation but also shortened its duration in Her2-overexpressing breast cancer cells. Knockdown of Erbin remarkably promotes cell migration, induces invasive phenotype of breast cancer cells and antagonized the anti-proliferative effect of therapeutic antibody trastuzumab. Treatment with AKT inhibitor GDC0941 dramatically reversed the effects of Erbin knockdown on the cell migration and trastuzumab resistance, which is mainly mediated by aberrant activation of AKT. The data reveal that Erbin is a negative regulator of AKT activation and suggest that Erbin may play a role in breast cancer progression.
    Molecular Immunology 05/2013; 56(1-2):104-112. DOI:10.1016/j.molimm.2013.04.007 · 3.00 Impact Factor
  • Ming Shi · Dan Liu · Zhengyan Yang · Ning Guo
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    ABSTRACT: Central and sympathetic nervous systems govern functional activities of many organs. Solid tumors like organs are also innervated by sympathetic nerve fibers. Neurotransmitters released from sympathetic nerve fibers can modulate biological behaviors of tumor cells. Multiple physiologic processes of tumor development may be dominated by central and sympathetic nervous systems as well. Recent studies suggest that dysfunction of central and sympathetic nervous systems and disorder of the hormone network induced by psychological stress may influence malignant progression of cancer by inhibiting the functions of immune system, regulating metabolic reprogramming of tumor cells, and inducing interactions between tumor and stromal cells. Over-release of inflammatory cytokines by tumors may aggravate emotional disorder, triggering the vicious cycles in tumor microenvironment and host macroenvironment. It is reasonable to hypothesize that cancer progression may be controlled by central and sympathetic nervous systems. In this review, we will focus on the recent information about the impacts of central and sympathetic nervous systems on tumor invasion and metastasis.
    CANCER AND METASTASIS REVIEW 05/2013; 32(3-4). DOI:10.1007/s10555-013-9440-x · 7.23 Impact Factor
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    ABSTRACT: Trastuzumab is currently used for patients with Her2(+) advanced gastric cancer. However, the response rate to trastuzumab among the patients is low. The molecular mechanisms underlying trastuzumab resistance in gastric cancer are unknown. Our in vitro data show that activation of β2-adrenergic receptor (β2-AR) triggered by catecholamine caused "targeting failure" of trastuzumab in gastric cancer cells. The antitumor activities of trastuzumab were significantly impeded by chronic catecholamine stimulation in gastric cancer cells and in the mice bearing human gastric cancer xenografts. Mechanistically, catecholamine induced upregulation of the MUC4 expression at both transcription and protein levels via activating STAT3 and ERK. The effects of catecholamine could be effectively blocked by β2-AR antagonist ICI-118,551, indicating that β2-AR-mediated signaling pathway plays a key role in upregulation of MUC4, which was previously demonstrated to interfere with the recognition and physical binding of trastuzumab to Her2 molecules. Moreover, a significant elevation of the MUC4 level was observed in the xenograft tissues in nude mice chronically treated with isoproterenol. Knockdown of MUC4 restored the binding activities of trastuzumab to Her2-overexpressing gastric cancer cells. In addition, coexpression of β2-AR and MUC4 were observed in gastric cancer tissues. Our data indicated a novel trastuzumab resistance mechanism, by which catecholamine-induced β2-AR activation mediates desensitization of gastric cancer cells to trastuzumab through upregulating the MUC4 expression.
    The Journal of Immunology 04/2013; 190(11). DOI:10.4049/jimmunol.1202364 · 5.36 Impact Factor
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    L Guo · C Chen · M Shi · F Wang · X Chen · D Diao · M Hu · M Yu · L Qian · N Guo
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    ABSTRACT: Inflammation can act as a crucial mediator of epithelial-to-mesenchymal transition (EMT). In this study, we show that oncostatin M (OSM) is expressed in an autocrine/paracrine fashion in invasive breast carcinoma. OSM stimulation promotes spontaneous lung metastasis of MCF-7 xenografts in nude mice. A conspicuous epigenetic transition was induced by OSM stimulation not only in breast cancer cell lines but also in MCF-7 xenografts in nude mice. The expression of miR-200 and let-7 family members in response to OSM stimulation was downregulated in a signal transducer and activator of transcription factor 3 (Stat3)-dependent manner, resulting in comprehensive alterations of the transcription factors and oncoproteins targeted by these microRNAs. Inhibition of Stat3 activation or the ectopic expression of let-7 and miR-200 effectively reversed the mesenchymal phenotype of breast cancer cells. Stat3 promotes the transcription of Lin-28 by directly binding to the Lin-28 promoter, resulting in the repression of let-7 expression and concomitant upregulation of the let-7 target, high-mobility group A protein 2 (HMGA2). Knock down of HMGA2 significantly impairs OSM-driven EMT. Our data indicate that downregulation of let-7 and miR-200 levels initiates and maintains OSM-induced EMT phenotypes, and HMGA2 acts as a master switch of OSM-induced EMT. These findings highlight the importance of Stat3-coordinated Lin-28B-let-7-HMGA2 and miR-200-ZEB1 circuits in the cytokine-mediated phenotypic reprogramming of breast cancer cells.Oncogene advance online publication, 14 January 2013; doi:10.1038/onc.2012.573.
    Oncogene 01/2013; 32(45). DOI:10.1038/onc.2012.573 · 8.56 Impact Factor
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    ABSTRACT: Changes in the expression of glycosyltransferases directly influence the oligosaccharide structures and conformations of cell surface glycoproteins and consequently cellular phenotype transitions and biological behaviors. In the present study, we show that all-trans-retinoic acid (ATRA) modulates the N-glycan composition of intercellular adhesion molecule-1 (ICAM-1) by manipulating the expression of two N-acetylglucosaminyltransferases, GnT-III and GnT-V, via the ERK signaling pathway. Exposure of various cells to ATRA caused a remarkable gel mobility down-shift of ICAM-1. Treatment with PNGase F confirmed that the reduction of the ICAM-1 molecular mass is attributed to the decreased complexity of N-glycans. We noticed that the expression of the mRNA encoding GnT-III, which stops branching, was significantly enhanced following ATRA exposure. In contrast, the level of the mRNA encoding GnT-V, which promotes branching, was reduced following ATRA exposure. Silencing of GnT-III prevented the molecular mass shift of ICAM-1. Moreover, ATRA induction greatly inhibited the adhesion of SW480 and U937 cells to the HUVEC monolayer, whereas knock-down of GnT-III expression effectively restored cell adhesion function. Treatment with ATRA also dramatically reduced the trans-endothelial migration of U937 cells. These data indicate that the alteration of ICAM-1 N-glycan composition by ATRA-induced GnT-III activities hindered cell adhesion and cell migration functions simultaneously, pinpointing a unique regulatory role of specific glycosyltransferases in the biological behaviors of tumor cells and a novel function of ATRA in the modulation of ICAM-1 N-glycan composition.
    PLoS ONE 12/2012; 7(12):e52975. DOI:10.1371/journal.pone.0052975 · 3.23 Impact Factor
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    ABSTRACT: Glucocorticoids are stress-responsive neuroendocrine mediators and play an important role in malignant progression, especially in solid tumours. We demonstrate a novel mechanism by which glucocorticoids modulate p53-dependent miR-145 expression in HPV-positive cervical cancer cells through induction of E6 proteins. We found that expression of miR-145 was reduced in cervical cancer tissues. Cortisol induced HPV-E6 expression and suppressed p53 and miR-145 in cervical cancer cells. MiR-145 expression in cervical cancer cells was wild-type p53-dependent, and cortisol-induced down-regulation of miR-145 expression prevented chemotherapy-induced apoptosis, whereas over-expression of miR-145 enhanced sensitivity to mitomycin and reversed the chemoresistance induced by glucocorticoids. We also show that miR-145 augments the effects of p53 by suppressing the inhibitors of p53 in cervical cancer cells, suggesting that miR-145 plays a role in p53 tumour suppression. Finally, we demonstrate that miR-145 inhibits both the motility and invasion of cervical cancer cells. Our findings identify a novel pathway through which the neuroendocrine macroenvironment affects cervical tumour growth, invasion and therapy resistance and show that miR-145 may serve as a target for cervical cancer therapy. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
    The Journal of Pathology 10/2012; 228(2):148-57. DOI:10.1002/path.3997 · 7.43 Impact Factor
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    ABSTRACT: In the present study, we demonstrated the cell cycle periodicity of Erbin expression with the maximal expression of Erbin in G2/M phase. A significant increase in Erbin promoter activity was observed in G2/M phase-synchronized cells. Sequence analysis revealed a c-Myb site in the core promoter region of Erbin. Mutagenesis of c-Myb consensus sequences abrogated the increased Erbin promoter activity in G2/M phase. ChIP and oligonucleotide pull-down assays validated that the recruitment of c-Myb to the consensus sequences was specific. The interaction of c-Myb with c-Myb site in the Erbin promoter was significantly enhanced in G2/M phase. Ectopic overexpression of c-Myb led to the up-regulation of Erbin promoter activity and c-Myb silencing by small interfering RNA significantly decreased Erbin protein level. Transfection of c-Myb rescued Erbin expression that was impaired by c-Myb knockdown. It proves that c-Myb and the c-Myb response element mediate the cell cycle-dependent expression of Erbin. Inactivation of Erbin causes an acceleration of the G1/S transition, the formation of multipolar spindles and abnormal chromosome congression. These results unravel a critical role of c-Myb in promoting Erbin transcription in G2/M phase and also predict an unappreciated function of Erbin in cell cycle progression.
    PLoS ONE 08/2012; 7(8):e42903. DOI:10.1371/journal.pone.0042903 · 3.23 Impact Factor
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    ABSTRACT: BACKGROUND: Her2 and β2-adrenergic receptor (β2-AR) can form a heterocomplex in cardiomyocytes and agonists can induce Her2 transactivation, which is important for cardiovascular homeostasis. The scaffolding molecules that mediate β2-AR/Her2 interaction are currently unknown. Erbin, a PDZ domain-containing protein is a binding partner of Her2. The C-terminus of β2-AR harbors a PDZ domain-binding motif. Hypothesis of this study is that Erbin may organize the assembly of β2-AR/Her2 complex. METHODS: The interaction among β2-AR, Her2 and Erbin was investigated in COS-7, HEK-293 and H9c2 cells and rat brain and heart tissues by coimmunoprecipitation. The β2-AR binding region of Erbin was identified by utilizing the Erbin deletion mutants. The functional significance of Erbin in cardiomyocytes was determined by Erbin silencing, contraction frequency measurement and cellular apoptosis assays. RESULTS: Erbin was able to form a complex with both exogenous and endogenous β2-AR and Her2 in the presence of isoproterenol (ISO). Deletion of the Erbin LRR domain did not affect its binding to β2-AR and Her2, whereas lacking of the PDZ domain lost the ability of Erbin. Silencing of Erbin greatly abrogated ISO-induced activation of ERK. The treatment of H9c2 cells transfected with the Erbin siRNA with ISO caused severe cell apoptosis. Knock-down of Erbin expression in primary neonatal rat cardiomyocytes led to a remarkable reduction of the beating frequency after ISO stimulation. CONCLUSIONS: Erbin mediates catecholamine-induced β2-AR/Her2 complexation and promotes catecholamine-induced activation of ERK signaling in cardiomyocytes, conferring protection of cardiomyocytes from apoptosis induced by chronic catecholamine stimulation.
    International journal of cardiology 05/2012; 167(4). DOI:10.1016/j.ijcard.2012.04.093 · 6.18 Impact Factor
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    ABSTRACT: Interferon (IFN)-γ plays crucial roles in regulating both innate and adaptive immunity. The existence of IFN-γ receptor 1 (IFNGR1) molecules on the cell surface is a prerequisite to the initiation of IFN-γ signaling; low expression of IFNGR1 leads to a functional blockade of IFN-γ signaling. However, the molecular mechanisms by which IFNGR1 expression is controlled are unclear. In the present study, we demonstrated that IFNGR1 expression was reduced or lost in breast cancer. Heterogeneous IFNGR1 immunoreactivity appeared to be associated with the morphological heterogeneity of breast cancer, and loss of IFNGR1 expression was predominantly observed in poorly differentiated areas. We identified the functional activating protein (AP)-2 and specificity protein (SP)-1 sites within the IFNGR1 promoter. Ectopic expression of AP-2α drastically repressed the expression of IFNGR1 and hindered IFN-γ signaling, whereas AP-2α gene silencing elevated IFNGR1 levels. Overexpression of SP-1 effectively antagonized the repressive effects of AP-2α. Simultaneous recruitment of both transcription factors to the AP-2 and SP-1 motifs, respectively, in the IFNGR1 promoter was demonstrated, implying that AP-2α and SP-1 may synergistically modulate IFNGR1 transcription. Moreover, AP-2α overexpression in AP-2-deficient SW480 cells remarkably inhibited Stat1 phosphorylation and the anti-proliferative effects of IFN-γ, whereas knockdown of the AP-2α expression dramatically enhanced the sensitivities of HeLa cells highly expressing AP-2 to IFN-γ, indicating that dysregulation of AP-2α expression is associated with impaired IFN-γ actions in cancer cells.
    American Journal Of Pathology 12/2011; 180(2):661-71. DOI:10.1016/j.ajpath.2011.10.040 · 4.60 Impact Factor
  • Liu Dan · Ming Shi · Huijun Duan · Caili Han · Ning Guo
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    ABSTRACT: Erbin belongs to the LAP protein family. It represents a novel type of adaptor protein that features targeting of basolateral localization of the Her2 receptor through direct binding to the Her2 C terminus. Recent studies demonstrated that Erbin could inhibit the Ras-mediated activation of the mitogen-activated protein kinase (MAPK), nuclear factor-κB (NF-κB) and transforming growth factor β (TGF-β) signaling pathways. It suggests that Erbin may function as a signaling molecule. The functions of Erbin in determining cell polarity and cell adhesion have been well described. This review mainly focuses on the recent findings in regulation of signaling pathways by Erbin.
    Current Protein and Peptide Science 12/2010; 11(8):759-64. DOI:10.2174/138920310794557673 · 2.33 Impact Factor
  • Ming Shi · Dan Liu · Huijun Duan · Beifen Shen · Ning Guo
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    ABSTRACT: Breast cancer is the most common malignancy with the highest incidence among women in the world. Metastasis is the major reason for breast cancer-related deaths. The precise molecular circuitry that governs the metastasis process has not been completely understood. Discoveries of microRNAs (miRNAs) open a new avenue for cancer metastasis research. It has become clear that alterations of miRNA expression contribute to cancer pathogenesis. miRNAs control a wide array of physiological and pathological processes, including development, differentiation, cellular proliferation, programmed cell death, oncogenesis, and metastasis by modulating the expression of their cognate target genes through cleaving mRNA molecules or inhibiting their translation. Some miRNAs are associated with the invasive and metastatic phenotype of breast cancer cell lines or identified in metastatic tumor tissues and lymph nodes. Some miRNAs serve as metastasis suppressors and their expression is frequently downregulated or lost in both breast cancer cell lines and metastatic foci. Some miRNAs are considered to play key roles in the phenotype formation of breast cancer stem cells. This review will focus on recent discoveries related to the miRNAs involved in the metastasis of breast cancer and discuss the implications for the diagnosis, prognosis, and therapeutic strategies of breast cancer.
    CANCER AND METASTASIS REVIEW 10/2010; 29(4):785-99. DOI:10.1007/s10555-010-9265-9 · 7.23 Impact Factor
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    ABSTRACT: Stress, anxiety and depression can cause complex physiological and neuroendocrine changes, resulting in increased level of stress related hormone catecholamine, which may constitute a primary mechanism by which physiological factors impact gene expression in tumors. In the present study, we investigated the effects of catecholamine stimulation on MMP-7 expression in gastric cancer cells and elucidated the molecular mechanisms of the up-regulation of MMP-7 level by catecholamine through an adrenergic signaling pathway. Increased MMP-7 expression was identified at both mRNA and protein levels in the gastric cancer cells in response to isoproterenol stimulation. β2-AR antigonist effectively abrogated isoproterenol-induced MMP-7 expression. The activation of STAT3 and AP-1 was prominently induced by isoproterenol stimulation and AP-1 displayed a greater efficacy than STAT3 in isoproterenol-induced MMP-7 expression. Mutagenesis of three STAT3 binding sites in MMP-7 promoter failed to repress the transactivation of MMP-7 promoter and silencing STAT3 expression was not effective in preventing isoproterenol-induced MMP-7 expression. However, isoproterenol-induced MMP-7 promoter activities were completely disappeared when the AP-1 site was mutated. STAT3 and c-Jun could physically interact and bind to the AP-1 site, implicating that the interplay of both transcriptional factors on the AP-1 site is responsible for isoproterenol-stimulated MMP-7 expression in gastric cancer cells. The expression of MMP-7 in gastric cancer tissues was found to be at the site where β2-AR was overexpressed and the levels of MMP-7 and β2-AR were the highest in the metastatic locus of gastric cancer. Up-regulation of MMP-7 expression through β2-AR-mediated signaling pathway is involved in invasion and metastasis of gastric cancer.
    Molecular Cancer 10/2010; 9:269. DOI:10.1186/1476-4598-9-269 · 5.40 Impact Factor
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    ABSTRACT: In the present study, we show that the treatment of Epstein-Barr virus (EBV) latently infected Raji cells with TPA/SB caused the cell growth arrest. The Zta-positive cells were predominantly enriched in G0/G1 phase of cell cycle. When Zta expression reached a maximal level, a fraction of Zta expressing cell population reentered S phase. Analysis of the expression pattern of a key set of cell cycle regulators revealed that the expression of Zta and Rta substantially interfered with the cell cycle regulatory machinery in Raji cells, strongly inhibiting the expression of Rb and p53 and inducing the expression of E2F1. Down-regulation of Rb was further demonstrated to be mediated by proteasomal degradation, and p53 and p21 affected at transcription level. The data indicate that both Zta and Rta promote entry into S phase of Raji cells. The important roles of Zta and Rta in EBV lytic reactivation were also demonstrated. Our finding suggests that these two transcriptional activators may act synergistically to govern the expression of downstream early and late genes as well as cellular genes and initiation of lytic cycle and manipulation of cell cycle regulatory mechanisms require the joint and interactive contributions of Rta and Zta.
    Molecular Immunology 03/2010; 47(9):1783-92. DOI:10.1016/j.molimm.2010.02.017 · 3.00 Impact Factor
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    ABSTRACT: In this study, β2-AR level was found to be up-regulated in MCF-7 cells overexpressing Her2 (MCF-7/Her2). Correlation of β2-AR level with Her2 status was demonstrated in breast cancer tissue samples. Constitutive phosphorylation of ERK, mRNA expression up-regulation of catecholamine-synthesis enzymes, and increased epinephrine release were detected in MCF-7/Her2 cells. β2-AR expression induced by epinephrine and involvement of ERK signaling were validated. The data indicate that Her2 overexpression and excessive phosphorylation of ERK cause epinephrine autocrine release from breast cancer cells, resulting in up-regulation of β2-AR expression. The data also showed that catecholamine prominently stimulated Her2 mRNA expression and promoter activity. The activation and nuclear translocation of STAT3 triggered by isoproterenol were observed. Enhanced binding activities of STAT3 to the Her2 promoter after isoproterenol stimulation were verified. Using STAT3 shRNA and dominant negative STAT3 mutant, the role of STAT3 in isoproterenol-induced Her2 expression was further confirmed. The data support a model where β2-AR and Her2 comprise a positive feedback loop in human breast cancer cells.
    Breast Cancer Research and Treatment 03/2010; 125(2):351-62. DOI:10.1007/s10549-010-0822-2 · 4.20 Impact Factor
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    ABSTRACT: The BZLF1 gene-encoded protein, Zta (EB1, ZEBRA), is a key transcriptional activator of induction of the lytic cycle of EBV. Zta; it contains a basic region with homology to the DNA binding domains of the AP-1 family. In this study, an alternatively spliced BZLF1 (Delta BZLF1) cDNA lacking exon 2, which encodes the DNA-binding domain of Zta, was isolated from B95-8 marmoset cell line releasing EBV. The cDNA was inserted into a prokaryotic expression vector pET-28a+. The His-tagged recombinant protein was overproduced in E. coli BL21(DE3) and purified by nickel affinity chromatography. The purified fraction was characterized by Western blot and MALDI-TOF-MS analysis and used as an antigen to immunize mice. The antibody against Delta Zta can recognize both denatured and natural Zta protein. The Delta Zta protein and its antibody can be used to further investigate its unknown functions.
    Preparative Biochemistry &amp Biotechnology 01/2010; 40(1):46-56. DOI:10.1080/10826060903392780 · 0.70 Impact Factor
  • Ming Shi · Dan Liu · Beifen Shen · Ning Guo
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    ABSTRACT: Recent findings position microRNA (miRNAs) as novel key players in regulating expression of protein-coding genes by interfering with the stability and/or translation of specific target mRNAs and in controlling cell proliferation and differentiation by actively functioning in the p53 tumor suppression network. Accumulating evidence reveal the intimate relationship between p53 and miRNAs. P53 regulates the expression of miRNAs at multiple levels. miRNAs influence the post-transcriptional regulation and activities of p53 by invoking a myriad of mechanisms. These findings are unveiling the unknown mechanisms of the p53-mediated biological effects.
    Biochimica et Biophysica Acta 12/2009; 1805(2):218-25. DOI:10.1016/j.bbcan.2009.12.001 · 4.66 Impact Factor

Publication Stats

483 Citations
158.59 Total Impact Points

Institutions

  • 2012–2014
    • Government of the People's Republic of China
      Peping, Beijing, China
  • 2010–2013
    • Beijing FivePlus Molecular Medicine Institute
      Peping, Beijing, China
    • Hebei Medical University
      Chentow, Hebei, China
  • 2008
    • Academy of Military Medical Sciences
      T’ien-ching-shih, Tianjin Shi, China
    • Chinese Academy of Medical Sciences
      Peping, Beijing, China