Bing Su

State University of New York, New York City, New York, United States

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Publications (26)71.59 Total impact

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    ABSTRACT: Metastatic melanoma, the primary cause of skin cancer-related death, warrants new diagnostic and therapeutic approaches that target the regulatory machinery at molecular level. The heterogeneity and complexity of melanoma result in the difficulty to find biomarkers and targets for early detection and treatment. Here, we investigated metastasis-associated proteins by comparing the proteomic profiles of primary cutaneous melanomas to their matched lymph node metastases, which minimizes heterogeneity among samples from different patients. Results of two-dimensional gel electrophoresis (2-DE) followed by proteomic analysis revealed eight differentially expressed proteins. Among them, seven proteins (α-enolase, cofilin-1, LDH, m-β-actin, Nm23, GRP78, and MDA-9) showed increased and one (annexin A2) showed decreased expression in metastatic lymph node tissues than in primary melanomas. MDA-9 and GRP78 were the most highly expressed proteins in lymph node metastases, which was validated by immunohistochemical staining. Moreover, exosomes from serum samples of metastatic melanoma patients contained higher levels of MDA-9 and GRP78 than those of patients without metastases, indicating the potential of MDA-9 and GRP78 to be biomarkers for early detection of metastasis. Further, small interfering RNA (siRNA)-mediated knockdown confirmed a functional role for MDA-9 and GRP78 to promote cell invasion in the A375 cells. Finally, we showed that GRP78 co-localized with MDA-9 in 293T cells. Taken together, our findings support MDA-9, co-expressed with GRP78, as a melanoma protein associated with lymph node metastasis. Investigating how MDA-9 and GRP78 interact to contribute to melanoma metastasis and disease progression could reveal new potential avenues of targeted therapy and/or useful biomarkers for diagnosis and prognosis.
    Tumor Biology 12/2014; 36(4). DOI:10.1007/s13277-014-2930-9 · 2.84 Impact Factor
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    ABSTRACT: Chemotaxis is controlled by interactions between receptors, Rho-family GTPases, phosphatidylinositol 3-kinases, and cytoskeleton remodeling proteins. We investigated how the metastasis suppressor, SSeCKS, attenuates chemotaxis. Chemotaxis activity inversely correlated with SSeCKS levels in mouse embryo fibroblasts (MEF), DU145 and MDA-MB-231 cancer cells. SSeCKS loss induced chemotactic velocity and linear directionality, correlating with replacement of leading edge lamellipodia with fascin-enriched filopodia-like extensions, the formation of thickened longitudinal F-actin stress fibers reaching to filopodial tips, relative enrichments at the leading edge of phosphatidylinositol (3,4,5)P3 (PIP3), Akt, PKC-ζ, Cdc42-GTP and active Src (SrcpoY416), and a loss of Rac1. Leading edge lamellipodia and chemotaxis inhibition in SSeCKS-null MEF could be restored by full-length SSeCKS or SSeCKS deleted of its Src-binding domain (ΔSrc), but not by SSeCKS deleted of its three MARCKS (myristylated alanine-rich C kinase substrate) polybasic domains (ΔPBD), which bind PIP2 and PIP3. The enrichment of activated Cdc42 in SSeCKS-null leading edge filopodia correlated with recruitment of the Cdc42-specific guanine nucleotide exchange factor, Frabin, likely recruited via multiple PIP2/3-binding domains. Frabin knockdown in SSeCKS-null MEF restores leading edge lamellipodia and chemotaxis inhibition. However, SSeCKS failed to co-immunoprecipitate with Rac1, Cdc42 or Frabin. Consistent with the notion that chemotaxis is controlled by SSeCKS-PIP (vs. -Src) scaffolding activity, constitutively-active phosphatidylinositol 3-kinase could override the ability of the Src inhibitor, SKI-606, to suppress chemotaxis and filopodial enrichment of Frabin in SSeCKS-null MEF. Our data suggest a role for SSeCKS in controlling Rac1 vs. Cdc42-induced cellular dynamics at the leading chemotactic edge through the scaffolding of phospholipids and signal mediators, and through the reorganization of the actin cytoskeleton controlling directional movement.
    PLoS ONE 10/2014; 9(10):e111534. DOI:10.1371/journal.pone.0111534 · 3.53 Impact Factor
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    ABSTRACT: We recently reported that occupational exposure to trimethyltin (TMT) is a risk factor for developing kidney stones. To further examine the association between TMT exposure and the formation of kidney stones, we conducted a 180-day animal study and exposed the randomly grouped Sprague–Dawley (SD) rats to TMT in the drinking water at doses of 0, 8.2, 32.8 and 131.3 µg kg–1 day–1. Transient behavioral changes were observed in the high-dose group during the first 2 weeks of exposure. TMT exposure led to a significant dose-dependent inhibition of renal H+/K+-ATPase and an increase in urinary pH. In comparison to no kidney stones being identified in the control and the lowest dose group, 1 rat in the 32.8 µg kg–1 day–1 dose group and 3 out of 9 rats in the 131.3 µg kg–1 day–1 dose group were found to have stones in the kidney/urinary tract. Pathological analysis showed that more wide spread calcium disposition was observed in kidneys of rats with TMT exposure compared with the rats in the control group. However, X-ray diffraction (XRD) analysis found that the kidney stones were mainly composed of struvite with the formula: NH4MgPO4 6H2O, while calcium-containing components were also detected. Together, this study further demonstrates through animal studies that chronic exposure to a relatively low level of TMT induces nephrotoxicity and increases the risk for developing kidney stones. Copyright © 2014 John Wiley & Sons, Ltd.
    Journal of Applied Toxicology 09/2014; 35(5). DOI:10.1002/jat.3054 · 3.17 Impact Factor
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    ABSTRACT: Activation of the PI3K/AKT signal pathway is a known driving force for the progression to castration-recurrent prostate cancer (CR-CaP), which constitutes the major lethal phenotype of CaP. Here, we identify using a genomic shRNA screen the PI3K/AKT-inactivating downstream target, FOXO4, as a potential CaP metastasis suppressor. FOXO4 protein levels inversely correlate with the invasive potential of a panel of human CaP cell lines, with decreased mRNA levels correlating with increased incidence of clinical metastasis. Knockdown (KD) of FOXO4 in human LNCaP cells causes increased invasion in vitro and lymph node (LN) metastasis in vivo without affecting indices of proliferation or apoptosis. Increased Matrigel invasiveness was found by KD of FOXO1 but not FOXO3. Comparison of differentially expressed genes affected by FOXO4-KD in LNCaP cells in culture, in primary tumors and in LN metastases identified a panel of upregulated genes, including PIP, CAMK2N1, PLA2G16 and PGC, which, if knocked down by siRNA, could decrease the increased invasiveness associated with FOXO4 deficiency. Although only some of these genes encode FOXO promoter binding sites, they are all RUNX2-inducible, and RUNX2 binding to the PIP promoter is increased in FOXO4-KD cells. Indeed, the forced expression of FOXO4 reversed the increased invasiveness of LNCaP/shFOXO4 cells; the forced expression of FOXO4 did not alter RUNX2 protein levels, yet it decreased RUNX2 binding to the PIP promoter, resulting in PIP downregulation. Finally, there was a correlation between FOXO4, but not FOXO1 or FOXO3, downregulation and decreased metastasis-free survival in human CaP patients. Our data strongly suggest that increased PI3K/AKT-mediated metastatic invasiveness in CaP is associated with FOXO4 loss, and that mechanisms to induce FOXO4 re-expression might suppress CaP metastatic aggressiveness.
    PLoS ONE 07/2014; 9(7):e101411. DOI:10.1371/journal.pone.0101411 · 3.53 Impact Factor
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    ABSTRACT: A multiplex snapback primer system was developed for the simultaneous detection of JAK2 V617F and MPL W515L/K mutations in Philadelphia chromosome- (Ph-) negative myeloproliferative neoplasms (MPNs). The multiplex system comprises two snapback versus limiting primer sets for JAK2 and MPL mutation enrichment and detection, respectively. Linear-After exponential (LATE) PCR strategy was employed for the primer design to maximize the amplification efficiency of the system. Low ionic strength buffer and rapid PCR protocol allowed for selective amplification of the mutant alleles. Amplification products were analyzed by melting curve analysis for mutation identification. The multiplex system archived 0.1% mutation load sensitivity and <5% coefficient of variation inter-/intra-assay reproducibility. 120 clinical samples were tested by the multiplex snapback primer assay, and verified with amplification refractory system (ARMS), quantitative PCR (qPCR) and Sanger sequencing method. The multiplex system, with a favored versatility, provided the molecular diagnosis of Ph-negative MPNs with a suitable implement and simplified the genetic test process.
    03/2014; 2014:458457. DOI:10.1155/2014/458457
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    ABSTRACT: Recurrence of prostate cancer (CaP) after androgen-deprivation therapy continues to have the greatest impact on patient survival. Castration-recurrent (CR)-CaP is likely driven by the activation of androgen receptor (AR) through multiple mechanisms including induction of AR coregulators, AR mutants or splice variants, and AR posttranslational modification such as phosphorylation by Src-family and Ack1 tyrosine kinases. Here, we address whether Src is required for the CR growth of human CWR22 CaP xenografts. The shRNA-mediated Src knockdown or treatment with the Src inhibitors, dasatinib or KXO1, reduced CaP recurrence over controls and increased time-to-recurrence following castration. Moreover, CR-CaP [Src-shRNA] tumors that recurred had similar Src protein and activation levels as those of parental cells, strengthening the notion that Src activity is required for progression to CR-CaP. In contrast, the ability of dasatinib or KXO1 to inhibit Src kinase activity in vitro did not correlate with their ability to inhibit serum-driven in vitro proliferation of CR and androgen-dependent stable cell lines derived from CWR22 tumors (CWR22Rv1 and CWR22PC, respectively), suggesting that the in vitro proliferation of these CaP lines is Src independent. Taken together, these findings strongly suggest that Src is a potent and specific therapeutic target for CR-CaP progression.
    Cancer Medicine 12/2013; 2(6). DOI:10.1002/cam4.144
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    ABSTRACT: Metastatic melanoma, the primary cause of skin cancer-related death, warrants new therapeutic approaches that target the regulatory machinery at molecular level. While long noncoding RNAs (lncRNAs) are dysregulated in a number of cancer types, limited data are available on the expression and function of lncRNAs in melanoma metastasis. The primary objective of this study was to investigate the role of 6 metastasis-related lncRNAs in pairs of primary melanoma and matched lymph node metastatic tissues. Among the tested lncRNAs, HOTAIR was the most highly expressed in lymph node metastasis. The role of HOTAIR in melanoma cell motility and invasion was further evaluated by knocking down HOTAIR with siRNAs. Knockdown of HOTAIR resulted in the reduction of motility and invasion of human melanoma cell line A375, as assessed by wound healing assay and Matrigel-based invasion assay. siHOTAIR also suppressed the degradation of gelatin matrix, suggesting that HOTAIR promotes gelatinase activity. Together, our study shows that HOTAIR is overexpressed in metastatic tissue, which is associated with the ability of HOTAIR to promote melanoma cell motility and invasion. These data indicate that lncRNAs may be involved in the metastasis of melanoma and provide support for further evaluation of lncRNAs in melanoma.
    06/2013; 2013:251098. DOI:10.1155/2013/251098
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    ABSTRACT: BACKGROUND: The active metabolite of vitamin D 1α,25-dihydroxycholecalciferol (1,25D(3) ) has exhibited broad-spectrum antitumor activity in xenograft animal models. However, its activity against metastatic disease has not been extensively investigated. METHODS: Squamous cell carcinoma (SCC) or 1,25D(3) -resistant variant SCC-DR cells were treated with 1,25D(3) . Actin organization was examined by immunofluorescence assay. Cell migration was assessed by "wound" healing and chemotactic migration assays. Cell invasion was assessed by a Matrigel-based invasion assay and in situ zymography. Matrix metalloproteinase 2 (MMP-2) and MMP-9 expression and secretion were examined by immunoblot analysis and an enzyme-linked immunosorbent assay, respectively. E-cadherin expression was assessed by flow cytometry, immunoblot analysis, and immunohistochemistry. Knockdown of E-cadherin was achieved by small interfering RNA. An experimental metastasis mouse model was created by intravenous injection of tumor cells; and lung tumor development in the mice was assessed by magnetic resonance imaging, gross observation, and histology. RESULTS: SCC cellular morphology and actin organization were altered by 10 nM 1,25D(3) . 1,25D(3) inhibited SCC cell motility and invasion, which were associated with reduced expression and secretion of MMP-2 and MMP-9, and 1,25D(3) promoted the expression of E-cadherin. These findings were not observed in SCC-DR cells. Knock down of E-cadherin rescued 1,25D(3) -inhibited cell migration. Intravenous injection of SCC or SCC-DR cells resulted in the establishment of extensive pulmonary lesions in saline-treated C3H mice. Treatment with 1,25D(3) resulted in a marked reduction in the formation of lung tumor colonies in mice that were injected with SCC cells, but not in mice that were injected with SCC-DR cells. CONCLUSIONS: 1,25D(3) suppressed SCC cell motility, invasion, and metastasis, partially through the promotion of E-cadherin-mediated cell-cell adhesion. Cancer 2012. © 2012 American Cancer Society.
    Cancer 02/2013; 119(3). DOI:10.1002/cncr.27531 · 4.90 Impact Factor
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    ABSTRACT: Oral squamous cell carcinoma (OSCC) is a common and lethal malignancy. Thus, improvement in current knowledge of molecular changes associated with OSCC is urgently needed to explore novel avenues of diagnostics and treatment of this disease. While aberrant expression of long non‑coding RNAs (lncRNAs) has been functionally associated with certain types of cancer, including lung, breast and prostate carcinomas, their expression pattern and biological relevance in OSCC is currently unknown. In the present study, the relative abundance of a collection of lncRNAs in tissue or saliva samples from OSCC patients was investigated. It was shown that subsets of lncRNAs are expressed across non‑tumor, tumor and metastatic tissue samples. Some detected lncRNAs were shown to be aberrantly expressed in cases of oral cancer and metastasis. Moreover, whole saliva contained a detectable amount of some lncRNAs, which appeared to be potential markers for OSCC. These findings suggest that the detection of lncRNAs in saliva may be used as a noninvasive and rapid diagnostic tool for the diagnosis of oral cancer.
    Molecular Medicine Reports 12/2012; 7(3). DOI:10.3892/mmr.2012.1254 · 1.48 Impact Factor
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    ABSTRACT: Metastatic cell migration and invasion are regulated by altered adhesion-mediated signaling to the actin-based cytoskeleton via activated Src-FAK complexes. Src-suppressed C-kinase substrate (SSeCKS, the rodent orthologue of human Gravin/AKAP12), whose expression is downregulated by oncogenic Src and in many human cancers, antagonizes oncogenic Src pathways including those driving neovascularization at metastatic sites, metastatic cell motility and invasiveness. This is likely manifested through its function as a scaffolder of F-actin and signaling proteins such as cyclins, calmodulin, protein kinase C and A. Here we show that in contrast to its ability to inhibit haptotaxis, SSeCKS increased prostate cancer cell adhesion to fibronectin and type I collagen in a FAK-dependent manner, correlating with a relative increase in FAK(poY397) levels. In contrast, SSeCKS suppressed adhesion-induced Src activation (Src(poY416)) and phosphorylation of FAK at Y925, a known Src substrate site. SSeCKS also induced increased cell spreading, cell flattening, integrin β1 clustering and formation of mature focal adhesion plaques. An in silico analysis identified a Src-binding domain on SSeCKS(aa 153-166) that is homologous to the Src-binding domain of caveolin-1, and this region is required for SSeCKS-Src interaction, for SSeCKS-enhanced Src activity and sequestration to lipid rafts and for SSeCKS-enhanced adhesion of MAT-LyLu and CWR22Rv1 prostate cancer cells. Our data suggest a model in which SSeCKS suppresses oncogenic motility by sequestering Src to caveolin-rich lipid rafts, thereby disengaging Src from FAK-associated adhesion and signaling complexes.Oncogene advance online publication, 18 June 2012; doi:10.1038/onc.2012.218.
    Oncogene 06/2012; 32(16). DOI:10.1038/onc.2012.218 · 8.56 Impact Factor
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    ABSTRACT: The product of the SSeCKS/GRAVIN/AKAP12 gene ("SSeCKS") is a major protein kinase (PK) C substrate that exhibits tumor- and metastasis-suppressing activity likely through its ability to scaffold multiple signaling mediators such as PKC, PKA, cyclins, calmodulin, and Src. Although SSeCKS and PKCα bind phosphatidylserine, we demonstrate that phosphatidylserine-independent binding of PKC by SSeCKS is facilitated by two homologous SSeCKS motifs, EG(I/V)(T/S)XWXSFK(K/R)(M/L)VTP(K/R)K(K/R)X(K/R)XXXEXXXE(E/D) (amino acids 592-620 and 741-769). SSeCKS binding to PKCα decreased kinase activity and was dependent on the two PKC-binding motifs. SSeCKS scaffolding of PKC was increased in confluent cell cultures, correlating with significantly increased SSeCKS protein levels and decreased PKCα activity, suggesting a role for SSeCKS in suppressing PKC activation during contact inhibition. SSeCKS-null mouse embryo fibroblasts displayed increased relative basal and phorbol ester (phorbol 12-myristate 13-acetate)-induced PKC activity but were defective in phorbol 12-myristate 13-acetate-induced actin cytoskeletal reorganization and cell shape change; these responses could be rescued by the forced expression of full-length SSeCKS but not by an SSeCKS variant deleted of its PKC-binding domains. Finally, the PKC binding sites in SSeCKS were required to restore cell rounding and/or decreased apoptosis in phorbol ester-treated LNCaP, LNCaP-C4-2, and MAT-LyLu prostate cancer cells. Thus, PKC-mediated remodeling of the actin cytoskeleton is likely regulated by the ability of SSeCKS to control PKC signaling and activity through a direct scaffolding function.
    Journal of Biological Chemistry 09/2011; 286(44):38356-66. DOI:10.1074/jbc.M111.258830 · 4.60 Impact Factor
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    ABSTRACT: The expression of AKAP12 (A Kinase anchoring protein 12) is markedly reduced in a variety of cancers. The purpose of this study was to establish a methylation-sensitive high resolution melting (MS-HRM) assay for the quantitative detection of AKAP12 promoter methylation and expression and the association with clinicopathological variables in human colorectal cancer. We also assessed the effect of AKAP12 re-expression on cell growth and colony formation. Downregulation or loss of AKAP12 mRNA expression was detected in 31 of 45 tissue samples (68.9%). No significant correlation was observed between the reduced expression levels and patient age, gender, Duke's stage or tumor differentiation. Methylation (>1%) of the AKAP12 promoter region was present in 35 of 45 (77.8%) carcinoma tissue samples and 6 of 45 (13.3%) adjacent tissue samples. AKAP12 methylation was significantly higher in the colorectal cancer tissues exhibiting advanced Duke's stages. Treatment of the three colorectal carcinoma cell lines (LoVo, COLO320 and SW480) with completely methylated AKAP12 with inhibitors of DNA methyltransferase (5-Aza-2'-deoxycytidine) markedly increased expression of AKAP12 and decreased methylation levels. Ectopic expression of AKAP12 in the LoVo cell line suppressed cell growth and inhibited colony formation. The AKAP12 gene was examined by quantitative RT-PCR, MS-HRM analysis and bisulfite sequencing in 45 paired tissue samples obtained from primary colorectal carcinomas and the corresponding adjacent tissues. In addition, five colorectal carcinoma cell lines (LoVo, COLO205, SW480, LS174T and COLO320) were investigated and western blot analysis was used to investigate changes in protein expression. A proliferation assay and soft agar assay were performed after overexpression of AKAP12. Our study demonstrated that MS-HRM is a robust, fast and sensitive method for AKAP12 methylation analysis. AKAP12 methylation represents a potential molecular biomarker for predicting the malignancy of this cancer.
    Cancer biology & therapy 06/2010; 9(11):862-71. DOI:10.4161/cbt.9.11.11633 · 3.63 Impact Factor
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    ABSTRACT: Colorectal cancer is the third most common form of cancer and hypermethylation has been shown to increase the risk of developing this disease. DNA hypermethylation in the A kinase anchor protein 12 (AKAP12/Gravin) promoter region and the accompanied underexpression of it has been noted in a variety of human cancers. We applied methylation-specific high resolution melting (MS-HRM) technology to detect quantitatively A kinase anchor protein 12 (AKAP12/Gravin) methylation in peripheral blood from 100 colorectal cancer patients and 50 healthy volunteers and in 3 colorectal cancer cell lines. In this study 48 of the 100 colorectal cancer samples (48%) were found to be methylated at the AKAP12 promoter region. AKAP12 methylation was significantly higher in the colorectal cancer samples with differentiation (p=0.03). We also compared the results generated by MS-HRM with a traditional methylation-specific PCR (MSP) assay. We found that intra-assay variability ranged from 6.14 to 9.90% and inter-assay variability ranged from 14.5 to 17.2%. The AKAP12 MS-HRM assay was able to reproducibly detect 1% methylated DNA, whereas the MSP method was unable to detect less than 5% methylation. We demonstrate the utility of quantitative AKAP12 MS-HRM analysis of promoter methylation in peripheral blood samples. AKAP12 MS-HRM quantitative methods with excellent detection capabilities have many promising applications in the research and diagnosis of colorectal cancer.
    Clinica chimica acta; international journal of clinical chemistry 03/2010; 411(13-14):940-6. DOI:10.1016/j.cca.2010.03.003 · 2.76 Impact Factor
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    ABSTRACT: SSeCKS/Gravin/AKAP12 ("SSeCKS") encodes a cytoskeletal protein that regulates G(1) --> S progression by scaffolding cyclins, protein kinase C (PKC) and PKA. SSeCKS is down-regulated in many tumor types including prostate, and when re-expressed in MAT-LyLu (MLL) prostate cancer cells, SSeCKS selectively inhibits metastasis by suppressing neovascularization at distal sites, correlating with its ability to down-regulate proangiogenic genes including Vegfa. However, the forced re-expression of VEGF only rescues partial lung metastasis formation. Here, we show that SSeCKS potently inhibits chemotaxis and Matrigel invasion, motility parameters contributing to metastasis formation. SSeCKS suppressed serum-induced activation of the Raf/MEK/ERK pathway, resulting in down-regulation of matrix metalloproteinase-2 expression. In contrast, SSeCKS had no effect on serum-induced phosphorylation of the Src substrate, Shc, in agreement with our previous data that SSeCKS does not inhibit Src kinase activity in cells. Invasiveness and chemotaxis could be restored by the forced expression of constitutively active MEK1, MEK2, ERK1, or PKCalpha. SSeCKS suppressed phorbol ester-induced ERK1/2 activity only if it encoded its PKC binding domain (amino acids 553-900), suggesting that SSeCKS attenuates ERK activation through a direct scaffolding of conventional and/or novel PKC isozymes. Finally, control of MLL invasiveness by SSeCKS is influenced by the actin cytoskeleton: the ability of SSeCKS to inhibit podosome formation is unaffected by cytochalasin D or jasplakinolide, whereas its ability to inhibit MEK1/2 and ERK1/2 activation is nullified by jasplakinolide. Our findings suggest that SSeCKS suppresses metastatic motility by disengaging activated Src and then inhibiting the PKC-Raf/MEK/ERK pathways controlling matrix metalloproteinase-2 expression and podosome formation.
    Journal of Biological Chemistry 12/2009; 285(7):4578-86. DOI:10.1074/jbc.M109.073494 · 4.60 Impact Factor
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    ABSTRACT: SSeCKS, a Src-suppressed protein kinase C substrate with metastasis suppressor activity, is the rodent orthologue of human gravin/AKAP12, a scaffolding protein for protein kinase A and protein kinase C. We show here that the tetracycline-regulated reexpression of SSeCKS in MatLyLu (MLL) prostate cancer cells suppressed formation of macroscopic lung metastases in both spontaneous and experimental models of in vivo metastasis while having minimal inhibitory effects on the growth of primary-site s.c. tumors. SSeCKS decreased angiogenesis in vitro and in vivo by suppressing vascular endothelial growth factor (VEGF) expression in MLL tumor cells as well as in stromal cells. The forced reexpression of VEGF(165) and VEGF(121) isoforms was sufficient to reverse aspects of SSeCKS metastasis-suppressor activity in both the experimental and spontaneous models. SSeCKS reexpression in MLL cells resulted in the down-regulation of proangiogenic genes, such as osteopontin, tenascin C, KGF, angiopoietin, HIF-1alpha, and PDGFRbeta, and the up-regulation of antiangiogenic genes, such as vasostatin and collagen 18a1, a precursor of endostatin. These results suggest that SSeCKS suppresses formation of metastatic lesions by inhibiting VEGF expression and by inducing soluble antiangiogenic factors.
    Cancer Research 07/2006; 66(11):5599-607. DOI:10.1158/0008-5472.CAN-05-4123 · 9.28 Impact Factor
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    ABSTRACT: METHOD. We observed the effect of tetracycline-regulated SSeCKS re-expression in MatLyLu (MLL) prostate cancer cells on i) primary tumor and lung metastasis formation and on ii) VEGF and angiogenesis-controlling gene expression, using focused microarrays, semi-quantitative RT-PCR, protein blots and ELISA assays for secreted VEGF. Angiogenesis was determined in primary s.c. tumors by CD31 staining and on endothelial cell tube formation in vitro. Finally, we evaluated whether the forced re-expression of VEGF165 and VEGF121 isoforms was sufficient to reverse the metastasis-suppressor activity of SSeCKS in vivo. RESULTS. Re-expression of SSeCKS in MLL prostate cancer cells significantly suppressed formation of lung metastases in both experimental and spontaneous models, correlating with decreased neovascular formation in the primary subcutaneous tumors. SSeCKS decreased the levels of secreted and intracellular VEGF in MLL cells and in stromal cells. VEGF165 re-expression rescued metastasis formation in the spontaneous and experimental models whereas VEGF121 only rescued in the spontaneous model. Besides VEGF, SSeCKS re-expression also inhibited expression of several pro-apoptotic genes such as osteopontin, tenascin C, KGF/FGF-7, angiogenin,
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    ABSTRACT: Promoter methylation is an important pathway in transcriptional silencing of tumor suppressor genes (TSGs) in brain tumors. The identified 3p21.3 tumor suppressor gene RAS association domain family protein 1A (RASSF1A) is highly methylated in primary lung, breast and other tumors. We investigated the promoter methylation and gene expression of RASSF1A in gliomas. The methylation status of the promoter region of RASSF1A, p16INK4A and death-associated protein kinase (DAPK) genes was analyzed by methylation-specific PCR (MSP) in 41 surgically resected gliomas. RASSF1A expression was also detected by reverse-transcription polymerase chain reaction (RT-PCR) in 28 glioma tissues. The frequencies of RASSF1A, p16INK4A and DAPK promoter methylation were 13/41 (31.7%), 3/41 (7.3%) and 6/41 (14.6%) respectively. However, the methylations of those genes were not correlated with the clinical characteristics of patients (tumor grade, tumor types and sex). Among 28 glioma tissues, 6 showed the loss of the gene (21.4%). Promoter hypermethylation of RASSF1A is associated with loss of gene expression in glioma tissues. (p=0.022). Our results suggested that the RASSF1A gene might play an important role in glioma carcinogenesis. It also gives us an insight for future glioma medical therapy with a demethylating agent.
    Clinica Chimica Acta 12/2004; 349(1-2):173-9. DOI:10.1016/j.cccn.2004.07.006 · 2.76 Impact Factor
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    ABSTRACT: To investigate the changes of sugar chain structures of alkaline phosphatase (ALP) in hepatoma tissue and its relation to the invasiveness of hepatocellular carcinoma (HCC). The binding ratios of ALP from 9 normal liver tissues, 16 hepatoma tissues and 16 noncancerous tissues surrounding hepatoma were analysed by affinity chromatography on various lectin columns including leukoagglutinating phytohemagglutinin (L-PHA), lentil lectin (LCA), Datura stramonium agglutinin (DSA), erythroagglutinating phytohemagglutinin (E-PHA) and Sambucus nigra bark agglutinin (SNA). The binding ratios of ALP on L-PHA (22.94%+/-5.30%), DSA (55.97%+/-13.72%), LCA (38.16%+/-8.87%), E-PHA (11.56%+/-4.81%) and SNA (69.80%+/-13.71%) in HCC tissues were significantly increased (P<0.01) compared with that in normal liver tissues (L-PHA 5.89%+/-2.75%, DSA 36.20%+/-11.58%, LCA 17.90%+/-6.71%, E-PHA 5.38%+/-2.20%, SNA 57.32%+/-11.27%), respectively. t values between the two groups were 8.94, 3.64, 5.94, 3.62 and 2.32, respectively. L-PHA-binding ratio (25.84%+/-4.67%) of ALP in HCC with invasiveness was significantly higher than that (18.10%+/-3.64%) without invasiveness (t=3.71, P<0.01). The changes of ALP sugar chain structures occur in HCC tissue. b1-6 branching sugar chain structure of ALP is related to the invasiveness of HCC.
    Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology 12/2003; 11(12):739-41.
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    ABSTRACT: Pigment epithelium derived factor (PEDF) was first isolated from medium conditioned by human fetal retinal pigment epithelial cells. PEDF was detected in a broad range of human fetal and adult tissues including almost all brain areas. It can also inhibit the proliferation of cultured rat astrocytes. Recent studies have implicated PEDF in activities that are inhibitory to angiogenesis. To investigate the expression of PEDF in gliomas to assess its "gliastatic" effects and its role in anti-angiogenesis. PEDF mRNA values were measured by quantitative real time reverse transcription polymerase chain reaction (RT-PCR) analysis of normal brain tissue and tumour specimens from both low and high grade gliomas. In addition, immunohistochemical staining for PEDF and vascular endothelial growth factor (VEGF) was performed on 32 paraffin wax embedded glioma samples, 10 of them grade IV, 10 grade III, seven grade II, and five grade I. RT-PCR showed that PEDF mRNA values were 5.0 (p < 0.001) and 15.4 (p < 0.001) times higher in normal human brain specimens (n = 5) than in tumour tissue specimens of low grade glioma (grades I and II; n = 15) and high grade glioma (grades III and IV; n = 10), respectively. VEGF was strongly positive in 90% of grade IV, 70% of grade III, 43% of grade II, and 20% of grade I cases. In contrast, PEDF was positive in none of grade IV, 20% of grade III, 43% of grade II, and 60% of grade I tumours. There was an inverse correlation between VEGF and PEDF expression, and a lack of PEDF in advanced grade gliomas. It is possible that the absence of PEDF expression is a potent factor for the enhancement of angiogenesis in glioma.
    Journal of Clinical Pathology 04/2003; 56(4):277-82. · 2.55 Impact Factor
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    ABSTRACT: Lipocalin-type prostaglandin D synthase (LPGDS; PGH(2)D-isomerase; EC 5.3.99.2) is a bifunctional protein first identified in the mammalian brain. It acts as a PGD(2)-producing enzyme and a retinoid transporter. Recent studies have shown that LPGDS is anomalously expressed in ovarian tumors and that retinoid may have a role as an ovarian cancer chemotherapeutic agent. To determine whether there is a relationship between retinoid and LPGDS in ovarian tumors, we examined the regulation of the gene encoding LPGDS by all-trans retinoic acid (RA). Real-time quantitative RT-PCR analysis showed that RA strongly induced the accumulation of LPGDS mRNA in human 3AO ovarian cancer cells. Furthermore, treatment of the cells with RA induced the synthesis and secretion of LPGDS into the culture medium. This increased expression of LPGDS was accompanied by an inhibition of cell proliferation in the ovarian cancer cells. Prostaglandin D synthase, ovarian cancer, retinoic acid, real-time quantitative RT-PCR.
    Cell Biology International 02/2003; 27(7):587-92. DOI:10.1016/S1065-6995(03)00100-8 · 1.64 Impact Factor

Publication Stats

363 Citations
71.59 Total Impact Points

Institutions

  • 2014
    • State University of New York
      New York City, New York, United States
  • 2006–2014
    • Roswell Park Cancer Institute
      • Department of Cancer Genetics
      Buffalo, New York, United States
  • 2013
    • Texas Biomedical Research Institute
      San Antonio, Texas, United States
  • 2012
    • Peking University
      Peping, Beijing, China
  • 2001–2010
    • Fudan University
      Shanghai, Shanghai Shi, China
  • 2002–2003
    • Chung Shan Hospital
      T’ai-pei, Taipei, Taiwan