Qian Huang

Shanghai University, Shanghai, Shanghai Shi, China

Are you Qian Huang?

Claim your profile

Publications (78)332.69 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Cytotoxic radiotherapy unfavorably induces tumor cells to generate various proangiogenic substances, promoting post-irradiation angiogenesis (PIA), which is one of major causes of radiotherapy failure. Though several studies have reported some mechanisms behind PIA, they have not yet described the beginning proangiogenic motivator buried in the irradiated microenvironment. In this work, we revealed that dying tumor cells induced by irradiation prompted PIA via a caspase 3 dependent mechanism. Proteolytic inactivation of caspase 3 in dying tumor cells by transducing a dominant-negative version weakened proangiogenic effects in vitro and in vivo. In addition, inhibition of caspase 3 activity suppressed tumor angiogenesis and tumorigenesis in xenograft mouse model. Importantly, we identified vascular endothelial growth factor (VEGF)-A as a downstream proangiogenic factor regulated by caspase 3 possibly through Akt signaling. Collectively, these findings indicated that besides acting as a key executioner in apoptosis, caspase 3 in dying tumor cells may play a central role in driving proangiogenic response after irradiation. Thus, radiotherapy in combination with caspase 3 inhibitors may be a novel promising therapeutic strategy to reduce tumor recurrence due to restrained PIA.
    Oncotarget 10/2015; 6(32):32353-67. DOI:10.18632/oncotarget.5898. · 6.36 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In a recent study, we report that mammalian cells exposed to stress such as ionizing radiation can survive with Caspase-3 or -7 activation. We found that sublethal activation of the executioner caspases promote chemical- and radiation-induced genetic instability and carcinogenesis, in contrast to their perceived roles as tumor suppressors.
    06/2015; DOI:10.1080/23723556.2015.1054550
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Dying tumor cells after irradiation could promote the proliferation of living tumor cells might cause tumor relapse and treatment failure. Our previous study showed that activated caspase-3 after irradiation probably participates in tumor repopulation. In this study, we investigated whether high mobility group box 1(HMGB1) is also involved in tumor repopulation. Colorectal tumor cells were irradiated. The cleaved caspase-3 (CC3) in irradiated tumor cells and HMGB1 in the supernatant of irradiated tumor cells were detected by Western blot. A large number of irradiated colorectal tumor cells (feeder cells) were then co-cultured with a small number of luciferase-labeled living colorectal tumor cells (reporter cells) and proliferation of reporter cells was measured by bioluminescence imaging. The CC3 and HMGB1 protein expression in colorectal tumor and peritumoral tissues were detected by immunohistochemistry and their correlation with prognosis were analyzed. The irradiated colorectal tumor cells underwent apoptosis and necrosis and produced CC3 in tumor cells and HMGB1 in the supernatant of cultured cells. The increased expression of secretory HMGB1 correlated with CC3 level and proliferating cell nuclear antigen (PCNA) after irradiation in vitro. The irradiated dying cells remarkably stimulated living tumor cell proliferation. Interestedly, immunohistochemistry staining showed that positive HMGB1, CC3, and Ki67 expression were significantly higher in colorectal tumor tissues than in peritumoral tissues (p <0.01). The Kaplan-Meier survival analysis revealed that high HMGB1, CC3, and Ki67 levels were significantly associated with poor prognosis (p <0.05, p <0.01). Multivariate analysis using Cox proportional hazards model showed that TNM staging and HMGB1 were independent prognostic factors in patients with colorectal cancer (CRC) (p <0.01, p <0.001). Both apoptotic and necrotic cells could stimulate proliferation of living tumor cells, and the increased expression of CC3 and HMGB1 in tumor cells could be new markers for poor prognosis in colorectal cancer patients.
    Journal of Experimental & Clinical Cancer Research 05/2015; 34(1):51. DOI:10.1186/s13046-015-0166-1 · 4.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Apoptosis is typically considered an anti-oncogenic process since caspase activation can promote the elimination of genetically unstable or damaged cells. We report that a central effector of apoptosis, caspase-3, facilitates rather than suppresses chemical- and radiation-induced genetic instability and carcinogenesis. We found that a significant fraction of mammalian cells treated with ionizing radiation can survive despite caspase-3 activation. Moreover, this sublethal activation of caspase-3 promoted persistent DNA damage and oncogenic transformation. In addition, chemically induced skin carcinogenesis was significantly reduced in mice genetically deficient in caspase-3. Furthermore, attenuation of EndoG activity significantly reduced radiation-induced DNA damage and oncogenic transformation, identifying EndoG as a downstream effector of caspase-3 in this pathway. Our findings suggest that rather than acting as a broad inhibitor of carcinogenesis, caspase-3 activation may contribute to genome instability and play a pivotal role in tumor formation following damage. Copyright © 2015 Elsevier Inc. All rights reserved.
    Molecular cell 04/2015; 58(2). DOI:10.1016/j.molcel.2015.03.003 · 14.02 Impact Factor
  • Source
    Jingjing Ma · Jin Cheng · Yanping Gong · Ling Tian · Qian Huang ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Tumor repopulation after radiotherapy is a big obstacle for clinical cancer therapy. The molecular mechanisms of tumor cell repopulation after radiotherapy remain unclear. This study investigated the role of sonic hedgehog (SHH) and Wnt signaling pathways in tumor repopulation after radiotherapy in an in vitro repopulation model. In this model, irradiated dying tumor cells functioned as feeder cells, while luciferase-labeled living tumor cells acted as reporter cells. Proliferation of reporter cells was measured by bioluminescence imaging. Results showed that irradiated dying HT29 and Panc1 cells significantly stimulated the repopulation of their living cells. In HT29 and Panc1 cells, radiation significantly inhibited Wnt activity. In the irradiated dying HT29 and Panc1 cells, the activated nuclear β-catenin was significantly decreased. Wnt agonist 68166 significantly decreased, whereas Wnt antagonist significantly increased repopulation in HT29 and Panc1 tumor cells in a dose dependent manner. β-catenin shRNA significantly promoted tumor cell repopulation. The level of secreted frizzled related protein-1, hedgehog, and Gli1 were increased in irradiated cells. Our results highlighted the interaction between Wnt and SHH signaling pathways in dying tumor cells and suggested that downregulation of Wnt signaling after SHH activation is negatively associated with tumor repopulation.
    Disease Models and Mechanisms 04/2015; 8(4):385-391. DOI:10.1242/dmm.018887 · 4.97 Impact Factor
  • Source
    Dian-Na Gu · Qian Huang · Ling Tian ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Increasing evidence supports that microRNAs (miRNAs) play crucial roles in cancer through post-transcriptional gene silencing of their target genes, therefore, more and more effort has been devoted to develop miRNA-targeting therapeutics in cancer. MicroRNA-7 (miR-7) has been characterized as a potential tumor suppressor and regulates diverse fundamental biological processes of cancer cells including initiation, proliferation, migration, invasion, survival and death by targeting a number of oncogenic signaling pathways. Areas covered: This review examines evidence of the biological responses of miR-7 in cancer, with an emphasis on its regulation of the vital oncogenic signaling pathways. It also discusses the rationale, strategies and challenges of miR-7 as a potential therapeutic target for cancer. Expert opinion: With the increasing understanding of molecular mechanisms of miR-7-mediated regulatory networks and the advancement of miRNA-based therapeutics, targeting miR-7 may be a potential and promising strategy for cancer therapy.
    Expert Opinion on Therapeutic Targets 03/2015; 19(3):415-426. DOI:10.1517/14728222.2014.988708 · 5.14 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pancreatic cancer is one of the most lethal human cancers, and radiotherapy is often implemented for locally advanced pancreatic ductal adenocarcinoma. Tumor cell repopulation is a major challenge in treating cancers after radiotherapy. In order to address the problem of tumor repopulation, our previous studies have demonstrated that dying cells stimulate the proliferation of living tumor cells after radiotherapy. In particular, dying cells undergoing apoptosis also activate survival or proliferation signals and release growth factors to surrounding living cells. In the present study, we used an in vitro model to examine the possible mechanisms for dying cell stimulated tumor repopulation in pancreatic cancer. In this model, a small number of living, luciferase-labeled pancreatic cancer cells (reporter) were seeded onto a layer of a much larger number of irradiated, unlabeled pancreatic cancer cells and the growth of the living cells was measured over time as a gage of tumor repopulation. Our results indicate that irradiated, dying Panc1 feeder cells significantly stimulated the proliferation of living Panc1 reporter cells. Importantly, we identified that the percentage of apoptotic cells and the cleavage of caspases 3 and 7 and protein kinase Cδ (PKCδ) were increased in irradiated Panc1 cells. We presumed that caspases 3 and 7 and PKCδ as integral mediators in the process of dying pancreatic cancer cell stimulation of living tumor cell growth. In order to demonstrate the importance of caspases 3, 7 and PKCδ, we introduced dominant-negative mutants of caspase 3 (DN_C3), caspase 7 (DN_C7), or PKCδ (DN_PKCδ) into Panc1 cells using lentiviral vectors. The stably transduced Panc1 cells were irradiated and used as feeders and we found a significant decrease in the growth of living Panc1 reporter cells when compared with irradiated wild-type Panc1 cells as feeders. Moreover, the role of PKCδ in the growth stimulation of living tumor cells was further confirmed using a pan PKC inhibitor GF109203x and a specific PKCδ inhibitor, rottlerin. Additionally, we found significantly increased phosphorylation of Akt, p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase/stress-activated protein kinase (JNK1/2) in the irradiated Panc1 cells. Mechanistically, PKCδ cleavage was attenuated in both DN_C3 and DN_C7 transduced Panc1 cells, and both Akt and p38 MAPK phosphorylation were attenuated in DN_PKCδ transduced Panc1 cells following radiation. Thus, this report suggests a novel finding that cellular signaling caspase 3/7-PKCδ-Akt/p38 MAPK is crucial to the repopulation in Panc1 cells after radiotherapy.
    Molecular Oncology 01/2015; 9(1):105-114. DOI:10.1016/j.molonc.2014.07.024 · 5.33 Impact Factor
  • Source
    XinJian Liu · Qian Huang · Fang Li · Chuan-Yuan Li ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Dopaminergic (DA) neuron-like cells obtained through direct reprogramming of primary human fibroblasts offer exciting opportunities for treatment of Parkinson's disease. A significant obstacle is the low efficiency of conversion during the reprogramming process. Here, we demonstrate that the suppression of p53 significantly enhances the efficiency of transcription factor-mediated conversion of human fibroblasts into functional dopaminergic neurons. In particular, blocking p53 activity using a dominant-negative p53 (p53-DN) in IMR90 cells increases the conversion efficiency by 5-20 fold. The induced DA neuron-like cells exhibit dopamine neuron-specific gene expression, significant dopamine uptake and production capacities, and enables symptomatic relief in a rat Parkinson's disease model. Taken together, our findings suggest that p53 is a critical barrier in direct reprogramming of fibroblast into dopaminergic neurons.
    Science China. Life sciences 08/2014; 57(9). DOI:10.1007/s11427-014-4730-2 · 1.69 Impact Factor
  • Source
    Fang Wei · Huiping Wang · Xiafang Chen · Chuanyuan Li · Qian Huang ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Oncolytic viruses have recently received widespread attention for their potential in innovative cancer therapy. Many telomerase promoter-regulated oncolytic adenoviral vectors retain E1A and E1B. However, the functions of E1A and E1B proteins in the oncolytic role of replication-competent adenovirus (RCAd) and RCAd enhanced transduction of replication defective adenoviruses (RDAd) have not been addressed well. In this study, we constructed viruses expressing E1A alone, E1A plus E1B-19 kDa, and E1A plus E1B-19 kDa/55 kDa. We then tested their roles in oncolysis and replication of RCAd as well as their roles in RCAd enhanced transfection rate and transgene expression of RDAd in various cancer cells in vitro and in xenografted human NCI-H460 tumors in nude mice. We demonstrated that RCAds expressing E1A alone and plus E1B-19 kDa exhibited an obvious ability in replication and oncolytic effects as well as enhanced RDAd replication and transgene expression, with the former showed more effective oncolysis, while the latter exhibited superior viral replication and transgene promotion activity. However, RCAd expressing both E1A and E1B-19kDa/55kDa was clearly worst in all these abilities. The effects of E1A and E1B observed through using RCAd were further validated by using plasmids expressing E1A alone, E1A plus E1B-19kDa, and E1A plus E1B-19kDa/55kDa proteins. Our study provided evidence that E1A was essential for inducing replication and oncolytic effects of RCAd as well as RCAd enhanced RDAd transduction, and expression of E1B-19kDa other than E1B-55kDa could promote these effects. E1B-55kDa is not necessary for the oncolytic effects of adenoviruses and somehow inhibits RCAd-mediated RDAd replication and transgene expression.
    Cancer biology & therapy 07/2014; 15(10). DOI:10.4161/cbt.29842 · 3.07 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Metastatic melanoma often relapses despite cytotoxic treatment, so the understanding of melanoma tumor repopulation is crucial to improving our current therapies. In this study, we aim to define the role of caspase 3 in melanoma tumor growth after cytotoxic therapy. We examined a paradigm-changing hypothesis that dying melanoma cells undergoing apoptosis during cytotoxic treatment activate paracrine signaling events that promote the growth of surviving tumor cells. We propose that caspase 3 plays a key role in the initiation of the release of signals from dying cells to stimulate melanoma tumor growth. We created a model for tumor cell repopulation in which a small number of luciferase-labeled, untreated melanoma cells are seeded onto a layer of a larger number of unlabeled, lethally treated melanoma cells. We found that dying melanoma cells significantly stimulate the growth of living melanoma cells in vitro and in vivo. Furthermore, we observed that caspase 3 gene knockdown attenuated the growth-stimulating effect of irradiated, dying cells on living melanoma cell growth. Finally, we showed that caspase 3-mediated dying melanoma cell stimulation of living cell growth involves secreted PGE2. Our study therefore suggests a counterintuitive strategy to inhibit caspase 3 for therapeutic gain in melanoma treatment.Journal of Investigative Dermatology accepted article preview online, 16 January 2014. doi:10.1038/jid.2014.18.
    Journal of Investigative Dermatology 01/2014; 134(6). DOI:10.1038/jid.2014.18 · 7.22 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The death of all the cancer cells in a tumor is the ultimate goal of cancer therapy. Therefore, much of the current effort in cancer research is focused on activating cellular machinery that facilitates cell death such as factors involved in causing apoptosis. However, recently, a number of studies point to some counterintuitive roles for apoptotic caspases in radiation therapy as well as in tissue regeneration. It appears that a major function of apoptotic caspases is to facilitate tissue regeneration and tumor cell repopulation during cancer therapy. Because tumor cell repopulation has been shown to be important for local tumor relapse, understanding the molecular mechanisms behind tumor repopulation would be important to enhance cancer radiotherapy. In this review, we discuss our current knowledge of these potentially paradigm-changing phenomena and mechanisms in various organisms and their implications on the development of novel cancer therapeutics and strategies.
    Seminars in radiation oncology 10/2013; 23(4):288-95. DOI:10.1016/j.semradonc.2013.05.003 · 4.03 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Radiotherapy remains one of most important treatment modalities for solid tumors. Current radiotherapy is mostly based on a set of concepts called the 4"R"s, which were established when there was lack of understanding of the underlying molecular mechanisms. However, progress made in the past two decades are beginning to allow us to see some of the molecular details involved in tumor response to radiation therapy. In this review, we will attempt to summarize some of the key discoveries in molecular radiation biology that have direct relevance to radiotherapy. We will focus our discussion on areas such as radiation induced tumor vasculogenesis, stem cell mobilization, and cellular repopulation. We hope our discussion will stimulate further studies in this important area of cancer research.
    Translational Cancer Research 10/2013; 2(5):442-448. DOI:10.3978/j.issn.2218-676X.2013.10.03
  • She-Hong Zhang · Qian Huang ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Pancreatic cancer is a highly aggressive malignant tumor. In the present study, we performed several methods, including CCK-8 assay, immunofluorescence technique, western blotting and flow cytometry, to determine the effects of VP16 (etoposide) on Panc-1 pancreatic cancer cells. The results demonstrated that VP16 inhibited the growth of and induced apoptosis in Panc-1 cells. Western blot analysis showed that VP16 inhibited the expression of Bcl-2 and enhanced the expression of Bax, caspases-3 and -9, cytochrome c and PARP. Notably, a strong inhibitory effect of VP16 on Panc-1 cells mainly occurred in non-CSCs. These data provide a new strategy for the therapy of pancreatic cancer.
    Oncology Reports 10/2013; 30(6). DOI:10.3892/or.2013.2767 · 2.30 Impact Factor
  • Ling Zhou · Ke Li · Yanli Luo · Ling Tian · Min Wang · Chuanyuan Li · Qian Huang ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by poor prognosis. Currently, no reliable markers have been identified as having a predictive role for the prognosis of TNBC patients. In this study, 119 breast cancer samples, including 31 TNBC and 89 non-TNBC subtypes, were collected. The protein levels of cleaved caspase-3 (CC3), aldehyde dehydrogenase 1 (ALDH1), cyclooxygenase-2, Ki-67, H2A histone family member X, and phosphorylated protein kinase B protein were measured by immunohistochemical staining. The percentage of positive CC3 (P = .017), ALDH1 (P = .015), Ki-67 (P = .001), and H2A histone family member X (P = .016) staining was significantly higher in TNBC than in non-TNBC cases. Positive CC3 and ALDH1 staining significantly correlated with poor prognosis of breast cancer, the TNBC subtype and non-TNBC subtype. Positive cyclooxygenase-2 expression significantly correlated with the survival of patients with TNBC. Multivariate analysis demonstrated that CC3 and ALDH1 are independent prognostic factors for BC and non-TNBC. ALDH1 is a prognostic marker for TNBC patients.
    Human pathology 07/2013; 44(10). DOI:10.1016/j.humpath.2013.03.021 · 2.77 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The expression of vascular endothelial growth factor (VEGF) is regulated by microenvironmental factors within the tumors, such as hypoxia, free radicals, pH imbalance and nutrient deficiency. The purpose of this study was to observe VEGF activity in tumor cells under different stress conditions. A plasmid was generated, consisting of green fluorescent protein (GFP) fused to a 1,217-bp sequence, which was located downstream and upstream of the transcriptional start site of VEGF, respectively. The plasmid was stably transfected into 4T1 mouse breast carcinoma cells. Cells were cultured in a medium with nitric oxide (NO) donor sodium nitroprusside (SNP), hypoxia-mimetic agent deferoxamine mesylate (DFX), H2O2, absence of serum and lowered or elevated pH, or were heat-shocked, followed by measurement of VEGF activity by reverse transcription polymerase chain reaction (RT-PCR) and ELISA. Hypoxia, SNP and H2O2 led to increments of VEGF mRNA and protein expression, as well as of GFP expression. The pH alterations, serum deprivation and heat shock reduced VEGF mRNA expression, but had little effect on GFP expression. The results demonstrated that VEGF expression may be influenced by a number of microenvironmental factors and these factors may play important roles in regulating VEGF expression during tumorigenesis.
    07/2013; 1(4):539-544. DOI:10.3892/br.2013.115
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Tumor growth after radiotherapy is a commonly recognized cause of therapeutic failure. In this way, we examined tumor cell growth after radiotherapy by establishing a cancer cell growth model in vitro. We accomplished this model by seeding non-irradiated firefly luciferase2 and green fluorescent protein fusion gene (Fluc) labeled living cancer reporter cells onto a feeder layer of irradiated cancer cells. The living tumor cell growth was monitored by bioluminescence imaging. The living reporter cells grew faster when seeded onto lethally irradiated feeder cells than when seeded onto non-irradiated feeder cells or when seeded in the absence of feeder cells. We found that the expression levels of the Shh and Gli1 proteins, both of which are critical proteins in Sonic hedgehog (SHH) signaling, were increased after irradiation and that this expression was positively correlated with reporter cell growth. Moreover, the dying cell stimulation of living tumor cell growth was enhanced by the addition of SHH signaling agonists and inhibited by SHH signaling antagonists. SHH agonists also enhanced reporter cell growth in the absence of irradiated feeder cells, suggesting this mechanism plays a role in feeder cell growth stimulation. Given these results, we conclude that SHH signaling activation plays an important role during tumor repopulation after radiotherapy.
    PLoS ONE 06/2013; 8(6):e65032. DOI:10.1371/journal.pone.0065032 · 3.23 Impact Factor
  • Ling Zhou · Yanli Luo · Ke Li · Ling Tian · Min Wang · Chuanyuan Li · Qian Huang ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Resistance to chemotherapy and endocrine therapy is a serious obstacle in the treatment of breast cancer. Highly specific biomarkers for predicting therapeutic resistance have not yet been identified. In this study, the amounts of aldehyde dehydrogenase 1, cleaved caspase 3, cyclooxygenase 2, phosphorylated Akt, Ki-67, and H2AX proteins were measured by immunohistochemical staining in 113 breast cancer tissues, and their predictive ability for therapeutic resistance was investigated. The patients were receiving chemotherapy (n = 30), endocrine therapy (n = 22), or combined chemotherapy and endocrine therapy (n = 61). Expression of aldehyde dehydrogenase 1, cleaved caspase 3, and cyclooxygenase 2 correlated significantly with a higher relapse rate (P < .05 or P < .01) and shorter survival (P < .01 or P < .001) in triple-negative patients receiving chemotherapy. In addition, cyclooxygenase 2 expression was an independent predictor of a poor prognosis (P < .05). On the other hand, aldehyde dehydrogenase 1 expression correlated significantly with shorter survival in patients receiving combined therapy (P < .01) but showed no association with relapse. No correlation was observed between Ki-67, phosphorylated Akt, and H2AX expression and survival or relapse in any group of patients. These data suggest that aldehyde dehydrogenase 1, cleaved caspase 3, and cyclooxygenase 2 are useful markers for therapeutic resistance in breast cancer.
    Human pathology 02/2013; 44(7). DOI:10.1016/j.humpath.2012.10.027 · 2.77 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background An adenovirus that expresses both interleukin (IL)-12 and granulocyte-macrophage colony-stimulating-factor (GM-CSF) has been proven to be very effective in treating several tumors, but causes serious normal tissue toxicities. Methods In this study, a novel adenoviral vector was constructed by placing the human GM-CSF gene under the control of the CMV-IE promoter and human IL-12 gene under the control of heat shock protein 70B gene promoter. Both hGM-CSF and hIL-12 expressions in virus-infected tumor cells were analyzed in vitro and in vivo when underlying single or multiple rounds of hyperthermia. Results We observed constitutive high expression of human GM-CSF and heat-induced expression of human IL-12 after a single round of hyperthermia post viral infection. The heat-induced hIL-12 expression exhibited a pulse-like pattern with a peak at 24 hrs followed by a decline 48 hrs post heat stress. Repeated heat treatment was more effective in inducing hIL-12 expression than a one-time heat treatment. Interestedly, we also observed that constitutive expression of hGM-CSF could be stimulated by heat stress in tested tumor cells. Conclusion Our study provided a novel strategy for combined gene therapy that allows constitutive expression of a non-toxic gene such as GM-CSF and heat-induced expression of a toxic gene such as IL-12. In addition, our study also showed that hyperthermia can be used to trigger gene expression in temporal and special manner.
    Journal of Experimental & Clinical Cancer Research 01/2013; 32(1):5. DOI:10.1186/1756-9966-32-5 · 4.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: Currently, choroidal melanoma is chemoresistant and there is no routine adjuvant chemotherapy for it. We investigated whether pigment epithelium-derived factor (PEDF) and its triple phosphomimetic mutants could more efficiently suppress melanoma tumor growth and metastasis, as well as how the triple phosphomimetic mutants act as antitumor agents. Methods: Phosphomimetic mutants of PEDF were constructed by site mutagenesis. Lentiviruses carrying wild type (WT) PEDF, S24E114E227A (EEA)-PEDF, and S24E114E227E (EEE)-PEDF were produced in 293 fast-growing, highly transfectable (FT) cells and used to infect human choroidal melanoma cell line (OCM-1). The growth, migration, invasion and metastasis abilities of OCM-1 cells expressing WT-PEDF, EEA-PEDF or EEE-PEDF were investigated in vitro and in vivo, while the underlying mechanism of PEDF phosphomimetic mutants were investigated via Western blotting. Results: OCM-1 cells infected with lentiviruses carrying WT-PEDF, EEA-PEDF, and EEE-PEDF displayed reduced proliferation, migration and invasion abilities, and were more prone to apoptosis. Cell media containing WT-PEDF, EEA-PEDF, or EEE-PEDF protein inhibited the tube forming capacity of human umbilical vein endothelial cells (HUVEC) in vitro. OCM-1 cells expressing WT-PEDF, EEA-PEDF, or EEE-PEDF displayed significantly reduced tumor growth and metastasis in the melanoma xenograft of nude mice models, with the PEDF mutants displaying much stronger effects than the wild type. The antitumor effects of PEDF are associated with the inhibition of VEGF and nuclear factor kappa-B (NF-κB) expression, as well as further inhibition of Akt phosphorylation. Conclusions: The phosphomimetic mutants of PEDF showed enhanced anti-melanoma activity by directly affecting tumor cells and indirectly affecting angiogenesis. These findings encourage the development of PEDF mutants as innovative anticancer agents.
    Investigative ophthalmology & visual science 09/2012; 53(11):6793-802. DOI:10.1167/iovs.12-10326 · 3.40 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pancreatic cancer is a disease with poor prognosis and high mortality. To identify novel molecular markers that could predict the prognosis of pancreatic ductal adenocarcinoma, a total of 114 pancreatic ductal adenocarcinomas and 99 peritumoral tissues were collected. Protein levels of cleaved caspase-3, cyclin D1, epidermal growth factor receptor and Her-2 (human epidermal growth factor receptor 2) were measured by immunohistochemistry. Molecular abnormalities of cyclin D1/q11, Her-2/q17, and epidermal growth factor receptor/p7 were detected using fluorescence in situ hybridization. Results demonstrated that the protein levels of cleaved caspase-3, epidermal growth factor receptor, Her-2, and cyclin D1 were significantly higher in pancreatic ductal adenocarcinoma than that in peritumoral tissues (P = .000). Significantly more amplifications of epidermal growth factor receptor, Her-2, and cyclin D1 were observed in pancreatic ductal adenocarcinoma patients than in peritumoral tissues. In addition, 51.8% of pancreatic ductal adenocarcinoma tumors showed polysomy 7, 50% showed polysomy 11, and 40.4% showed polysomy 17. However, no polysomy was observed in peritumoral tissues. Her-2 amplification and polysomy 17 significantly correlated with poor prognosis of pancreatic ductal adenocarcinoma (P = .008 and P = .005, respectively). Interestingly, only cleaved caspase-3 protein level significantly correlated with poor survival in pancreatic ductal adenocarcinoma patients (P = .000). We also observed significant correlations of cleaved caspase-3 level with epidermal growth factor receptor, Her-2, and cyclin D1 protein levels and the molecular abnormalities of Her-2 and cyclin D1. Conclusively, cleaved caspase-3 level is an ideal biomarker to predict prognosis in pancreatic ductal adenocarcinoma patients and might be a better target for pancreatic ductal adenocarcinoma treatment than epidermal growth factor receptor/Her-2 and cyclin D1.
    Human pathology 08/2012; 44(1). DOI:10.1016/j.humpath.2012.04.014 · 2.77 Impact Factor

Publication Stats

1k Citations
332.69 Total Impact Points


  • 2004-2015
    • Shanghai University
      • Department of Surgery
      Shanghai, Shanghai Shi, China
  • 2003-2015
    • Shanghai Jiao Tong University
      • • School of Medicine
      • • Shanghai First People's Hospital
      Shanghai, Shanghai Shi, China
  • 2010-2013
    • Renji Hospital
      Shanghai, Shanghai Shi, China
    • University of Colorado
      • Department of Radiation Oncology
      Denver, Colorado, United States
  • 1999-2013
    • Duke University Medical Center
      • • Department of Dermatology
      • • Department of Radiation Oncology
      Durham, North Carolina, United States
  • 2012
    • Sichuan University
      Hua-yang, Sichuan, China
  • 2004-2012
    • First People's Hospital Chenzhou
      Chenchow, Hunan, China
  • 2002-2011
    • Shanghai Putuo District People's Hospital
      Shanghai, Shanghai Shi, China
  • 2004-2008
    • Hangzhou First People's Hospital
      Hang-hsien, Zhejiang Sheng, China