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Qin Tian,
Chuang-Nian Zhang,
Xiu-Hua Wang,
Wei Wang,
Wei Huang,
Rui-Tao Cha,
Chun-Hong Wang,
Zhi Yuan, Min Liu,
Hai-Ying Wan,
Hua Tang
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ABSTRACT: A liver-targeted drug delivery carrier, composed of chitosan/poly(ethylene glycol)-glycyrrhetinic acid (CTS/PEG-GA) nanoparticles, was prepared by an ionic gelation process, in which glycyrrhetinic acid (GA) acted as the targeting ligand. The formation and characterization of these nanoparticles were confirmed by FT-IR, dynamic light scattering (DLS) and zeta potential measurements. The biodistribution of the nanoparticles was assessed by single-photon emission computed tomography (SPECT), and the cellular uptake was evaluated using human hepatic carcinoma cells (QGY-7703 cells). The anti-neoplastic effect of the doxorubicin.HCl-loaded nanoparticles (DOX-loaded nanoparticles) was also investigated in vitro and in vivo. The results showed that the CTS/PEG-GA nanoparticles were remarkably targeted to the liver, and keep at a high level during the experiment. The accumulation in the liver was 51.3% at 3 h after injection; this was nearly 2.6 times that obtained with the CTS/PEG nanoparticles. The DOX-loaded nanoparticles were greatly cytotoxic to QGY-7703 cells, and the IC(50) (50% inhibitory concentration) for the free doxorubicin.HCl (DOX.HCl) and the DOX-loaded CTS/PEG-GA nanoparticles were 47 and 79 ng/mL, respectively. Moreover, the DOX-loaded CTS/PEG-GA nanoparticles could effectively inhibit tumor growth in H22 cell-bearing mice.
Biomaterials 03/2010; 31(17):4748-56. · 7.40 Impact Factor
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ABSTRACT: Abstract
Background
MicroRNAs (miRNAs) are a new class of naturally occurring, small, non-coding RNAs that regulate protein-coding mRNAs by causing mRNA degradation or repressing translation. The roles of miRNAs in lineage determination and proliferation, as well as the localization of several miRNA genes at sites of translocation breakpoints or deletions, have led to speculation that miRNAs could be important factors in the development or maintenance of the neoplastic state.
Results
We showed that miR-9 was downregulated in human gastric adenocarcinoma. Overexpression of miR-9 suppressed the growth of human gastric adenocarcinoma cell line MGC803 cell as well as xenograft tumors derived from them in SCID mice. Bioinformatics analysis indicated a putative miR-9 binding site in the 3'-untranslated region (3'UTR) of the tumor-related gene NF-κB1 mRNA. In an EGFP reporter system, overexpression of miR-9 downregulated EGFP intensity, and mutation of the miR-9 binding site abolished the effect of miR-9 on EGFP intensity. Furthermore, both the NF-κB1 mRNA and protein levels were affected by miR-9. Finally, knockdown of NF-κB1 inhibited MGC803 cell growth in a time-dependent manner, while ectopic expression of NF-κB1 could rescue MGC803 cell from growth inhibition caused by miR-9.
Conclusion
These findings indicate that miR-9 targets NF-κB1 and regulates gastric cancer cell growth, suggesting that miR-9 shows tumor suppressive activity in human gastric cancer pathogenesis.
Molecular Cancer. 01/2010;
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ABSTRACT: MicroRNAs (miRNAs) are a new class of naturally occurring, small, non-coding RNAs that regulate protein-coding mRNAs by causing mRNA degradation or repressing translation. The roles of miRNAs in lineage determination and proliferation, as well as the localization of several miRNA genes at sites of translocation breakpoints or deletions, have led to speculation that miRNAs could be important factors in the development or maintenance of the neoplastic state.
We showed that miR-9 was downregulated in human gastric adenocarcinoma. Overexpression of miR-9 suppressed the growth of human gastric adenocarcinoma cell line MGC803 cell as well as xenograft tumors derived from them in SCID mice. Bioinformatics analysis indicated a putative miR-9 binding site in the 3'-untranslated region (3'UTR) of the tumor-related gene NF-kappaB1 mRNA. In an EGFP reporter system, overexpression of miR-9 downregulated EGFP intensity, and mutation of the miR-9 binding site abolished the effect of miR-9 on EGFP intensity. Furthermore, both the NF-kappaB1 mRNA and protein levels were affected by miR-9. Finally, knockdown of NF-kappaB1 inhibited MGC803 cell growth in a time-dependent manner, while ectopic expression of NF-kappaB1 could rescue MGC803 cell from growth inhibition caused by miR-9.
These findings indicate that miR-9 targets NF-kappaB1 and regulates gastric cancer cell growth, suggesting that miR-9 shows tumor suppressive activity in human gastric cancer pathogenesis.
Molecular Cancer 01/2010; 9:16. · 3.99 Impact Factor
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ABSTRACT: Two new kinds of amphiphilic copolymers were synthesized in this work. Poly(1-octene-co-acrylic acid) copolymers were prepared through the copolymerization of 1-octene and tert-butyl acrylate, and the hydrolysis of tert-butyl acrylate units. Poly(1-octene-co-acrylic acid)-g-poly (ethylene glycol) copolymers were obtained from the esterification reaction between poly(1-octene-co-acrylic acid) and poly(ethylene glycol) monomethyl ether. They were characterized by means of 1H-NMR, 13C-NMR, GPC, and FTIR. These amphiphilic copolymers can form stable micelles in aqueous solutions. The critical micelle concentration was determined by fluorescence spectroscopy. The micellar morphology and size distribution were investigated by transmission electron microscopy and dynamic light scattering. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010
Journal of Applied Polymer Science 10/2009; 115(4):2423 - 2431. · 1.29 Impact Factor
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ABSTRACT: Kazrin has recently been identified as a functional protein that is involved in cell-cell junctions and in signal transduction. Here, we identified a new isoform, Kazrin F, which is 518 aa in length and has 97 aa unique at the N-terminus. Knockdown of Kazrin F using siRNA caused cell apoptosis and a marked decrease in cell viability measured by MTT and TUNEL assays. Co-immunoprecipitation analysis revealed that Kazrin F interacts with ARC (apoptosis repressor with caspase recruitment domain) and Bax (Bcl-2-associated X protein). Co-localization of Kazrin F with ARC and Bax in the cytoplasm was determined by immunofluorescence analysis. These results suggested that Kazrin F might play an important role in regulating cellular apoptosis by interacting with ARC and Bax.
Acta Biochimica et Biophysica Sinica 10/2009; 41(9):763-72. · 1.38 Impact Factor
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ABSTRACT: MicroRNAs are a group of endogenously expressed, single-stranded, 18-24 nt RNAs that regulate diverse cellular pathways. Although documented evidence indicates that some microRNAs can function as oncogenes or tumor-suppressors, the role of miR-214 in regulating human cervical cancer cells remains unexplored. We determined the expression level of miR-214 and found it is downregulated in cervical cancer compared with normal tissue. Overexpression of miR-214 in HeLa cells, a human cervical cancer cell line, significantly inhibited cell proliferation according to the MTT and colony forming assays. HeLa cells that stably overexpress miR-214 downregulate the expression of MEK3 and JNK1 at both mRNA and protein levels. Further investigation revealed that miR-214 regulates the expression of MEK3 and JNK1 by targeting the 3'UTRs of these genes. Collectively, these results suggest that miR-214 negatively regulates HeLa cell proliferation by targeting the noncoding regions of MEK3 and JNK1 mRNAs.
International Union of Biochemistry and Molecular Biology Life 10/2009; 61(11):1075-82. · 3.51 Impact Factor
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ABSTRACT: MicroRNAs are emerging as important regulators of cancer-related processes. Our studies show that microRNA-9 (miR-9) is downregulated in human ovarian cancer relative to normal ovary, and overexpression of miR-9 suppresses cell growth in vitro. Furthermore, the 3'-UTR of NF-kappaB1 mRNA is found to be regulated directly by miR-9, demonstrating that NF-kappaB1 is a functionally important target of miR-9 in ovarian cancer cells. When miR-9 is overexpressed in ovarian cancer cells, the mRNA and protein levels of NF-kappaB1 are both suppressed, whereas inhibition of miR-9 results in an increase in the NF-kappaB1 expression level. Ovarian cancer tissues display significantly low expression of miR-9 and a high level of NF-kappaB1 compared with normal tissues, indicating that regulation of NF-kappaB1 by miR-9 is an important mechanism for miR-9 to inhibit ovarian cancer proliferation.
FEBS Journal 09/2009; 276(19):5537-46. · 3.79 Impact Factor
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ABSTRACT: Endothelialization is an ideal approach to improve the blood compatibility of synthetic polymers. However, cell detachment is inevitable under shear flow conditions. Therefore, the issue of blood compatibility needs to be addressed for both the bare and the endothelialized polymer. RGD-containing polymer P-GS5 was synthesized by modification of poly(D,L-lactide-co-beta-malic acid) (PLMA) with the peptide GRGDS. The compositions, molecular weights and hydrophilicities of poly(D,L-lactide) (PDLLA), PLMA, and P-GS5 were characterized by nuclear magnetic resonance (NMR), X-ray photoelectron spectroscopy (XPS), gel-permeation chromatography (GPC) and water contact angle measurements, respectively. The blood compatibilities of the bare and the endothelialized polymers were evaluated by clotting time and platelet adhesion tests. The results showed that the coagulation pathways were not influenced before and after cell culture; the bare P-GS5 attracted less platelet adhesion and induced lower pseudopodia extension compared with PDLLA and PLMA, and the platelet adhesion on P-GS5 was almost completely eliminated after cell seeding. The results suggest that P-GS5 could be a potentially useful material in vascular tissue engineering.
Colloids and surfaces. B, Biointerfaces 09/2009; 75(1):370-6. · 2.60 Impact Factor
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ABSTRACT: MicroRNAs are short regulatory RNAs that negatively modulate gene expression at the post-transcriptional level, and are deeply involved in the pathogenesis of several types of cancers. To investigate whether specific miRNAs and their target genes participate in the molecular pathogenesis of laryngeal carcinoma, oligonucleotide microarrays were used to assess the differential expression profiles of microRNAs and mRNAs in laryngeal carcinoma tissues compared with normal tissues. The oncogenic miRNA, microRNA-21 (miR-21), was found to be upregulated in laryngeal carcinoma tissues. Knockdown of miR-21 by specific antisense oligonucleotides inhibited the proliferation potential of HEp-2 cells, whereas overexpression of miR-21 elevated growth activity of the cells, as detected by the colony formation assay. The cell number reduction caused by miR-21 inhibition was due to the loss of control of the G1-S phase transition, instead of a noticeable increase in apoptosis. Subsequently, a new target gene of miR-21, BTG2, was found to be downregulated in laryngeal carcinoma tissues. BTG2 is known to act as a pan-cell cycle regulator and tumor suppressor. These findings indicate that aberrant expression of miR-21 may contribute to the malignant phenotype of laryngeal carcinoma by maintaining a low level of BTG2. The identification of the oncogenic miR-21 and its target gene, BTG2, in laryngeal carcinoma is potentially valuable for cancer diagnosis and therapy.
Cell Research 07/2009; 19(7):828-37. · 8.19 Impact Factor
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ABSTRACT: Despite their increasing uses for cardiovascular and cerebrovascular tissue engineering, synthetic polymeric conduits still have their limitations in clinical applications, particularly in small vessels, mainly due to the thrombus formation. Seeding the synthetic scaffolds with endothelial cells (ECs) will potentially solve this problem, but this endothelialization approach demands synthetic materials with better hemacompatibility and cell affinity. To improve the currently used materials and screen for better surface properties, we synthesized copolymer of poly(lactide-co-beta-malic acid) (PLMA), and its derivatives with pendant hydroxyl arms (PLMAHE) or extended carboxyl arms (PLMA-ECA). We analyzed their physical and chemical properties, their hydrophilicity, and their degradation in physiological conditions. More importantly, their blood compatibility was investigated by the measurements of prothrombin time, activated partial thromboplastin time, and interaction with platelets; their cell affinity and cell growth potentials were observed using the human umbilical vein EC cultures. Results from these experiments showed that the copolymer with the carboxyl arms attracted little platelets, and exhibited better cell affinity and supported the cell proliferation, thus demonstrating the potential usefulness of PLMA-ECA for tissue engineering. We speculate that this novel material will offer new opportunities for the design of better vascular-engineered scaffolds owing to its improved biological and chemical properties.
Tissue Engineering Part A 01/2009; 15(1):65-73. · 4.64 Impact Factor
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ABSTRACT: RNA interference (RNAi) has been shown to be an effective method for inhibiting the expression of a given gene in human cells by targeting with short duplex RNA (short-interfering RNA or siRNA). However, more and more studies suggest that non-specific effects can be induced by siRNAs, such as off-target inhibition, activation of interferon response, and saturation of cellular silencing machinery. It has been known that more than 90% of human tumors exhibit telomerase activity. Consequently, telomerase is believed to be a broad-spectrum molecular marker of malignancies. In the present study we attempt to develop a tumor-specific RNAi system using the human telomerase reverse transcriptase promoter. This system may provide a basis for RNAi therapy.
Acta Biochimica et Biophysica Sinica 12/2008; 40(11):928-33. · 1.38 Impact Factor
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ABSTRACT: MicroRNAs (miRNAs) may function as oncogenes or tumor suppressors. Here, we show that miR-27a is up-regulated in human gastric adenocarcinoma. Suppression of miR-27a inhibits gastric cancer cell growth. Subsequently, prohibitin is identified as a potential miR-27a target, combining bioinformatics and microarray analysis. EGFP report experiment also confirms that the 3' untranslated region (3'UTR) of prohibitin carries the directly binding site of miR-27a. After knockdown of miR-27a in gastric cancer cells, mRNA level and protein level of prohibitin are both elevated. Down-regulation of prohibitin by miR-27a may explain why suppression of miR-27a can inhibit gastric cancer cell growth, further supporting that miR-27a functions as an oncogene.
Cancer letters 10/2008; 273(2):233-42. · 4.86 Impact Factor
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ABSTRACT: AFP is a biomarker for primary liver cancer, yet little is known about its effect in the pathogenesis of hepatoma. We examined how AFP modulates the proliferation of hepatoma cells.
Recombinant adenovirus expressing siRNA against AFP was created. The repression of cell proliferation in vitro and growth of hepatoma in vivo were examined by colony formation assay and tumor xenograft in SCID mice, respectively. Cell cycle was assayed by flow cytometry. Expression profile was determined by microarrays.
siRNA targeting reduced expression of AFP specifically and markedly inhibited the proliferation of hepatoma cells. Local treatment using Adv-AFPsiRNA caused significant repression of the growth of hepatoma derived HepG2 cells in xenograft in SCID mice. Knockdown of AFP resulted in an obvious delay in the G(1)/S transition of cell cycle, but did not affect apoptosis in HepG2 cells. Some genes related to the cell cycle, including SKP2, Cyclin D1, Csk and EBAG9 were identified.
The endogenous AFP is a critical determinant of the growth of hepatoma cells, which functions by regulating the cell cycle. This study suggests that targeting of AFP with siRNA could be a potential therapeutic approach for hepatoma.
Clinica Chimica Acta 09/2008; 394(1-2):81-8. · 2.54 Impact Factor
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ABSTRACT: S100P is a member of the S100 family of calcium-binding proteins. Our previous studies have demonstrated its significant downregulation in oxaliplatin-resistant colon cancer cell line. The present study investigated whether it plays a role in the regulation of chemosensitivity to anticancer drugs using human ovarian cancer cell line OVCAR3. We firstly overexpressed S100P in the OVCAR3 cell line, and evaluated the expression level of S100P by semiquantitative RT-PCR, Western blotting and immunofluorescence assay. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay indicated that overexpression of S100P sensitized OVCAR3 cells for chemotherapeutic drugs (paclitaxel, oxaliplatin, 5-fluorouracil, etoposide and epirubicin) induced cytotoxicity more than vector-only controls. Further studies showed that downregulation of S100P by RNA interference in OVCAR3 cells led to a significant increase of resistance to each of these anticancer drugs. Taken together, our results suggest that S100P plays an important role in regulation of chemosensitivity to anticancer drugs in ovarian cancer cells. Using S100P as a molecular biomarker may increase our ability to predict tumor drug response in ovarian cancer.
Oncology Reports 08/2008; 20(2):325-32. · 1.84 Impact Factor
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ABSTRACT: Recent studies indicate that S100P expression may be a biomarker that can predict the success of cancer chemotherapy. Whether it is relevant to chemotherapeutics in ovarian cancer is unknown. In this study, we investigated the association of S100P expression with paclitaxel sensitivity in ovarian cancer cell lines.
We measured S100P expression and paclitaxel resistance profiles in parent SKOV3 and OVCAR3 cell lines. Then, the two cell lines were transiently transfected with S100P siRNA. We also constructed an OVCAR3 cell clone that stably overexpressed S100P. The effect of S100P expression level on the survival of cells exposed to paclitaxel was measured using the MTT assay. S100P expression was evaluated by semi-quantitative RT-PCR and Western blotting. Significance of differences was calculated using independent samples t-test and one way analysis of variance (ANOVA).
Lower S100P expression was associated with a survival advantage in OVCAR3 cells exposed to paclitaxel; the survival advantage in SKOV3 cells was smaller (P < 0.05). The survival advantage associated with decreased S100P expression was even greater for SKOV3 and OVCAR3 cells that had been transfected with S100P siRNA before being exposed to paclitaxel (P < 0.05). Consistent with this, the OVCAR3 cell clone that was transfected to overexpress S100P was more sensitive to paclitaxel (P < 0.05).
Low S100P expression contributes to drug resistance to paclitaxel in ovarian cancer cell lines. S100P expression thus might be a marker that can predict the effectiveness of paclitaxel based chemotherapy. Such a marker could be helpful in improving individual medication regimens for ovarian cancer patients.
Chinese medical journal 08/2008; 121(16):1563-8. · 0.86 Impact Factor
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ABSTRACT: To investigate the relationship between the S100P and the sensitivity of ovarian cancer to chemotherapeutics.
We established stable cell lines of ovarian cancer cells, SKOV3 and OVCAR3, that overexpress human S100P. We also transiently transfected the parent cell lines with S100P-targeted siRNA for down-regulation of S100P expression. The sensitivity of all transfected and untransfected cell lines to carboplatin and paclitaxel was detected by MTT assay.
For both cells, IC50s decreased to carboplatin and paclitaxel (p<0.05), with overexpression of S100P compared to untransfected cells. Alternatively, with down-regulation of S100P by siRNA, the IC50 to carboplatin and paclitaxel increased in each case (p<0.05), which was significantly higher compared to untransfected cells.
Changes in expression levels of S100P in SKOV3 and OVCAR3 cells results in variable susceptibility to carboplatin and paclitaxel. These data suggest that S100P contributes to chemosensitivity to carboplatin and paclitaxel in ovarian cancer cells.
Cancer letters 08/2008; 272(2):277-84. · 4.86 Impact Factor
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ABSTRACT: Geldanamycin (GA), an ansamycin antibiotic specifically binding heat shock protein 90 (Hsp90), exhibits a broad-spectrum antiviral effect. Herpes simplex virus type 1(HSV-1) replication in vitro was significantly inhibited by GA treatment. To explore the antiviral mechanism of GA against HSV-1, the 7267-spot human long oligonucleotide microarrays were applied to investigate the genes which might involved in the antiviral activity of GA in HeLa cells infected by HSV-1. Meanwhile, the reverse regulation of GA and HSV-1 on ACTG1, RAN, SOD1, HYAL1 were validated by using semi-quantitative RT-PCR. It is the first report of gene expression profile in cells infected by virus with GA treatment. The general impact of GA on cellular transcription may help to gain an insight into mechanism of its antiviral effect.
Bing du xue bao = Chinese journal of virology / [bian ji, Bing du xue bao bian ji wei yuan hui] 06/2008; 24(3):208-12.
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ABSTRACT: Poly(1-dodecene-co-para-methylstyrene) copolymers with a broad composition range were prepared by an MgCl2 supported TiCl4 catalyst. The effects of temperature and hydrogen on catalyst activity were investigated. It was found that catalyst activity reached a maximum at around 60 °C, and then decreased with the rising temperature. Hydrogen showed an activation effect on the Ziegler–Natta catalyst. 1H NMR and 13C NMR spectra showed that para-methylstyrene (pMS) could be effectively and randomly incorporated into the copolymer chains. The single glass transition indicated there was no block sequence in the copolymer. The copolymerization reaction was examined by the reactivity ratios of comonomers and the relatively low reactivity ratios of 1-dodecene and pMS indicated that both of them had little tendency of consecutive insertion and should be homogeneously distributed in the copolymer chains. Furthermore, the molecular weights of copolymers were regulated by chain transfer agents (diethyl zinc and hydrogen) and temperature. The molecular weights reduced greatly with the addition of diethyl zinc and hydrogen and with the increasing temperature.
European Polymer Journal.
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ABSTRACT: Poly(1-dodecene-co-pMS) copolymers were brominated by HBr/H2O2 system with high selectivity at the methyl groups of pMS units. It was found that longer reaction time, higher pMS content, and lower molecular weight of the copolymers were helpful for higher degree of bromination. Through a modified Williamson ether synthesis, poly(ethylene glycol) monomethyl ethers (PEG) were grafted onto the brominated copolymers, and the amphiphilic poly(1-dodecene-co-pMS)-graft-PEG copolymers which can be readily dissolved in n-octane were successfully synthesized. Due to their amphiphilic characteristics, they can self-assemble spontaneously into reverse micelles in n-octane. Their micellization behaviors were investigated by fluorescence probe technique, transmission electron microscopy (TEM), and dynamic light scattering (DLS). The critical micelle concentrations of the three copolymers in n-octane were determined at about 1.26 × 10−4, 1.58 × 10−4, and 1.95 × 10−4 g ml−1 by fluorescence measurements. The morphologies of micelles were preliminarily explored by TEM and were found to be spheres.
European Polymer Journal.
