Xi Wang

Fourth Military Medical University, Xi’an, Liaoning, China

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Publications (20)58.83 Total impact

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    ABSTRACT: Acute myeloid leukemia (AML) remains highly fatal, highlighting the need for improved understanding of signal pathways that can lead to the development of new therapeutic regimens targeting common molecular pathways shared across different AML subtypes. Here we demonstrate that Astrocyte elevated gene-1 (AEG-1) is one of such pathways, involving in cell cycle and apoptosis regulation and contributing to enhanced proliferation and chemoresistance in HL-60 and U937 AML cells. The pleiotropic effects of AEG-1 on AML were found to correlate with two novel target genes, Aurora kinase A (AURKA) and Akt1. Down-regulation of AEG-1 by short-hairpin RNA (shRNA) could not only decrease AURKA expression both on mRNA and protein levels but also decrease the levels of pAkt473 and pAkt308(the active forms of phosphorylated Akt), similar effect as using AURKA inhibitor Tozasertib (VX680). Furthermore, the AEG-1 shRNA-induced malignant phenotype changes could be mitigated by forced overexpression of AURKA through increased Akt1 activation and phosphorylation in AML cells. On the other hand, although exogenous expression of AEG-1 could increase both AURKA and Akt expression levels the simultaneous use of AURKA inhibitor Tozasertib blocked AEG-1's role of up-regulation of Akt expression in ECV304 cells, suggesting that AURKA might be a key mediator of AEG-1 in regulating Akt activation, and a key effector of AEG-1 in maintaining the malignant state of AML. Moreover, knockdown AEG-1 expression also changed the expression levels of PTEN, survivin and stathmin, the genes that have been reported to be involved in the development of several other malignant tumors. Our results provide evidence for AEG-1's carcinogenesis role in AML and reveal a novel functional link between AEG-1 and AURKA on Akt1 activation. AEG-1 can be an important candidate as a drug design target within AURKA signal pathway for more specific killing of AML cells while sparing normal cells.
    Cellular Signalling 03/2013; · 4.47 Impact Factor
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    ABSTRACT: Abstract miR-34a was identified as one of the downregulated microRNAs (miRNAs) in human lung cancer. However, the precise biological role of miR-34a in p53 deficient lung cancer cell lines remains largely elusive. In the present study, we aimed to identify the role of miR-34a in the regulation of lung cancer cell proliferation. Using quantitative RT-PCR analysis, we found that miR-34a was highly upregulated in the p53 wild-type A549 human lung cancer cell line when treated with the DNA damaging agent adriamycin (ADR), but not in the SBC-5 cells harboring mutated p53. Transient introduction of miR-34a into A549 and SBC-5 cell lines caused complete suppression of cell proliferation and induced the cell cycle arrested at the G(1) phase. When we knockdown the miR-34a downstream target-Sitr1- using the small-interfering RNA, there was also a cell growth inhibition in both cell lines though not as much as miR-34a did. Moreover, we demonstrated that pretransfection of miR-34a could increase the sensitivity of both lung cancer cell lines to cisplatin (DDP), and this could be reverted by the miR-34a inhibitor. Moreover, when cells pretreated with siR-Sirt1, they are more sensitive to DDP than the control pretreated cells as well. We thus hypothesize the miR-34a/Sirt1 cascade involved with p53-independent functions. Overall, in this study, we found the proliferation inhibition function of miR-34a in vitro in lung cancer cell lines is p53 independent, and also demonstrated the combination therapeutic potential of miR-34a and DDP in lung cancer cell lines.
    Cancer Biotherapy & Radiopharmaceuticals 10/2012; · 1.44 Impact Factor
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    ABSTRACT: Prostate-specific antigen (PSA), a serine protease, is a promising target for the development of prodrugs in prostate cancer treatment. In this study, we designed a novel fusion peptide, BSD352, containing three functional domains: a protein transduction domain from HIV transactivating regulatory protein (TAT) followed by the BH3 domain of the p53 upregulated modulator of apoptosis (TAT-BH3), an anti-vascular endothelial growth factor peptide (SP5.2), and an anti-basic fibroblast growth factor peptide (DG2). These different domains in BSD352 were linked together by a linker sequence corresponding to a PSA hydrolytic substrate peptide. The BSD352 fusion peptide could be selectively cleaved by PSA in PSA-producing LNCaP prostate cancer cells. Furthermore, the BSD352 fusion peptide was efficiently transduced into tumor cells both in vitro and in vivo, and the BH3 domain was found to induce tumor cell apoptosis by elevating the expression of Bax, cytochrome C release, and caspase-9 cleavage. Moreover, the SP5.2 and DG2 domains in the BSD352 fusion peptide also exhibited in-vitro endothelial cell growth inhibition and in-vivo antiangiogenic activities. Direct injection of BSD352 into an established LNCaP xenograft tumor in mice inhibited tumor growth, whereas a synergistic effect was observed with the combined use of wild-type BH3, SP5.2, and DG2 functional domains. These results suggest that BSD352 could be beneficial for the treatment of accessible prostate tumors and may provide a complementary strategy for prostate cancer therapy.
    Anti-cancer drugs 03/2011; 22(3):213-22. · 2.23 Impact Factor
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    ABSTRACT: Several conserved neutralizing epitopes have been identified in the HIV Env protein and among these, the MPER of gp41 has received great attention and is widely recognized as a promising target. However, little success has been achieved in eliciting MPER-specific HIV neutralizing antibodies by a number of different vaccine strategies. We investigated the ability of HA/gp41 chimeric protein-based vaccines, which were designed to enhance the exposure of the MPER in its native conformation, to induce MPER-specific HIV neutralizing antibodies. In characterization of the HA/gp41 chimeric protein, we found that by mutating an unpaired Cys residue (Cys-14) in its HA1 subunit to a Ser residue, the modified chimeric protein HA-C14S/gp41 showed increased reactivity to a conformation-sensitive monoclonal antibody against HA and formed more stable trimers in VLPs. On the other hand, HA-C14S/gp41 and HA/gp41 chimeric proteins expressed on the cell surfaces exhibited similar reactivity to monoclonal antibodies 2F5 and 4E10. Immunization of guinea pigs using the HA-C14S/gp41 DNA or VLP vaccines induced antibodies against the HIV gp41 as well as to a peptide corresponding to a segment of MPER at higher levels than immunization by standard HIV VLPs. Further, sera from vaccinated guinea pigs were found to exhibit HIV neutralizing activities. Moreover, sera from guinea pigs vaccinated by HA-C14S/gp41 DNA and VLP vaccines but not the standard HIV VLPs, were found to neutralize HIV pseudovirions containing a SIV-4E10 chimeric Env protein. The virus neutralization could be blocked by a MPER-specific peptide, thus demonstrating induction of MPER-specific HIV neutralizing antibodies by this novel vaccine strategy. These results show that induction of MPER-specific HIV neutralizing antibodies can be achieved through a rationally designed vaccine strategy.
    PLoS ONE 01/2011; 6(5):e14813. · 3.53 Impact Factor
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    ABSTRACT: Non-small-cell lung carcinomas (NSCLCs) exhibit poor prognosis and are usually resistant to conventional chemotherapy. Absence of p21WAF1/CIP1, a cyclin-dependent kinase (cdk) inhibitor, has been linked to drug resistance in many in vitro cellular models. RNA activation (RNAa) is a transcriptional activation phenomena guided by double-strand RNA (dsRNA) targeting promoter region of target gene. In this study, we explored the effect of up-regulation of p21 gene expression on drug-resistance in A549 non-small-cell lung carcinoma cells by transfecting the dsRNA targeting the promoter region of p21 into A549 cells. Enhanced p21 expression was observed in A549 cells after transfection of dsRNA, which was correlated with a significant growth inhibition and enhancement of chemosensitivity to cisplatin in A549 cells in vitro. Moreover, in vivo experiment showed that saRNA targeting the promoter region of p21 could significantly inhibit A549 xenograft tumor growth. These results indicate that p21 plays a role in lung cancer drug-resistance process. In addition, this study also provides evidence for the usage of saRNA as a therapeutic option for up-regulating lower-expression genes in lung cancer.
    BMC Cancer 11/2010; 10:632. · 3.33 Impact Factor
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    ABSTRACT: Although the mechanisms of arsenic trioxide (As2O3)-induced apoptosis have been elucidated extensively in hematologic cancers, those in solid tumors have yet to be clearly defined. In the present study, we show that As2O3 triggers apoptosis through the intrinsic pathway and significantly downregulates stathmin expression. Decreased stathmin expression is necessary for the dissipation of mitochondrial membrane potential (Δ ψm), the translocation of cytochrome C from the mitochondria to the cytosol, and subsequent cell death. Overexpression of wild type stathmin effectively delays As2O3-mediated mitochondrial events. Conversely, expression of a small interfering RNA (siRNA) targeting stathmin enhances As2O3-triggered apoptosis in cell culture and in mouse models. Furthermore, we demonstrate that As2O3-induced stathmin downregulation is mediated through the phosphatidylinositol-3-kinase (PI3K) signaling pathway, and that a PI3K inhibitor effectively attenuated stathmin downregulation and cell apoptosis upon As2O3-treatment. These data support a stathmin-dependent pathway of As2O3-mediated cell death in solid tumor cells, and indicate that stathmin is a target of the PI3K/Akt pathway in cervical cancer cells. All these results may provide a rationale for improving the efficacy of As2O3 as a therapeutic agent through combination treatment with stathmin inhibition or PI3K/Akt inhibitors.
    Cancer biology & therapy 09/2010; 10(6):632-43. · 3.29 Impact Factor
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    ABSTRACT: Arsenic trioxide (As2O3), a component of traditional Chinese medicine, has been used successfully for the treatment of acute promyelocytic leukemia (APL), and As2O3 is of potential therapeutic value for the treatment of other promyelocytic malignancies and some solid tumors including breast cancer. However, the precise molecular mechanisms through which As2O3 induces cell cycle arrest and apoptosis in solid tumors have not been clearly understood. The goal of our study is to gain insight into the general biological processes and molecular functions that are altered by As2O3 treatment in MCF-7 breast cancer cells and to identify the key signaling processes that are involved in the regulation of these physiological effects. In the present study, MCF-7 cells were treated with 5 μM As2O3, and the differential gene expression was then analyzed by DNA microarray. The results showed that As2O3 treatment changed the expression level of several genes that involved in cell cycle regulation, signal transduction, and apoptosis. Notably, As2O3 treatment increased the mRNA and protein levels of the cell cycle inhibitory proteins, p21 and p27. Interestingly, knocking down p21 or p27 individually did not alter As2O3-induced apoptosis and cell cycle arrest; however, the simultaneous down-regulation of both p21 and p27 resulted in attenuating of G1, G2/M arrest and reduction in apoptosis, thus indicating that p21 and p27 as the primary molecular targets of As2O3 against breast cancer. Overall, our results provide new insights into As2O3-related signaling activities, which may facilitate the development of As2O3-based anticancer strategies and/or combination therapies against solid tumors.
    Medical Oncology 05/2010; 28(4):1225-54. · 2.14 Impact Factor
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    ABSTRACT: Epigallocatechin-3-gallate (EGCG), the major component of green tea polyphenol, has potent efficiency to prevent the growth of a variety of cancer cells. As a novel anticancer agent for treatment of cancers, EGCG is promising and the mechanism has not been fully understood. Laryngeal squamous cell carcinoma (LSCC) is one common tumor in head and neck cancers. In the present study, we assess the effects of EGCG on LSCC cell line Hep-2, and their possible involvement in EGCG-induced apoptosis. The result showed that treatment of Hep-2 cells with EGCG decreased the cell viability, inhibited the growth and proliferation, induced apoptosis and increased the activity of caspase-3 in a dose-dependent manner. Furthermore, we found that EGCG-treatment repressed telomerase activity effectively in a concentration-dependent manner. The combined results show that EGCG induced apoptosis in Hep-2 cells via inhibiting the telomerase activity.
    Archives of Pharmacal Research 09/2009; 32(9):1263-9. · 1.54 Impact Factor
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    ABSTRACT: X-linked inhibitor of apoptosis protein (XIAP) is a novel member of the inhibitors of apoptosis (IAPs) family. The overexpression of XIAP is asscociated with radioresistance of human malignancies. The purpose of the present study was to investigate the effect of shRNA-targeted XIAP on the proliferation, apoptosis and radiosensitivity of human laryngeal carcinoma cells (Hep-2). A siRNA expression vector (pSilencer4.1-XIAPshRNA) was constructed and stably transfected into human laryngeal carcinoma cells (Hep-2). The downregulation of XIAP expression was evaluated by RT-PCR and Western blot analyses. Then, we investigated the effect of XIAP-shRNA on the proliferation, cell cycle changes and apoptosis in vitro of Hep-2 cells. Finally, the radiosensitivity of Hep-2 cells was investigated by clonogenic cell survival assay. We established stably transfected cell line (Hep-2/XIAPshRNA) in which the expression of XIAP gene was downregulated. The cell viability of Hep-2/XIAP-RNA cells was obviously decreased compared with that of untransfected Hep-2 cells. Morever, XIAP-shRNA induced cell arrest in the G(0)/G(1) phase of cell cycle by flow cytometry analysis. Results of TUNEL assay indicated that Hep-2 cells stably transfected pSilencer4.1-XIAP-shRNA showed obvious apoptosis characters. Furthermore, the downregulation of XIAP expression could lead to significant radiosensitivity enhancement in laryngeal carcinoma cells. RNAi-mediated downregulation of XIAP expression can inhibit proliferation, induce apoptosis and diminish the radioresistance of laryngeal carcinoma cells, so combined therapy with XIAP inhibition and radiation may be a potential strategy for the treatment of laryngeal carcinoma.
    Auris, nasus, larynx 12/2008; 36(3):332-9. · 0.58 Impact Factor
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    ABSTRACT: Colorectal cancer is the third most common cancer in both men and women around the world. Although much progress of the mechanism of colorectal carcinogenesis has been made, the studies centering on the mechanisms of tumorigenesis are much needed to be further exploited. The overexpression of RCK/p54 gene, a member of the DEAD box protein/RNA helicase family, has been found in this malignancy. Roles of RCK in the development of colon cancer, however, are unknown. In this report, we explored whether RCK/p54 plays a role in maintaining the malignant phenotype and functions in the canonical Wnt signaling pathway of colorectal cancer cells harboring an APC mutation. The ectopic overexpression of RCK/p54 gene in colorectal cancer cells by transfection with RCK/p54 cDNA could lead to a significant increase of Tcf transcriptional activity and expression levels of Wnt target genes. By RNAi assay, we also observed that the Tcf transcriptional activity in LoVo-shRNA cells was significantly decreased by approximately 61.3%, while the mRNA and protein expression levels of Wnt target genes were also obviously decreased. Furthermore, the anti-tumour effects and its possible mechanisms of actions in LoVo cells elicited by a decrease in the level of RCK/p54 by RNAi were examined. Results showed that RCK/p54 downregulation could significantly reduce the viability of LoVo cells, increased cell number of S phase, led to cell apoptosis induction, and inhibited tumor growth in nude mice. Taken together, RCK/ p54 might be a determinant of colorectal cancer proliferation by activating the canonical Wnt pathway and RCK/p54-shRNA might be a potential strategy for colorectal cancer gene therapy.
    Cancer biology & therapy 11/2008; 7(10):1669-76. · 3.29 Impact Factor
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    ABSTRACT: Survivin is a member of the inhibitors of apoptosis protein family, is expressed in most of human cancers. Thus, we hypothesized that using a survivin promoter-driven vector system, an apoptosis-inducible gene may be preferentially restricted to survivin-positive tumor cells. PUMA (p53 upregulated modulator of apoptosis) was recently identified a potent proapoptotic molecule. In the present study, our aim is to investigate whether adenovirus-mediated PUMA gene transfer using the survivin promoter could specifically enhance radiosensitivity of breast cancer cells in vitro and in vivo. Firstly, we performed RT-PCR assay to detect survivin mRNA expression in four human breast cancer cell lines and two normal cell lines. Then, we constructed plasmid vectors expressing luciferase or EGFP reporter gene driven by the survivin core promoter and evaluated its transcriptional activity in vitro. Next, a survivin promoter-driven adenoviral system expressing PUMA gene was constructed. Western blotting analysis of PUMA protein expression in MCF-7 and MCF210 cells treated with various adenovirus (empty, driven by CMV promoter or survivin promoter). Followingly, the effects of PUMA overexpression on the in vitro radiosensitivity of breast cancer cells were investigated by clonogenic formation assay. Cellular apoptosis were determined by FCM and TUNEL assays. The expression and activities of cellular caspase-3 were assayed by Western blot and colorimetry. Finally, we investigated the effect of PUMA overexpression on the radiosensitivity of breast carcinoma cells in vivo. The survivin mRNA expression was obviously upregulated in breast cancer cell lines but in normal cell lines. Moreover, the survivin promoter could drive high-level expression of luciferase or EGFP in breast cells but not in normal cells. Using a survivin promoter-driven adenoviral system expressing PUMA gene, we found that PUMA expression was specifically and efficiently induced in MCF-7 cell but not in MCF210 cell. Furthermore, we observed that the novel adenovirus system could significantly enhance radiosensitivity of MCF-7 cell in vitro and in vivo, which might be associated with apoptosis induction by activating cellular caspase-3. Our findings indicated that the survivin promoter-driven adenovirus system expression PUMA gene might be explored as a potential tool for radiosensitization of human breast cancer cells with tumor specificity and high efficacy.
    Breast Cancer Research and Treatment 10/2008; 117(1):45-54. · 4.47 Impact Factor
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    ABSTRACT: STK15 (Aurora A/BTAK) is an oncogenic serine/threonine kinase that plays a role in centrosome separation and in the formation of the mitotic bipolar spindle. It is highly expressed and constitutively activated in various human tumors including hepatocellular carcinoma (HCC). To investigate its possibility as a molecular target for future therapies directed against hepatocellular carcinoma, we constructed a tissue-specific RNA interference (RNAi) system mediated by hypoxia-inducible (HI) enhancer/alpha-fetoprotein (AFP) promoter and employed it to downregulate exogenous reporters (LUC and EGFP) and endogenous STK15 gene expression and analyzed the phenotypical changes in HCC cells. Results showed that the expression of exogenous reporters (LUC and EGFP) was specifically downregulated in hepatoma cells but not in non-hepatoma cells. Moreover, the specific downregulation of STK15 expression in hepatocellular carcinoma cells (HepG2) significantly inhibited in vitro cellular proliferation and in vivo tumorigenicity. Furthermore, we also found that the downregulation of STK15 expression led to cell arrest in the G(2)/M phase and finally apoptosis induction of HepG2 cells. Thus, the HI enhancer/AFP promoter-mediated RNAi targeting STK15 may be a potential therapeutic strategy for the treatment of hepatocellular carcinoma with tumor specificity and high efficacy.
    Cancer Science 10/2008; 99(11):2209-17. · 3.48 Impact Factor
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    ABSTRACT: Cyclooxygenase-2 (COX-2), one isoform of cyclooxygenase proinflammatary enzymes, is a causal factor for tumor development, invasion, metastasis, and chemoresistance. It is frequently overexpressed in a variety of human malignancies, including laryngeal carcinoma. To investigate its possibility as a therapeutic target for the treatment of laryngeal carcinoma, we employed RNA interference technology to downregulate endogenous gene COX-2 expression in laryngeal carcinoma cells and analyzed its phenotypical changes. Results showed that shRNA-mediated downregulation of COX-2 expression in human laryngeal carcinoma cells significantly inhibited cell proliferation and colony formation in vitro and reduced the potential of tumorigenicity in vivo. The specific downregulation led to cell arrest in the G(0)/G(1) phase of cell cycle and final apoptosis induction. The increased apoptosis was associated with the ratios of Bcl-2 or Bcl-xL/Bax. In the present study, we also observed that the downregulation of COX-2 could obviously enhanced the cytotoxic effect of Taxanes both in vitro and in vivo. All these results suggest that knockdown of COX-2 expression can lead to potent antitumor activity and chemosensitizing activity to taxanes in human laryngeal carcinomas.
    Molecular and Cellular Biochemistry 08/2008; 317(1-2):179-88. · 2.33 Impact Factor
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    ABSTRACT: Bcl-xL, a novel member of anti-apoptotic Bcl-2 family that play important roles in regulating cell survival and apoptosis, is frequently overexpressed in various kinds of human cancers, including prostatic carcinoma. To explore its possibility as a therapeutic target for prostatic carcinoma, we developed a novel tumor-specific RNA interference system by using survivin promoter and employed it to suppress exogenous reporters (LUC and EGFP) and endogenous gene Bcl-xL expression and analyzed its phenotypes. We found that expression of exogenous reporters (LUC and EGFP) was specifically inhibited in tumor cells but not in normal cells. We also observed that the specific inhibition of Bcl-xL in human prostatic carcinoma cells (PC3) strongly suppressed in vitro cell proliferation and in vivo tumorigenicity. We observed significant apoptosis induction and radiosensitivity enhancement in PC3 cells by the RNA interference-mediated suppression of Bcl-xL expression. All these results indicate that inhibition of Bcl-xL expression can result in potent antitumor activity and radiosensitization in human prostatic carcinoma.
    Cancer Chemotherapy and Pharmacology 06/2008; 61(6):943-52. · 2.80 Impact Factor
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    ABSTRACT: Eukaryotic initiation factor eIF4E, an important regulator of translation, plays a crucial role in the malignant transformation, progression and chemoresistance of many human solid tumors. The overexpression of this gene has been found in a variety of human malignancies including breast carcinoma. In the present study, we attempted to explore the possibility of eIF4E as a therapeutic target for the treatment of human breast carcinoma using breast carcinoma cell line (MCF-7). The survivin promoter-driven eIF4E-shRNA vector was constructed on the basis of pSUPER.retro vector. Then, we established stably transfected MCF-7 and MCF210 (normal human mammary epithelial cell) cells expressing eIF4E-shRNAs or control-shRNAs. Firstly, the changes of eIF4E expression were detected by RT-PCR and Western blot assays. Next, the optimal shRNA vector (eIF4E-shRNA2) was selected to knock down eIF4E expression and investigate the effect of eIF4E-shRNA on eIF4E-regulated gene expression and cell proliferation both in vitro and in vivo. Followingly, the changes of cell cycle and apoptosis in the stably transfectants (MCF-7) were detected by flow cytometry and TUNEL methods, while we also explored possible apoptosis pathways. Finally, we investigated the effect of shRNA targeting eIF4E on the chemosensitivity of breast carcinoma cells to cisplatin in vitro and in vivo. Two survivin promoter-driven eIF4E-shRNA vectors were successfully constructed. eIF4E-shRNA2 but not eIF4E-shRNA1 efficiently downregulated the levels of eIF4E expression in the stably transfected MCF-7-s2 cells but not in the stably transfected MCF210-s2 cells, while MCF-7-s2 showed obvious proliferation suppression but MCF210-s2 did not. The downregulation of eIF4E expression significantly reduced the levels of VEGF, FGF-2 and cyclinD1 expression, suppressed cell growth, induced cell cycle arrest in G(0)/G(1) phase and subsequent apoptosis by activating caspase 3 in MCF-7 cells. The results of FCM and TUNEL staining assays indicated that the classic apoptosis characters of the MCF-7 cells stably expressing eIF4E-shRNA2 manifested an apoptosis rate of 18.3%, significantly higher than those in the control groups (P < 0.05). Moreover, we found that downregulation of c-IAP1, c-IAP2 and c-Myc but not Bcl-2 family proteins were involved in the apoptosis induced by eIF4E-shRNA2. In tumorigenicity assay, xenograft tumors developed from MCF-7-s2 cells in mice showed a significant slowdown in the growth speed and formation rate compared with control groups. Furthermore, we also testified that eIF4E-shRNA could synergistically enhance the cytotoxicity effects of cisplatin to MCF-7 cells both in vitro and in vivo. Survivin promoter-driven RNA interference system could efficiently and specifically downregulate eIF4E expression in human breast carcinoma cells but not in normal human mammary epithelial cell cells. Thus, eIF4E might play an important role in chemosensitivity to cisplatin, and survivin promoter-driven RNAi targeting eIF4E can be used as adjuvant therapy for human breast carcinomas with tumor specificity and high efficacy.
    Breast Cancer Research and Treatment 04/2008; 113(3):443-56. · 4.47 Impact Factor
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    ABSTRACT: The green tea polyphenol (GTP) has been shown to possess cancer therapeutic effect through induction of apoptosis, while the underlying molecular mechanism of its anticancer effect is not well understood. PUMA (p53-upregulated modulator of apoptosis) plays an important role in the process of apoptosis induction in a variety of human tumor cells in both p53-dependent and -independent manners. However, whether or not PUMA is involved in the process of GTP-induced apoptosis in cancer cells has not been well reported. In the present study, we treated HT-29 (mutant p53) and LoVo (wild type p53) human colorectal cancer cells with different concentrations of GTP, which led to repression of cell proliferation and induction of apoptosis in both cell lines. Meanwhile, we also observed increased PUMA expression and decreased ERK (extracellular signal-regulated kinase) activity in both of GTP-treated tumor cell lines carrying different genotypes of p53. To determine the role of PUMA in GTP-induced apoptosis, we used stable RNA interference (RNAi) to suppress PUMA expression. As a result, apoptosis was abrogated in response to GTP-treatment. We also found that suppression of ERK activity by either RNAi or its specific inhibitor significantly enhanced GTP-induced PUMA expression. All these results indicate that PUMA plays a critical role in GTP-induced apoptosis pathway in human colorectal cancer cells and can be regulated partly by ERK inactivation. Demonstration of the molecular mechanism involved in the anti-cancer effect of GTP may be useful in the therapeutic target selection for p53 deficient colorectal cancer.
    Cancer biology & therapy 04/2008; 7(6):902-8. · 3.29 Impact Factor
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    ABSTRACT: Resistance to chemotherapy is a major cause of treatment failure and poor prognosis in pancreatic carcinoma. Myeloid cell leukemia-1 (Mcl-1) is highly up-regulated in pancreatic carcinoma and is associated with the anti-apoptosis and the resistance to chemotherapy drugs. Suppression of Mcl-1 would be an approach to induce apoptosis and enhance the chemosensitivity. In this study, three pancreatic cancer cell lines (PANC-1, BxPC-3 and SW1900) stably expressing shRNAs targeting Mcl-1 gene were established and gene expression inhibition was assessed by Real-Time QPCR and Western blotting. The effects of Mcl-1 downregulation mediated by RNAi were explored in vitro and in vivo. We showed that the specific downregulation of Mcl-1 strikingly inhibited cell growth, colony formation, cell cycle arrest and induced apoptosis in pancreatic cancer cells in vitro, and markedly decreased the tumorigenicity in a mouse xenograft model. Moreover, knockdown of Mcl-1 significantly increased the chemosensitivity to Gemcitabine in pancreatic carcinoma cells. Our data suggests that the specific downregulation of Mcl-1 by RNAi is a promising approach to induce apoptosis and enhance the chemosensitivity for pancreatic carcinoma gene therapy.
    Cancer Chemotherapy and Pharmacology 03/2008; 62(6):1055-64. · 2.80 Impact Factor
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    ABSTRACT: Stathmin, also called oncoprotein 18, is a founding member of the family of microtubule-destabilizing proteins that play a critical role in the regulation of mitosis. Stathmin is non-expressed in normal tissues, but stathmin gene is expressed at high levels in many human malignancies and the relationships between the levels of this gene expression in tumors and prognosis of the patients have been addressed. In this report, we explored the relationships between stathmin mRNA expression in ovarian carcinoma tissues and clinicopathological parameters. We collected and analyzed paraffin wax-embedded ovarian tumor biopsy tissues from 42 ovarian cancer patients in our hospital. We employed RT-PCR method and performed a densitometric analysis to determine the ratio of stathmin relative to beta-actin as an internal marker. Results showed that the stathmin mRNA expression was detected in all the ovarian carcinoma tissue samples and those samples with metastasis had higher levels of stathmin mRNA expression in initial biopsy specimens (P<0.05). Moreover, the levels of stathmin mRNA expression between samples with and without metastasis showed a statistically significant difference (P<0.05).
    Acta Histochemica 01/2008; 110(1):59-65. · 1.61 Impact Factor
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    ABSTRACT: Human telomerase is a ribonucleoprotein complex composed of two subunits, an RNA component (hTR) and a human telomerase reverse transcriptase component (hTERT). The activation of telomerase, a process regulated by the human telomerase reverse transcriptase (hTERT), is a crucial step during cellular immortalization and malignant transformation. hTERT is overexpressed in most malignant cells but undetectable in most normal somatic cells. To explore its possibility as a therapeutic target for human cervical carcinoma, we developed a novel tumor-specific RNA interference system targeting hTERT by using the survivin promoter and investigated the effects of it on the proliferation, apoptosis and radiosensitivity in human cervical carcinoma cells (HeLa). The treatment of HeLa cells by hTERT gene RNAi not only could inhibit the proliferation of human cervical carcinoma cells (HeLa), but also could enhance the radiosensitivity of those cells via downregulation of their mRNA and protein expression. Therefore, survivin promoter-driven siRNA expression vector targeting hTERT may have potential use in radiosensitization therapy with targeted tumor gene silencing effect in human cervical carcinomas.
    Cancer biology & therapy 09/2007; 6(8):1295-301. · 3.29 Impact Factor
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    ABSTRACT: Stathmin (Oncoprotein18), a signal transduction regulatory factor, plays an important role in cell division and malignant tumor development. Stathmin is a ubiquitous intracellular phosphoprotein that is overexpressed in a variety of human malignancies, including osteosarcoma. To investigate the potential use of stathmin as a therapeutic target for human osteosarcomas, we employed RNA interference [small interfering RNA (siRNA)] to reduce stathmin expression in human osteosarcoma cell lines and analyzed their phenotypic changes. Results showed that the downregulation of stathmin expression in human osteosarcoma cells significantly inhibited cell proliferation in vitro and tumorigenicity in vivo. The specific downregulation induced cell arrest in the G(2)/M phase of cell cycle and eventually apoptotic cell death. Taxanes are a group of effective chemotherapeutic agents whose activity is mediated through stabilization of the microtubules of the mitotic spindle. In the present study, we also observed a synergistic enhancement of the cytotoxicity effect by combination use of taxanes and RNA interference-mediated stathmin downregulation. All these experimental data indicate that stathmin downregulation can lead to potent antitumor activity and chemosensitizing activity to taxanes in human osteosarcomas.
    Molecular Medicine 13(11-12):567-75. · 4.47 Impact Factor