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Ma X.,Central South University | Yang L.,Central South University | Xiao L.,Central South University | Tang M.,Central South University | And 6 more authors.
PLoS ONE | Year: 2011

Background: The latent membrane protein 1 (LMP1) encoded by EBV is expressed in the majority of EBV-associated human malignancies and has been suggested to be one of the major oncogenic factors in EBV-mediated carcinogenesis. In previous studies we experimentally demonstrated that down-regulation of LMP1 expression by DNAzymes could increase radiosensitivity both in cells and in a xenograft NPC model in mice. Results: In this study we explored the molecular mechanisms underlying the radiosensitization caused by the down-regulation of LMP1 in nasopharyngeal carcinoma. It was confirmed that LMP1 could up-regulate ATM expression in NPCs. Bioinformatic analysis of the ATM ptomoter region revealed three tentative binding sites for NF-κB. By using a specific inhibitor of NF-κB signaling and the dominant negative mutant of IkappaB, it was shown that the ATM expression in CNE1-LMP1 cells could be efficiently suppressed. Inhibition of LMP1 expression by the DNAzyme led to attenuation of the NF-κB DNA binding activity. We further showed that the silence of ATM expression by ATM-targeted siRNA could enhance the radiosensitivity in LMP1 positive NPC cells. Conclusions: Together, our results indicate that ATM expression can be regulated by LMP1 via the NF-κB pathways through direct promoter binding, which resulted in the change of radiosensitivity in NPCs. © 2011 Ma et al. Source

Zhao L.,Central South University | Zhao L.,Key Laboratory of Carcinogenesis and Invasion | Zhao L.,Key Laboratory of Carcinogenesis | Lu X.,University of Houston | And 3 more authors.
Cellular Signalling | Year: 2013

Tumor radiation response is an essential issue in radiotherapy and a core determining factor of tumor radioresistance or radiosensitivity. Multiple factors can influence tumor radiation response, and among them tumor genetic and epigenetic background, tumor microenvironment and tumor blood flow status may take a leading role. During the whole process of tumor radiation response, tumor radiosensitivity can be regulated in an orderly manner through some classical signal transduction pathways. Although these pathways have already owned multiple biological functions and involved in the process of carcinogenesis, their regulatory roles in tumor radiation response can not be ignored. MicroRNA (miRNA) is a class of non-coding RNA of about 22 nucleotides in length, which binds to the 3'-untranslated region (3'-UTR) of target gene and controls the expression of it at the post-transcriptional level. MiRNA participates in numerous physiology and pathology processes and acts as oncogene or tumor suppressor to affect cancer progression. Through interplaying with the key components in radiation related signal transduction pathways, miRNA could effectively activate the expression of DNA damage response genes and cell cycle related genes in the nucleus, and play a critical role in the modulation of radiation response and radiosensitivity in tumor cells. In this review, we mainly elucidate the regulatory mechanisms and functions of miRNA in these radiation related signal transduction pathways from three different aspects which include the upstream receptors, midstream transducer pathways, and downstream effector genes. © 2013 Elsevier Inc. Source

Zhao L.,Central South University | Zhao L.,Key Laboratory of Carcinogenesis and Invasion | Zhao L.,Key Laboratory of Carcinogenesis | Bode A.M.,University of Minnesota | And 4 more authors.
Carcinogenesis | Year: 2012

MicroRNA (miRNA) influences carcinogenesis at multiple stages and it can effectively control tumor radiosensitivity by affecting DNA damage repair, cell cycle checkpoint, apoptosis, radio-related signal transduction pathways and tumor microenvironment. MiRNA also efficiently modulates tumor radiosensitivity at multiple levels by blocking the two essential non-homologous end-joining repair and homologous recombination repair pathways in the DNA damage response. It interferes with four radio-related pathways in ionizing radiation, including the PI3-K/Akt, NF-κB, MAPK and TGFβ signaling pathways. Moreover, the regulatory effect of miRNA in radiosensitivity can be enhanced when interacting with various key molecules, including H2AX, BRCA1, ATM, DNA-PK, RAD51, Chk1, Cdc25A, p53, PLK1, HIF-1 and VEGF, which are involved in these processes. Therefore, thoroughly understanding the mechanism of miRNA in tumor radiosensitivity could assist in finding novel targets to improve the radiotherapeutic effects and provide new clinical perspectives and insights for developing effective cancer treatments. © The Author 2012. Published by Oxford University Press. Source

Zhao L.,Key Laboratory of Carcinogenesis and Invasion | Zhao L.,Key Laboratory of Carcinogenesis | Zhao L.,Central South University | Chen X.,Key Laboratory of Carcinogenesis and Invasion | And 5 more authors.
Acta Biochimica et Biophysica Sinica | Year: 2011

MicroRNA (miRNA) is a cluster of small non-encoding RNA molecules of 2123 nucleotides in length, which controls the expression of target gene at the post-transcriptional level. Recent researches have indicated that miRNA plays an essential role in carcinogenesis, such as affecting the cell growth, differentiation, apoptosis, and cell cycle. Nowadays, multiple promising roles of miRNA involved in carcinogenesis are emerging, and it is shown that miRNA closely relates to the process of epithelial-mesenchymal transition (EMT), the regulation of cancer stem cells (CSCs), the development of tumor invasion and migration. miRNA also acts as a biomarker stably expressed in serum and provides new target for molecular target therapy of various cancers. The aim of this review is to illustrate the new role of miRNA in carcinogenesis and highlight the new prospects of miRNA in cancer clinical application, such as in serological diagnosis and molecular-targeted therapeutics. © The Author 2011. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. Source

Huang J.,Central South University | Huang J.,Key Laboratory of Carcinogenesis | Huang J.,Key Laboratory of Carcinogenesis and Invasion | Li Y.,Central South University | And 17 more authors.
Journal of Central South University (Medical Sciences) | Year: 2011

Objective To express and purify the human scFv antibody, SA3 , against the hepatoma fused to enhanced green fluorecsent protein, and to observe the targeted capacity of fusion protein EGFP-SA3 in vivo. Methods SA3 and EGFP genes were cloned into plasmid pET-25b(+) to construct the recombinant plasmid EGFP-SA3/pET-25b (+) , followed by DNA sequencing. Then it was transformed into E. coli BL2I (DE3) and induced for fusion expression of EGFP-SA3 with IPTG. The expressed fusion protein EGFP-SA3 was purified and detected with SDS-PAGE. HepG2 cells were incubated with the fusion protein EGFP-SA3 in vitro, and the binding bioactivity was observed under the fluorecsent microscope. Further more, we injected the EGFP-SA3 by caudal vein into nude mice planted by hepatoma and observed the whole body fluorescence image of EGFP. Results SA3 and EGFP genes were successfully cloned into pET-25b( + ) , which was confirmed by restriction enzyme Ncol-Xho I or Nco I-Eco RI. A band migrated at the position 750 bp, same to EGFP gene, emerged when recombinant plasmid was digested by restriction enzyme Nco I Eco RI. Similarly, a band, about 1500 bp, emerged when digested by Nco I-Xho I. The open-reading frame was confirmed by DNA sequencing. Fusion protein EGFP-SA3 was expressed as inclusion body. After purification and refolding, the result of immunofluorecsence detection verified that EGFP-SA3 could specifically bind to HepG2 cells and maximum tumor penetration was at 24 h after the injection. Conclusion The purified fusion protein EGFP-SA3 has strong binding capacity to HepG2 cells, indicating the scFv SA3 has a potential value as a targeting molecule for diagnosis and targeted therapy for liver cancer. Source

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