Yung-Luen Yu

I-Shou University, Kao-hsiung-shih, Kaohsiung, Taiwan

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Publications (39)180.81 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: Acetaminophen (APAP), is a safe analgesic and antipyretic drug at therapeutic dose, and is widely used in the clinic. However, high doses of APAP can induce hepatotoxicity and nephrotoxicity. Most studies have focused on high‑dose APAP‑induced acute liver and kidney injury. So far, few studies have investigated the effects of the therapeutic dose (1/10 of the high dose) or of the low dose (1/100 of the high dose) of APAP on the cells. The aim of this study was to investigate the cellular effects of therapeutic- or low‑dose APAP treatment on hepatoma cells and kidney fibroblasts. As expected, high‑dose APAP treatment inhibited while therapeutic and low‑dose treatment did not inhibit cell survival of kidney tubular epithelial cells. In addition, therapeutic-dose treatment induced an increase in the H2O2 level, activated the caspase‑9/‑3 cascade, and induced cell apoptosis of hepatoma cells. Notably, APAP promoted fibroblast proliferation, even at low doses. This study demonstrates that different cellular effects are exerted upon treatment with different APAP concentrations. Our results indicate that treatment with the therapeutic dose of APAP may exert an antitumor activity on hepatoma, while low‑dose treatment may be harmful for patients with fibrosis, since it may cause proliferation of fibroblasts.
    Molecular Medicine Reports 03/2014; · 1.17 Impact Factor
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    ABSTRACT: Frog ribonucleases have been demonstrated to have anticancer activities. However, whether RC-6 ribonuclease exerts anticancer activity on human embryonal carcinoma cells remains unclear. In the present study, RC-6 induced cytotoxicity in NT2 cells (a human embryonal carcinoma cell line) and our studies showed that RC-6 can exert anticancer effects and induce caspase-9 and -3 activities. Moreover, to date, there is no evidence that frog ribonuclease-induced cytotoxicity effects are related to cellular senescence. Therefore, our studies showed that RC-6 can increase p16 and p21 protein levels and induce cellular senescence in NT2 cells. Notably, similar to retinoic acid-differentiated NT2 cells, neuron-like morphology was found on some remaining live cells after RC-6 treatment. In conclusion, our study is the first to demonstrate that RC-6 can induce cytotoxic effects, caspase-9/-3 activities, cellular senescence and neuron-like morphology in NT2 cells.
    Oncology Reports 02/2014; · 2.30 Impact Factor
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    ABSTRACT: The aim of this study was to examine the plasma level changes of soluble Axl (sAxl) prior to and following treatment with antibiotics in hospitalized adult patients with community-acquired pneumonia (CAP), and to investigate the correlating clinical and laboratory manifestations of CAP with plasma sAxl levels. Blood samples were obtained from 61 adult CAP patients (prior to and following treatment with antibiotics) and 60 healthy controls in order to measure the plasma concentrations of sAxl using the enzyme-linked immunosorbent assay. The plasma-soluble Axl concentration level was markedly elevated in patients with CAP prior to treatment, compared with the controls, and decreased markedly following treatment. The levels of white blood cells, neutrophils, and C-reactive protein decreased markedly following treatment with antibiotics and did not correlate with the concentration level of sAxl. However, the plasma concentration of sAxl correlated with the severity of CAP with the pneumonia severity index score (r=0.350, P=0.006, n=61), the CURB-65 score (r=0.281, P=0.028, n=61) and the acute physiology and chronic health evaluation II score (r=0.313, P=0.014, n=61). In conclusion, plasma sAxl may be involved in the clinical assessment of the severity of CAP, which may guide the development of treatment strategies and predict the clinical outcome.
    Molecular Medicine Reports 02/2014; · 1.17 Impact Factor
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    ABSTRACT: The gene EZH2, the polycomb group protein enhancer of zeste 2, encodes a transcriptional repressor that also serves as a histone methyltransferase that is associated with progression to more advanced disease in a variety of malignancies. EZH2 expression level in urothelial cell carcinoma (UCC) is highly correlated with tumor aggressiveness, but it has not been determined if specific EZH2 genetic variants are associated with UCC risk. This study investigated the potential associations of EZH2 single-nucleotide polymorphisms with UCC susceptibility and its clinicopathologic characteristics. A total of 233 UCC patients and 552 cancer-free controls, all of whom were from Taiwan, were analyzed for four EZH2 single-nucleotide polymorphisms (rs6950683, rs2302427, rs3757441, and rs41277434) using real-time PCR genotyping. After adjusting for other co-variants, we found that individuals carrying at least one C allele at EZH2 rs6950683 had a lower risk of developing UCC than did major allele carriers. The CCCA or TGTA haplotype among the four EZH2 sites was also associated with a reduced risk of UCC. Furthermore, UCC patients who carried at least one G allele at rs2302427 had a lower invasive tumor stage than did patients carrying the major allele. The rs6950683 SNPs of EZH2 might contribute to the prediction of UCC susceptibility. This is the first study to provide insight into risk factors associated with EZH2 variants in carcinogenesis of UCC in Taiwan.
    PLoS ONE 01/2014; 9(4):e93635. · 3.73 Impact Factor
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    ABSTRACT: Epigenetic regulation plays a critical role in glioblastoma (GBM) tumorigenesis. However, how microRNAs (miRNAs) and cytokines cooperate to regulate GBM tumor progression is still unclear. Here, we show that interleukin-6 (IL-6) inhibits miR142-3p expression and promotes GBM propagation by inducing DNA methyltransferase 1-mediated hypermethylation of the miR142-3p promoter. Interestingly, miR142-3p also suppresses IL-6 secretion by targeting the 3' UTR of IL-6. In addition, miR142-3p also targets the 3' UTR and suppresses the expression of high-mobility group AT-hook 2 (HMGA2), leading to inhibition of Sox2-related stemness. We further show that HMGA2 enhances Sox2 expression by directly binding to the Sox2 promoter. Clinically, GBM patients whose tumors present upregulated IL-6, HMGA2, and Sox2 protein expressions and hypermethylated miR142-3p promoter also demonstrate poor survival outcome. Orthotopic delivery of miR142-3p blocks IL-6/HMGA2/Sox2 expression and suppresses stem-like properties in GBM-xenotransplanted mice. Collectively, we discovered an IL-6/miR142-3p feedback-loop-dependent regulation of GBM malignancy that could be a potential therapeutic target.
    Molecular cell 12/2013; 52(5):693-706. · 14.61 Impact Factor
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    ABSTRACT: Triple-negative breast cancer (TNBC), a subtype of breast cancer with negative expressions of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), is frequently diagnosed in younger women and has poor prognosis for disease-free and overall survival. Due to the lack of known oncogenic drivers for TNBC proliferation, clinical benefit from currently available targeted therapies is limited, and new therapeutic strategies are urgently needed. Triple-negative breast cancer cell lines were treated with proteasome inhibitors in combination with lapatinib (a dual epidermal growth factor receptor (EGFR)/HER2 tyrosine kinase inhibitor). Their in vitro and in vivo viability was examined by MTT assay, clonogenic analysis, and orthotopic xenograft mice model. Luciferase reporter gene, immunoblot, and RT-qPCR, immunoprecipitation assays were used to investigate the molecular mechanisms of action. Our data showed that nuclear factor (NF)-kappaB activation was elicited by lapatinib, independent of EGFR/HER2 inhibition, in TNBCs. Lapatinib-induced constitutive activation of NF-kappaB involved Src family kinase (SFK)-dependent p65 and IkappaBalpha phosphorylations, and rendered these cells more vulnerable to NF-kappaB inhibition by p65 small hairpin RNA. Lapatinib but not other EGFR inhibitors synergized the anti-tumor activity of proteasome inhibitors both in vitro and in vivo. Our results suggest that treatment of TNBCs with lapatinib may enhance their oncogene addiction to NF-kappaB, and thus augment the anti-tumor activity of proteasome inhibitors. These findings suggest that combination therapy of a proteasome inhibitor with lapatinib may benefit TNBC patients.
    Breast cancer research: BCR 11/2013; 15(6):R108. · 5.87 Impact Factor
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    ABSTRACT: Globo H, a cancer-associated carbohydrate antigen, is highly expressed in various types of cancers. However, the role of Globo H in hepatocellular carcinoma (HCC) remains elusive. In the current study, we performed glycan microarray analysis of 134 human serum samples to explore anti-Globo H antibody changes and found that Globo H is up-regulated in hepatitis B virus (HBV)-positive HCC. Likewise, immunohistochemistry showed that Globo H expression was higher in tumors compared with normal tissues. In addition, fucosyltransferase 2 (FUT2), the main synthetic enzyme of Globo H, was also increased in HCC cells overexpressing HBV X protein (HBX). HBX plays an important role in promoting cell proliferation and may be related to increased levels of FUT2 and Globo H. Furthermore, using microRNA profiling, we observed that microRNA-15b (miR-15b) was down-regulated in patients with HCC and confirmed association of FUT2 expression with expression of its product, Globo H. Therefore, our results suggest that HBX suppressed the expression of miR-15b, which directly targeted FUT2 and then increased levels of Globo H to enhance HCC cell proliferation. Additionally, proliferation of HBX-overexpressing HCC cells was significantly inhibited by treatment with Globo H antibody in vitro. In xenograft animal experiments, we found that overexpression of miR-15b effectively suppressed tumor growth. The newly identified HBX/miR-15b/FUT2/Globo H axis suggests one possible molecular mechanism of HCC cell proliferation and represents a new potential therapeutic target for HCC treatment. © 2013 Wiley Periodicals, Inc.
    International Journal of Cancer 10/2013; · 6.20 Impact Factor
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    ABSTRACT: Stress-inducible protein-1 (STI-1) is the proposed ligand for the cellular prion protein (PrP(C) ), which is thought to facilitate recovery following stroke. Whether STI-1 expression is affected by stroke and how its signalling facilitates recovery remain elusive. Brain slices from patients that died of ischemic stroke were collected for STI-1 immunohistochemistry. These findings were compared to results from cell cultures, mice with or without the PrP(C) knockout, and rats. Based on these findings, molecular and pharmacological interventions were administered to investigate the underlying mechanisms and to test the possibility for therapy in experimental stroke models. STI-1 was upregulated in the ischemic brains from humans and rodents. The increase in STI-1 expression in vivo was not cell-type specific, as it was found in neurons, glia and endothelial cells. Likewise, this increase in STI-1 expression can be mimicked by sublethal hypoxia in primary cortical cultures (PCCs) in vitro, and appear to have resulted from the direct binding of the hypoxia inducible factor-1α (HIF-1α) to the STI-1 promoter. Importantly, this STI-1 signalling promoted bone marrow derived cells (BMDCs) proliferation and migration in vitro and recruitment to the ischemic brain in vivo, and augmenting its signalling facilitated neurological recovery in part by recruiting BMDCs to the ischemic brain. Our results thus identified a novel mechanism by which ischemic insults can trigger a self-protective mechanism to facilitate recovery.
    EMBO Molecular Medicine 07/2013; · 7.80 Impact Factor
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    ABSTRACT: Here, we have examined the plasma levels of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1), the MMP-9/TIMP-1 molar ratio, the TIMP-1 single nucleotide polymorphisms (SNPs) 372C/T and the susceptibility to community-acquired pneumonia (CAP). An enzyme-linked immunosorbent assay (ELISA) was used to measure plasma MMP-9 and TIMP-1 concentrations in 60 patients with CAP and 60 healthy individuals. A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was used to detect the TIMP-1 SNPs 372C/T. The plasma MMP-9, TIMP-1 levels and the MMP-9/TIMP-1 molar ratio were significantly increased in patients with CAP compared to normal controls. The MMP-9/TIMP-1 molar ratio decreased significantly in patients with CAP after treatment. Furthermore, the plasma TIMP-1 concentration was positively correlated with the pneumonia severity index (PSI), the CURB score, the results of the acute physiology and chronic health evaluation II (APACHE II) and the length of the hospital stay. No significant difference was found in the genotype distribution of TIMP-1 372C/T between patients with CAP and normal controls. We hypothesize that MMP-9 levels and the MMP-9/TIMP-1 molar ratio plays a role in the development of CAP and is related to the severity of CAP. Based on our data, we suggest that incorporating plasma MMP-9 levels and the MMP-9/TIMP-1 molar ratio into a clinical evaluation will aid in CAP diagnosis.
    Clinica chimica acta; international journal of clinical chemistry 06/2013; · 2.54 Impact Factor
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    ABSTRACT: Exchange protein activated by cAMP-1 (Epac1) plays an important role in cell proliferation, cell survival and neuronal signaling, and activation of Epac1 in endothelial progenitor cells increases their homing to ischemic muscles and promotes neovascularization in a model of hind limb ischemia. Moreover, upregulation of Epac1 occurs during organ development and in diseases such as myocardial hypertrophy, diabetes, and Alzheimer's disease. We report here that hypoxia upregulated Epac1 through HIF-1α induction in the CD34-immunosorted human umbilical cord blood hematopoietic stem cells (hUCB(34)). Importantly, implantation of hUCB(34) subjected to hypoxia-preconditioning (HP-hUCB(34)) improved stroke outcome, more than did implantation of untreated hUCB(34), in rodents subjected to cerebral ischemia, and this required Epac1-to-matrix metalloproteases (MMPs) signaling. This improved therapeutic efficacy correlated with better engraftment and differentiation of these cells in the ischemic host brain. In addition, more than did implantation of untreated HP-hUCB(34), implantation of HP-hUCB(34) improved cerebral blood flow into the ischemic brain via induction of angiogenesis, facilitated proliferation/recruitment of endogenous neural progenitor cells in the ischemic brain, and promoted neurite outgrowth following cerebral ischemia. Consistent with our proposed role of Epac1-to-MMPs signaling in hypoxia-preconditioning, the above mentioned effects of implanting HP-hUCB(34) could be abolished by pharmacological inhibition and genetic disruption/deletion of Epac1 or MMPs. We have discovered a HIF-1α-to-Epac1-to-MMPs signaling pathway that is required for the improved therapeutic efficacy resulting from hypoxia preconditioning of hUCB(34) in vitro prior to their implantation into the host brain in vivo.
    Neurobiology of Disease 05/2013; · 5.62 Impact Factor
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    ABSTRACT: EZH2 plays an important role in stem cell renewal and maintenance by inducing gene silencing via its histone methyltransferase activity. Previously, we showed that EZH2 downregulation enhances neuron differentiation of human mesenchymal stem cells (hMSCs); however, the underlying mechanisms of EZH2-regulated neuron differentiation are still unclear. Here, we identify Smurf2 as the E3 ubiquitin ligase responsible for the polyubiquitination and proteasome-mediated degradation of EZH2, which is required for neuron differentiation. A ChIP-on-chip screen combined with gene microarray analysis revealed that PPARγ was the only gene involved in neuron differentiation with significant changes in both its modification and expression status during differentiation. Moreover, knocking down PPARγ prevented cells from undergoing efficient neuron differentiation. In animal model, rats implanted with intracerebral EZH2-knocked-down hMSCs or hMSCs plus treatment with PPARγ agonist (rosiglitazone) showed better improvement than those without EZH2 knockdown or rosiglitazone treatment after a stroke. Together, our results support Smurf2 as a regulator of EZH2 turnover to facilitate PPARγ expression, which is specifically required for neuron differentiation, providing a molecular mechanism for clinical applications in the neurodegenerative diseases.
    EMBO Molecular Medicine 03/2013; · 7.80 Impact Factor
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    ABSTRACT: Lapatinib, a dual EGFR/HER2 kinase inhibitor, showed clinical benefits in advanced HER2-positive breast cancer patients. Because some triple-negative breast cancers (TNBCs) frequently overexpress EGFR, the anti-tumor activity of lapatinib in such diseases was also tested. However, the results showed a worse event-free survival rate. It remains unknown whether and how lapatinib elicits the aggressiveness of such cancer cells. In this study, our results demonstrated that lapatinib facilitated axillary and lung metastases of triple-negative MDA-MB-231 breast cancer cells without affecting their viability, leading to worse survival in orthotopic xenograft mice. The lapatinib-increased motility was attributed by the elevation of EGFR through the downregulation of microRNA-7 and by the subsequent overexpression of cyclooxygenase-2 (COX-2). Strikingly, independent of its kinase activity, the elevated EGFR at least partly stabilized COX-2 expression by enhancing the binding of HuR to COX-2 mRNA. Our results suggest that lapatinib may increase the migration and invasion of MDA-MB-231 cells by upregulating EGFR and COX-2 through the downregulation of microRNA-7, providing a potential explanation for the worse clinical outcome of TNBC patients who receive lapatinib-based treatment. These findings also shed new light on the molecular mechanism of COX-2 mRNA stabilization by EGFR in a kinase-independent manner.
    Molecular pharmacology 01/2013; · 4.53 Impact Factor
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    ABSTRACT: Japanese encephalitis virus (JEV), a mosquito‑borne flavivirus, causes acute encephalitis and nervous damage. Previous studies have demonstrated that JEV induces apoptosis in infected cells. However, to date the mechanisms of JEV‑induced apoptosis are unclear. In order to identify the viral proteins associated with JEV‑induced apoptosis, pEGFP‑non‑structural protein 3 (NS3) 1‑619 (expressing the JEV NS3 intact protein, including the protease and helicase domains), pEGFP‑NS3 1‑180 (expressing the protease domain) and pEGFP‑NS3 163‑619 (expressing the helicase domain) were transfected into target cells to study cell death. Results demonstrate that the JEV NS3 intact protein and protease and helicase domains induce cell death. In addition, cell death was identified to be significantly higher in cells transfected with the NS3 protease domain compared with the intact protein and helicase domain. Caspase activation was also analyzed in the current study. NS3 intact protein and NS3 protease and helicase domains activated caspase‑9/‑3‑dependent and ‑independent pathways. However, caspase‑8 activity was not found to be significantly different in NS3‑transfected cells compared with control. In summary, the present study demonstrates that the NS3 helicase and protease domains of JEV activate caspase‑9/‑3‑dependent and ‑independent cascades and trigger cell death.
    Molecular Medicine Reports 01/2013; · 1.17 Impact Factor
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    ABSTRACT: The enhancer of zeste 2 (EZH2) gene encodes the histone methyltransferase that is the catalytic component of the polycomb repressive complex-2, which initiates epigenetic silencing of genes. The expression level of EZH2 in hepatocellular carcinoma (HCC) is highly correlated with tumor progression; however, it has not been determined if specific EZH2 genetic variants are associated with the risk of HCC. This study investigated the potential associations of EZH2 single-nucleotide polymorphisms with HCC susceptibility and its clinicopathologic characteristics. A total of 220 HCC patients and 552 cancer-free controls were analyzed for four EZH2 single-nucleotide polymorphisms (rs6950683, rs2302427, rs3757441, and rs41277434) using real-time PCR genotyping. After adjusting for other co-variants, the individuals carrying at least one C allele at EZH2 rs6950683 and rs3757441 had a 0.611-fold and a 0.660-fold lower risk of developing HCC than did wild-type (TT) carriers, respectively. The CCCA or CCTA haplotype among the four EZH2 sites (rs6950683, rs2302427, rs3757441, and rs41277434), respectively, was also associated with a reduced risk of HCC. Furthermore, HCC patients who carried at least one C allele at rs6950683 or rs3757441 had a higher lymph-node-metastasis risk but a lower liver-cirrhosis risk than did patients carrying the wild-type allele. The rs6950683 and rs3757441 polymorphic genotypes of EZH2 might contribute to the prediction of susceptibility to and pathological development of HCC. This is the first study to provide insight into risk factors associated with EZH2 variants in carcinogenesis of HCC in Taiwan.
    PLoS ONE 01/2013; 8(9):e74870. · 3.73 Impact Factor
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    ABSTRACT: Tyrosine 211 (Y211) phosphorylation of proliferation cell nuclear antigen (PCNA) coincides with pronounced cancer cell proliferation and correlates with poor survival of breast cancer patients. In epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-resistant cells, both nuclear EGFR (nEGFR) expression and PCNA Y211 phosphorylation are increased. Moreover, the resistance to EGFR TKI is a major clinical problem in treating EGFR-overexpressing triple-negative breast cancer (TNBC). Thus, effective treatment to combat resistance is urgently needed. Here, we show that treatment of cell-penetrating PCNA peptide (CPPP) inhibits growth and induces apoptosis of human TNBC cells. The Y211F CPPP specifically targets EGFR and competes directly for PCNA tyrosine Y211 phosphorylation and prevents nEGFR from binding PCNA in vivo; it also suppresses tumor growth by sensitizing EGFR TKI resistant cells, which have enhanced nEGFR function and abrogated classical EGFR membrane signaling. Furthermore, we identify an active motif of CPPP, RFLNFF (RF6 CPPP), which is necessary and sufficient to inhibit TKI-resistant TNBC cell growth of orthotopic implanted tumor in mice. Finally, the activity of its synthetic retro-inverted derivative, D-RF6 CPPP, on an equimolar basis, is more potent than RF6 CPPP. Our study reveals a drug candidate with translational potential for the future development of safe and effective therapeutic for EGFR TKI resistance in TNBC.
    PLoS ONE 01/2013; 8(4):e61362. · 3.73 Impact Factor
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    ABSTRACT: Fisetin (3,3',4',7-tetrahydroxyflavone), a naturally occurring flavonoid, has been reported to inhibit proliferation and induce apoptosis in several cancer types. However, its effect on the anti-metastatic potential of cervical cancer cells remains unclear. In the present study, we found that fisetin inhibits the invasion and migration of cervical cancer cells. The expression and activity of urokinase plasminogen activator (uPA) was significantly suppressed by fisetin in a dose-dependent manner. We also demonstrated that fisetin reduces the phosphorylation of p38 MAPK, but not that of ERK1/2, JNK1/2, or AKT. Addition of a p38 MAPK inhibitor, SB203580, further enhanced the inhibitory effect of fisetin on the expression and activity of uPA and the invasion and motility in cervical cancer cells. Fisetin suppressed the TPA (tetradecanoylphorbol-13-acetate)-induced activation of p38 MAPK and uPA, and inhibited the TPA-enhanced migratory and invasive abilities. Furthermore, the promoter activity of the uPA gene was dramatically repressed by fisetin, which disrupted the nuclear translocation of NF-κB and its binding amount on the promoter of the uPA gene, and these suppressive effects could be further enhanced by SB203580. This study provides strong evidence for the molecular mechanism of fisetin in inhibiting the aggressive phenotypes by repression of uPA via interruption of p38 MAPK-dependent NF-κB signaling pathway in cervical cancer cells and thus contributes insight to the potential of using fisetin as a therapeutic strategy against cervical cancer by inhibiting migration and invasion.
    PLoS ONE 01/2013; 8(8):e71983. · 3.73 Impact Factor
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    ABSTRACT: Hepatitis B virus (HBV) infection accounts for over a half of cases of hepatocellular carcinoma (HCC), the most frequent malignant tumor of the liver. HBV-encoded X (HBx) plays critical roles in HBV-associated hepatocarcinogenesis. However, it is unclear whether and how HBx regulates the expression of epidermal growth factor receptor (EGFR), an important gene for cell growth. Therefore, the study aimed to investigate the association between HBx and EGFR expression. In this study, we found that HBx upregulates miR-7 expression to target 3'UTR of EGFR mRNA, which in turn results in the reduction of EGFR protein expression in HCC cells. HBx-mediated EGFR suppression renders HCC cells a slow-growth behavior. Deprivation of HBx or miR-7 expression or restoration of EGFR expression can increase the growth rate of HCC cells. Our data showed the miR-7-dependent EGFR suppression by HBx, supporting an inhibitory role of HBx in the cell growth of HCC. These findings not only identify miR-7 as a novel regulatory target of HBx, but also suggest HBx-miR-7-EGFR as a critical signaling in controlling the growth rate of HCC cells.
    Evidence-based Complementary and Alternative Medicine 01/2013; 2013:682380. · 1.72 Impact Factor
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    ABSTRACT: The DOC-2/DAB2 interactive protein (DAB2IP) is a new member of the Ras GTPase-activating protein family. Recent studies have shown that, in addition to its tumor suppressive role in various tumors, DAB2IP also plays an important role in regulating neuronal migration and positioning during brain development. In this study, we determined the roles of DAB2IP in the neuronal differentiation of human mesenchymal stem cells (hMSCs). We found that lentiviral short hairpin RNA (shRNA)-mediated knockdown of DAB2IP promoted the mesenchymal-to-neuroepithelial stem cell transition (MtNeST) and neuronal differentiation, which were accompanied by a reduction of cell proliferation but not apoptosis or cellular senescence. This suggests that DAB2IP plays an important role in the neuronal induction of hMSCs. Moreover, our finding that reduction of glycogen synthase kinase 3 beta (GSK3β) activity upon LiCl pretreatment inhibited both the MtNeST and production of MAP2-positive cells upon DAB2IP knockdown suggests that this transition is most likely mediated by regulation of the GSK3β signaling pathway. Our study demonstrates that DAB2IP participates in the first step of neuron induction of hMSCs, which implies a potentially important role for DAB2IP in the MtNeST during neurogenesis.
    PLoS ONE 01/2013; 8(9):e75884. · 3.73 Impact Factor
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    ABSTRACT: Glioblastoma is the most aggressive primary brain tumor and its prognosis remains poor despite different treatment modalities including surgery, radiotherapy and chemotherapy. Therefore, more useful treatments for glioblastoma patients are required. Human interleukin 15 (hIL15) is an immunomodulator that has antitumor activities. hIL15 combined with gene therapy method is also currently under cosideration as a treatment option. Since recombinant adeno-associated virus serotype 2 (rAAV2) with low immunogenicity and long-term gene expression in human clinical trials has been demonstrated, rAAV2 encoding hIL15 (rAAV2-hIL15) were used to inhibit human glioblastoma growth in the present study. rAAV2-hIL15, which is able to express IL15 protein with bioactivity, was successfully produced and purified. Data of this study demonstrated that the long-term expression of rAAV2-hIL15 enhances immunoglobulin (Ig) production and the cytotoxic activity of lymphokine-activated killer (LAK) cells. In addition, results of the present study showed that rAAV2-hIL15 delays tumor growth on a xenografted human glioblastoma mice model. Taken together, these results indicated that rAAV2-hIL15 constitutes a powerful and potent gene immunotherapy method for human glioblastoma treatment.
    Molecular and clinical oncology. 01/2013; 1(2):321-325.
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    ABSTRACT: Poly(ADP-ribose) polymerase 1 (Parp1) catalyzes poly(ADP-ribosylation) (PARylation) and induces replication networks involved in multiple nuclear events. Using mass spectrometry and Western blotting, Parp1 and PARylation activity were intensively detected in induced pluripotent stem cells (iPSCs) and embryonic stem cells, but they were lower in mouse embryonic fibroblasts (MEFs) and differentiated cells. We show that knockdown of Parp1 and pharmacological inhibition of PARylation both reduced the efficiency of iPSC generation induced by Oct4/Sox2/Klf4/c-Myc. Furthermore, Parp1 is able to replace Klf4 or c-Myc to enhance the efficiency of iPSC generation. In addition, mouse iPSCs generated from Oct4/Sox2/Parp1-overexpressing MEFs formed chimeric offspring. Notably, the endogenous Parp1 and PARylation activity was enhanced by overexpression of c-Myc and repressed by c-Myc knockdown. A chromatin immunoprecipitation assay revealed a direct interaction of c-Myc with the Parp1 promoter. PAR-resin pulldown, followed by proteomic analysis, demonstrated high levels of PARylated Chd1L, DNA ligase III, SSrp1, Xrcc-6/Ku70, and Parp2 in pluripotent cells, which decreased during the differentiation process. These data show that the activation of Parp1, partly regulated by endogenous c-Myc, effectively promotes iPSC production and helps to maintain a pluripotent state by posttranslationally modulating protein PARylation.
    Journal of Experimental Medicine 12/2012; · 13.21 Impact Factor

Publication Stats

296 Citations
499 Downloads
2k Views
180.81 Total Impact Points

Institutions

  • 2013
    • I-Shou University
      Kao-hsiung-shih, Kaohsiung, Taiwan
  • 2009–2013
    • Asia University
      • Department of Biotechnology
      臺中市, Taiwan, Taiwan
  • 2008–2013
    • China Medical University Hospital
      臺中市, Taiwan, Taiwan
    • Tzu Chi University
      • Institute of Medical Sciences
      Hua-lien, Taiwan, Taiwan
  • 2010
    • China Medical University (ROC)
      臺中市, Taiwan, Taiwan
  • 2007–2010
    • University of Texas MD Anderson Cancer Center
      • Department of Molecular and Cellular Oncology
      Houston, TX, United States