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Restoration of tumor suppressor miR-34 inhibits human p53-mutant gastric cancer tumorspheres
dc.contributor.author | Ji, Qing | |
dc.contributor.author | Hao, Xinbao | |
dc.contributor.author | Meng, Yang | |
dc.contributor.author | Zhang, Min | |
dc.contributor.author | DeSano, Jeffrey | |
dc.contributor.author | Fan, Daiming | |
dc.contributor.author | Xu, Liang | |
dc.date.accessioned | 2014-08-13T17:54:01Z | |
dc.date.available | 2014-08-13T17:54:01Z | |
dc.date.issued | 2008-09-21 | |
dc.identifier.citation | Ji, Q., Hao, X., Meng, Y., Zhang, M., DeSano, J., Fan, D., Xu, L. Restoration of tumor suppressor miR-34 inhibits human p53-mutant gastric cancer tumorspheres. BMC Cancer 2008, 8:266. http://dx.doi.org/10.1186/1471-2407-8-266. | |
dc.identifier.uri | http://hdl.handle.net/1808/14918 | |
dc.description.abstract | Background: MicroRNAs (miRNAs), some of which function as oncogenes or tumor suppressor genes, are involved in carcinogenesis via regulating cell proliferation and/or cell death. MicroRNA miR-34 was recently found to be a direct target of p53, functioning downstream of the p53 pathway as a tumor suppressor. miR-34 targets Notch, HMGA2, and Bcl-2, genes involved in the self-renewal and survival of cancer stem cells. The role of miR-34 in gastric cancer has not been reported previously. In this study, we examined the effects of miR-34 restoration on p53-mutant human gastric cancer cells and potential target gene expression. Methods: Human gastric cancer cells were transfected with miR-34 mimics or infected with the lentiviral miR-34-MIF expression system, and validated by miR-34 reporter assay using Bcl-2 3'UTR reporter. Potential target gene expression was assessed by Western blot for proteins, and by quantitative real-time RT-PCR for mRNAs. The effects of miR-34 restoration were assessed by cell growth assay, cell cycle analysis, caspase-3 activation, and cytotoxicity assay, as well as by tumorsphere formation and growth. Results: Human gastric cancer Kato III cells with miR-34 restoration reduced the expression of target genes Bcl-2, Notch, and HMGA2. Bcl-2 3'UTR reporter assay showed that the transfected miR-34s were functional and confirmed that Bcl-2 is a direct target of miR-34. Restoration of miR-34 chemosensitized Kato III cells with a high level of Bcl-2, but not MKN-45 cells with a low level of Bcl-2. miR-34 impaired cell growth, accumulated the cells in G1 phase, increased caspase-3 activation, and, more significantly, inhibited tumorsphere formation and growth. Conclusion: Our results demonstrate that in p53-deficient human gastric cancer cells, restoration of functional miR-34 inhibits cell growth and induces chemosensitization and apoptosis, indicating that miR- 34 may restore p53 function. Restoration of miR-34 inhibits tumorsphere formation and growth, which is reported to be correlated to the self-renewal of cancer stem cells. The mechanism of miR-34-mediated suppression of self-renewal appears to be related to the direct modulation of downstream targets Bcl-2, Notch, and HMGA2, indicating that miR-34 may be involved in gastric cancer stem cell self-renewal/ differentiation decision-making. Our study suggests that restoration of the tumor suppressor miR-34 may provide a novel molecular therapy for p53-mutant gastric cancer. | |
dc.language.iso | en | |
dc.publisher | BioMed Central | |
dc.rights | This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. | |
dc.rights.uri | http://creativecommons.org/licenses/by/2.0 | |
dc.title | Restoration of tumor suppressor miR-34 inhibits human p53-mutant gastric cancer tumorspheres | |
dc.type | Article | |
kusw.kuauthor | Xu, Liang | |
kusw.kudepartment | Molecular Biosciences | |
kusw.oastatus | na | |
dc.identifier.doi | 10.1186/1471-2407-8-266 | |
kusw.oaversion | Scholarly/refereed, publisher version | |
kusw.oapolicy | This item does not meet KU Open Access policy criteria. | |
dc.rights.accessrights | openAccess |
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