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ToxSci Advance Access published online on June 20, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn122
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Silencing of N-Ras Gene Expression Using shRNA Decreases Transformation Efficiency and Tumor Growth in Transformed Cells Induced by Anti-BPDE

Lanlan Zhou*, Yiguo Jiang*,1, Aijun Tan{dagger}, Anne R Greenlee{ddagger}, Yuelan Shen*, Linhua Liu* and Qiaoyuan Yang*

* Institute for Chemical Carcinogenesis, State Key Laboratory of Respiratory Diseases, Guangzhou Medical College, Guangzhou 510182, China {dagger} Disease Control and Prevention Center of Zhuhai, Zhuhai, 519000, China {ddagger} Eastern Oregon University and Center for Research on Occupational and Environmental Toxicology, La Grande, OR 97850,USA

1 To whom correspondence should be addressed at Institute for Chemical Carcinogenesis, Guangzhou Medical College, 195 Dongfengxi Road, Guangzhou 510182, China. Tel: (86-20)81340186, Fax: (86-20)81340724. E-mail: jiangyiguo{at}yahoo.com

Received May 22, 2008; revision received June 9, 2008; accepted June 11, 2008


  Abstract

Anti-benzo[a]pyrene-trans-7,8-diol-9,10-epoxide (anti-BPDE) is the most important metabolite of benzo[a]pyrene (B[a]P) which is a ubiquitous environmental pollutant, and may cause human cancer, especially of the lung. Ras genes (H, K and N) are activated in 40% of human tumors and may contribute to carcinogenesis. Here, we used malignant human bronchial epithelial cells transformed by anti-BPDE (16HBE-T) to help characterize possible molecular mechanisms of carcinogenesis. We compared H-, K- and N-Ras mRNA and protein expression levels in 16HBE-T cells and untransformed control 16HBE cells (16HBE-N), using RT-PCR and Western blotting. We further used short hairpin RNA to silence N-Ras gene expression in 16HBE-T cells to determine the effects of silencing on the cell cycle, transformation efficiency and tumor growth. We observed overexpression of H-, K- and N-Ras genes at both mRNA and protein levels in 16HBE-T cells, compared with 16HBE-N cells. Silencing of N-Ras in 16HBE-T cells using stable RNA interference increased the proportion of cells in G0/G1 phase, decreased the proportion in S phase, decreased transformation efficiency, and inhibited tumor growth. Our findings suggest that overexpression of N-Ras gene plays an important role in malignant transformation of 16HBE cells by anti-BPDE. N-Ras gene may be a useful target for gene therapy.

Key Words: anti-BPDE; short hairpin RNA; RNA interference; H-Ras, K-Ras, N-Ras; human bronchial epithelial cells; malignant transformation.


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