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Research Paper
Knockdown of Mutant K-ras Expression by Adenovirus-Mediated siRNA Inhibits the In Vitro and in Vivo Growth of Lung Cancer Cells
Zhiping Zhang, Guanchao Jiang, Fan Yang and Jun Wang
volume 5 | issue 11
November 2006Pages: 1481 - 1486
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The ras mutation, which is observed in 20-30% of human non-small cell lung cancers (NSCLCs), is one of common genetic alterations and has been proposed to be a prognostic factor in lung cancer. Oncogene ras appears to be essential for tumor progression and maintenance. Several therapeutic agents have been developed to inhibit ras, such as FTIs and antisense oligonucleotides. A new tool for blocking oncogenes in cancer cells has emerged with the discovery that RNA interference can specifically silence expression of endogenous human genes. In the current study, we used small interfering RNA (siRNA) directed against mutant K-ras to determine the anti-tumor effects of decreasing the levels of this protein in lung cancer cell lines. Adenovirus-mediated siRNA (AdH1/siK-rasV12) against K-rasV12 markedly decreased K-rasV12 gene expression and inhibited cellular proliferation of NSCLC H441 cells that express the relevant mutation (K-ras codon 12 GGT→GTT), but produced minimal growth inhibition on NSCLC H1650 cells that lack the relevant mutation. Pre-treatment with AdH1/siK-rasV12 completely abrogated subcutaneous engraftment of H441 cells, as compared with a 100% tumor take in animals that received control vector-treated tumor cells. The in vivo effect of AdH1/siK-rasV12 treatment was further examined by intratumoral injections after tumor induction. Preexisting tumor growth was reduced by 45% by a single intratumoral injection. Three or five repeat injections resulted in complete tumor regression in eight of ten nude mice. Further, 23.12% of AdH1/siK-rasV12 treated H441 cells underwent apoptosis, as compared with 6.13%, and 8.27% in untreated and control vector-treated cells, respectively. These results indicate that adenovirus-mediated siRNA can specifically and efficiently target factors whose expression is altered in malignancy and may have the potential as a therapeutic modality to treat human lung cancer.
Authors
Zhiping Zhang
Peking University, Beijing, PR China
Guanchao Jiang
Peking University, Beijing, PR China
Fan Yang
Peking University, Beijing, PR China
Jun Wang
Peking University, Beijing, PR China
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDFIf the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.