• Title, Summary, Keyword: PDGF-D

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Overexpression of Platelet-derived Growth Factor-D as a Poor Prognosticator in Endometrial Cancer

  • Ding, Jie;Li, Xiao-Mao;Liu, Sui-Ling;Zhang, Yu;Li, Tian
    • Asian Pacific Journal of Cancer Prevention
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    • v.15 no.8
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    • pp.3741-3745
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    • 2014
  • Background: Emerging evidence implicates the platelet-derived growth factor-D (PDGF-D) in many types of human solid tumors. We investigated whether PDGF-D plays an important role in endometrial cancer (EC) in relation to clinicopathologic phenotype, angiogenesis, and patient prognosis. Materials and Methods: We analyzed PDGF-D protein expression by Western blotting in twenty-seven human endometrial cancer tissues, and matched normal endometrial controls collected at the third Affiliated hospital of Sun Yat-sen University during 2012-2013 (n=27). Immunohistochemical staining was performed using a human PDGF-D antibody on the endometrial cancer patients collected in the same facility during January 2001 and October 2013 (n=152). Patients were followed from the time of primary surgery in 2001-2013 until death or last follow-up. We correlated the PDGF-D expression levels with clinicopathologic parameters and prognosis in human endometrial cancer patients. Results: Compared with matched normal endometrial cases, PDGF-D was up-regulated in endometrial cancer. Expression of PDGF-D protein, found in 78% of the cases, was associated with nonendometrioid histologic type (p=0.028), FIGO stage III/IV (p=0.039), >50% solid tumor growth (p=0.048), pelvic LN metastasis (p=0.035) and ER and PR negativity (p=0.04 and 0.002). PDGF-D expression was also significantly associated with expression of VEGF-A (p=0.021). In multivariate analysis, PDGF-D expression proved to be an independent prognostic factor in addition to histologic grade and FIGO stage. Patients with high expression levels of PDGF-D had a significantly poorer overall survival rate compared with patients with no expression. Conclusions: PDGF-D expression is frequently up-regulated in endometrial cancer, and is associated with aggressive features and poor prognosis.

5,8-Dimethoxy-2-Nonylamino-Naphthalene-1,4-Dione Inhibits Vascular Smooth Muscle Cell Proliferation by Blocking Autophosphorylation of PDGF-Receptor ${\beta}$

  • Kim, Yohan;Lee, Jung-Jin;Lee, Sang-Gil;Jung, Sang-Hyuk;Han, Joo-Hui;Yang, So Young;Yun, Eunju;Song, Gyu-Yong;Myung, Chang-Seon
    • The Korean Journal of Physiology and Pharmacology
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    • v.17 no.3
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    • pp.203-208
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    • 2013
  • As the abnormal proliferation of vascular smooth muscle cells (VSMCs) plays a critical role in the development of atherosclerosis and vascular restenosis, a candidate drug with antiproliferative properties is needed. We investigated the antiproliferative action and underlying mechanism of a newly synthesized naphthoquinone derivative, 5,8-dimethoxy-2-nonylamino-naphthalene-1,4-dione (2-nonylamino-DMNQ), using VSMCs treated with platelet-derived growth factor (PDGF). 2-Nonylamino-DMNQ inhibited proliferation and cell number of VSMCs induced by PDGF, but not epidermal growth factor (EGF), in a concentration-dependent manner without any cytotoxicity. This derivative suppressed PDGF-induced $[^3H]$-thymidine incorporation, cell cycle progression from $G_0/G_1$ to S phase, and the phosphorylation of phosphor-retinoblastoma protein (pRb) as well as the expression of cyclin E/D, cyclin-dependent kinase (CDK) 2/4, and proliferating cell nuclear antigen (PCNA). Importantly, 2-nonylamino-DMNQ inhibited the phosphorylation of PDGF receptor${\beta}$(PDGF-$R{\beta}$) enhanced by PDGF at $Tyr^{579}$, $Tyr^{716}$, $Tyr^{751}$, and $Tyr^{1021}$ residues. Subsequently, 2-nonylamino-DMNQ inhibited PDGF-induced phosphorylation of STAT3, ERK1/2, Akt, and $PLC{\gamma}1$. Therefore, our results indicate that 2-nonylamino-DMNQ inhibits PDGF-induced VSMC proliferation by blocking PDGF-$R{\beta}$ autophosphorylation, and subsequently PDGF-$R{\beta}$-mediated downstream signaling pathways.

Clinical Significance of Serum PDGF-BB and IGF-1 in Coal Workers' Pneumoconiosis (석탄광부 진폐증 환자에서 PDGF-BB, IGF-1의 의의)

  • Shin, Pyo Jin;Yong, Suk Joong;Shin, Kye Chul;Lee, Won Yeon;Kim, Shin Tae;Cha, Bong Suk;Jeon, Geun Jae
    • Tuberculosis and Respiratory Diseases
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    • v.52 no.4
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    • pp.338-345
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    • 2002
  • Background : Coal workers' pneumoconiosis(CWP) is a fibrotic lung disease resulting from the chronic inhalation of coal dust. Various cytokines and growth factors secreted from macrophages and monocytes play a key role in the pathogenesis of pneumoconiosis. The platelet-derived growth factor (PDGF)-BB and the insulin-like growth factor(IGF)-1 secreated from the macrophages and monocytes are believed to stimulate the accumulation of mesenchymal cells and fibrosis of the lower respiratory tract that is observed in fibrotic lung disease. The serum concentraion of PDGF-BB and IGF-1 in 30 CWP patients and 10 healthy controls were measured in order to determine if PDGF-BB and IGF-1 can be used as sensitive biomarkers in CWP. Method : Serum was collected from 30 patients with CWP(13 with simple CWP and 17 with complicated CWP) and 10 healthy controls. The serum concentrations of PDGF-BB and IGF-1 were measured using ELISA (R&D system, Minneapolis, MN). Results : The serum PDGF-BB concentration in patients with complicated CWP($10083.76{\pm}639.07pg/mL$) was significantly higher than in the patients with simple CWP ($8493.88{\pm}848.51pg/mL$) and the healthy controls ($3726.17{\pm}292.20pg/mL$) (p<0.05). Compared to the healthy controls ($413.40{\pm}1.94ng/mL$), there was no significant difference in the serum IGF-1 concentration in patients with simple ($366.77{\pm}183.67ng/mL$) and complicated CWP ($403.18{\pm}15.39ng/mL$) (p>0.05). Conclusion : These results show the important role of the PDGF-BB mediated pathways in the pathogenesis of CWP. These data suggests that the PDGF-BB serum concentration is a useful biomarkers of the fibrotic extent in CWP patients.

Studies on the Differentiation of Skeletal Muscle Cells in vitro:Protein Kinase C in the Differentiation of Skeletal Muscle Cells (근세포 분화에 관한 연구 : 근세포 분화에 있어서 Protein Kinase C)

  • 최원철;김한도;김정락
    • The Korean Journal of Zoology
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    • v.34 no.2
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    • pp.131-141
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    • 1991
  • Treating 12-O-tetradecanoyIphorboI 13-acetate -TPA) or platelet~derived growth factor(PDGF), the signal transduction of protein Idnase C (PKC) is occurred by the phosphoryladon. However the targeting proteins phosphorylated by PKC were found to be different proteins in molecular weights when WA or PDGF wa~ treated to the myoblast. In the WA-treated myoblast cells, the protein of Mr. 20 I(d was phosphorylated. In the PDGF-treated cells, the protein of Mr. 40 Kd was phosphrylated, while the protein of Mr. 20 Kd which phosphorylated in the WA-treatment was dephosphorylated. These results indicate that not only WA and PDGF &e different in activating the signal transduction pathways, but also they may involve in the down reguladon of PI(C during the long-term treatment But PDGF gave rise more rapidly down reguladon than in the case of WA. Using immunocytochemical approach, two disdnct PKC isozymes, PKC II and PKC III, have been localized in cytoplasm and both cytoplasm and nuclsolus, respectively. Ther'efore, the expression of two types of PKC in the myoblast suggests that the isozymes of PKC may involve in each different pathway of signal transduction or down-reguladon.

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Heat shock protein 90 inhibitor AUY922 attenuates platelet-derived growth factor-BB-induced migration and proliferation of vascular smooth muscle cells

  • Kim, Jisu;Lee, Kang Pa;Kim, Bom Sahn;Lee, Sang Ju;Moon, Byung Seok;Baek, Suji
    • The Korean Journal of Physiology and Pharmacology
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    • v.24 no.3
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    • pp.241-248
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    • 2020
  • Luminespib (AUY922), a heat shock proteins 90 inhibitor, has anti-neoplastic and antitumor effects. However, it is not clear whether AUY922 affects events in vascular diseases. We investigated the effects of AUY922 on the platelet-derived growth factor (PDGF)-BB-stimulated proliferation and migration of vascular smooth muscle cells (VSMC). VSMC viability was detected using the XTT (2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide) reagent. To detect the attenuating effects of AUY922 on PDGF-BB-induced VSMCs migration in vitro, we performed the Boyden chamber and scratch wound healing assays. To identify AUY922-mediated changes in the signaling pathway, the phosphorylation of protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) 1/2 was analyzed by immunoblotting. The inhibitory effects of AUY922 on migration and proliferation ex vivo were tested using an aortic ring assay. AUY922 was not cytotoxic at concentrations up to 5 nM. PDGF-BB-induced VSMC proliferation, migration, and sprout outgrowth were significantly decreased by AUY922 in a dose-dependent manner. AUY922 significantly reduced the PDGF-BB-stimulated phosphorylation of Akt and ERK1/2. Furthermore, PD98059 (a selective ERK1/2 inhibitor) and LY294002 (a selective Akt inhibitor) decreased VSMC migration and proliferation by inhibiting phosphorylation of Akt and ERK1/2. Greater attenuation of PDGF-BB-induced cell viability and migration was observed upon treatment with PD98059 or LY294002 in combination with AUY922. AUY922 showed anti-proliferation and anti-migration effects towards PDGF-BB-induced VSMCs by regulating the phosphorylation of ERK1/2 and Akt. Thus, AUY922 is a candidate for the treatment of atherosclerosis and restenosis.

The Effect of decalcified Root Surface as PDGF Carrier (PDGF 함유매개체로서 탈회된 치근면의 효과)

  • Woo, Hyo-Sang;Lee, Jae-Mok;Suh, Jo-Young
    • Journal of Periodontal and Implant Science
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    • v.26 no.4
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    • pp.889-905
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    • 1996
  • It is known that growth factors function as potent biologic mediators regulating numerous activities of wound healing via cell proliferation, migration and extracellular matrix formation and they also promote periodontal regeneration. But, method of growth factor application is controversial yet. So purpose of this study is to evaluate the effect of demineralized root surface as one of method of growth factor application. The ginigival fibroblasts were primary cultured and fifth or sixth subpassages were used in these experiments. In first experiment, root surface blocks demineralized with 100mg/ml tetracycline for 5 minutes and pH 1 citric acid for 3 minutes(experimental groups) and nonteminerilized root surface blocks (control groups) were placed in 100ng/ml PDGF-BB for 5 minutes. Then the cells were seeded on each root surface blocks and cultured for 6, 24, 48, 72 hours. In second experiment, root surface blocks deminerilized with tetracycline and citric acid and nondemineralized root surface blocks were placed in 200ng/ml PDGF-BB for 5 minutes and another non-demineralized root surfcae blocks were placed in DMEM without PDGF-BB. At 1, 2, 4, 6, 8 days, the cells were seeded in 24-well plate and using of each eluent, cultured for 72 hours. The results of the four determinants were presented as mean and S.D.. The results were as follows : The attachment and proliferation of human gingival fibroblast on root surface were more increased when PDGF-BB was applicated on root surfrace demineralized with tetracycline or citric acid than non-demineralized root surface. And, in comparision tetracycline with citric acid, there were more attachment and proliferation of human gingival fibroblast on root surface demineralized with tetracycline than citric acid, and proliferation of human gingival fibroblast on demineralized root surface was increased time dependently 1 day to 3 days. In second experiment using eluent, proliferation of human gingival fibroblast was more increased to 6 days when human gingival fibroblast was cultured in eluent that PDGF-BB was applicated on demineralized root surface than two control groups, and degree of proliferation was decreased time dependently 1 day to 6 days. Proliferation of human gingival fibroblast cultured in eluent without PDGF-BB was constant 1 day to 6 days. After 6 days, degree of proliferation of human gingival fibroblast was similar in four groups. This means that release duration of PDGF-BB from demineralized root surface is 6 days. And in comparision tetracycline with citric acid, there was more proliferation of human gingival fibroblast in tetracycline-treated group than citric acid. In conclusion, demineralized root surface as primary site for PDGF-BB application, especially demineralized with tetracycline has important roles in attachment and proliferation of human gingival fibroblast, and may be useful clinical applications in periodontal regenerative procedures.

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Murrayafoline A Induces a G0/G1-Phase Arrest in Platelet-Derived Growth Factor-Stimulated Vascular Smooth Muscle Cells

  • Han, Joo-Hui;Kim, Yohan;Jung, Sang-Hyuk;Lee, Jung-Jin;Park, Hyun-Soo;Song, Gyu-Yong;Nguyen, Manh Cuong;Kim, Young Ho;Myung, Chang-Seon
    • The Korean Journal of Physiology and Pharmacology
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    • v.19 no.5
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    • pp.421-426
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    • 2015
  • The increased potential for vascular smooth muscle cell (VSMC) growth is a key abnormality in the development of atherosclerosis and post-angioplasty restenosis. Abnormally high activity of platelet-derived growth factor (PDGF) is believed to play a central role in the etiology of these pathophysiological situations. Here, we investigated the anti-proliferative effects and possible mechanism(s) of murrayafoline A, a carbazole alkaloid isolated from Glycosmis stenocarpa Guillamin (Rutaceae), on PDGF-BB-stimulated VSMCs. Murrayafoline A inhibited the PDGF-BB-stimulated proliferation of VSMCs in a concentration-dependent manner, as measured using a non-radioactive colorimetric WST-1 assay and direct cell counting. Furthermore, murrayafoline A suppressed the PDGF-BB-stimulated progression through $G_0/G_1$ to S phase of the cell cycle, as measured by [$^3H$]-thymidine incorporation assay and cell cycle progression analysis. This anti-proliferative action of murrayafoline A, arresting cell cycle progression at $G_0/G_1$ phase in PDGF-BB-stimulated VSMCs, was mediated via down-regulation of the expression of cyclin D1, cyclin E, cyclin-dependent kinase (CDK)2, CDK4, and proliferating cell nuclear antigen (PCNA), and the phosphorylation of retinoblastoma protein (pRb). These results indicate that murrayafoline A may be useful in preventing the progression of vascular complications such as restenosis after percutaneous transluminal coronary angioplasty and atherosclerosis.