MicroRNA-34b and MicroRNA-34c are targets of p53 and cooperate in control of cell proliferation and adhesion-independent growth.

By David C. Corney, A. Flesken-Nikitin, A. Godwin, Wei Wang, A. Nikitin. Cancer Research, 2007

722 citations recorded by the source corpus.

MicroRNAs (miRNA) are a recently discovered class of noncoding RNAs that negatively regulate gene expression. Recent evidence indicates that miRNAs may play an important role in cancer. However, the mechanism of their deregulation in neoplastic transformation has only begun to be understood. To elucidate the role of tumor suppressor p53 in regulation of miRNAs, we have analyzed changes in miRNA microarray expression profile immediately after conditional inactivation of p53 in primary mouse ovarian surface epithelium cells. Among the most significantly affected miRNAs were miR-34b and miR-34c, which were down-regulated 12-fold according to quantitative reverse transcription-PCR analysis. Computational promoter analysis of the mir-34b/mir-34c locus identified the presence of evolutionarily conserved p53 binding sites approximately 3 kb upstream of the miRNA coding sequence. Consistent with evolutionary conservation, mir-34b/mir-34c were also down-regulated in p53-null human ovarian carcinoma cells. Furthermore, as expected from p53 binding to the mir-34b/c promoter, doxorubicin treatment of wild-type, but not p53-deficient, cells resulted in an increase of mir-34b/mir-34c expression. Importantly, miR-34b and miR-34c cooperate in suppressing proliferation and soft-agar colony formation of neoplastic epithelial ovarian cells, in agreement with the partially overlapping spectrum of their predicted targets. Taken together, these results show the existence of a novel mechanism by which p53 suppresses such critical components of neoplastic growth as cell proliferation and adhesion-independent colony formation.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/e8007137250b41e4c91ee22434a74c388f9c3bb8

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Citations in the corpus

MicroRNA and cancer (2012, background): “Oncogenic functions have been ascribed to their many target genes involved in growth control, including Cyclin E2, MYC, MET, BCL2, SIRT1 and E2F family members (Bommer et al., 2007; Christoffersen et al., 2009; Corney et al., 2007; Hermeking, 2012; Tazawa et al., 2007; Yamakuchi et al., 2008).”
microRNAs in cancer (2013, background): “In accordance with the loss of p53, miR-34 paralogs (miR-34a, miR-34b, and miR-34c) are repressed: miR-34a expression is decreased in 100% and miR-34b∗/c in 72% of epithelial ovarian tumors with p53 mutation (97).”
Normalization of microRNA expression levels in quantitative RT-PCR assays: identification of suitable reference RNA targets in normal and cancerous human solid tissues. (2008, background): “To date, only a handful of miRNA qRT-PCR studies have described some form of normalization, using RNA targets such as 5S (Takamizawa et al. 2004; Pineles et al. 2007), U6 (Choong et al. 2007; Corney et al. 2007; Shell et al. 2007), 18S (Iorio et al. 2007), or miR-16 or let-7a (Mattie et al. 2006).”
MicroRNAs: key players in the immune system, differentiation, tumorigenesis and cell death (2008, background): “…apoptotic sensitivity possibly through translational or indirect repression of anti-apoptotic factors CDK6, c-Meta and c-Myca Bommer et al. (2007); Corney et al. (2007); Raver-Shapira et al. (2007) miR-122 Hepatocellular-specific miRNA highly expressed in the normal liver and involved in fatty…”
MicroRNAs in development and disease. (2011, background): “P53-deficient OC cells are low in miR-34b and miR-34c, which are transcriptional targets of p53 (118).”
MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer (2011, background): “It is also interesting to note the down-regulation of mir-34b in patients with worse DFS, because mir-34b is a well known target of p53, which cooperates to control cell proliferation and adhesion-independent growth (31).”
MicroRNA miR-34 Inhibits Human Pancreatic Cancer Tumor-Initiating Cells (2009, positive): “The results demonstrate that the transfected miR-34s are functional and confirm that Bcl-2 is a direct target of miR-34, consistent with earlier reports [8,10,21].”
The mammalian ovary from genesis to revelation. (2009, background): “Overexpression of mir-34b and mir34c in p53 null mouse OSE cell lines suppressed their proliferation and anchorage-independent growth (651).”
Blinded by the Light: The Growing Complexity of p53. (2009, background): “…select microRNAs (miRNAs), most dramatically the miR-34 locus consisting of miR-34a, miR-34b, and miR-34c (Bommer et al., 2007; Chang et al., 2007; Corney et al., 2007; He et al., 2007; Raver-Shapira et al., 2007; Tarasov et al., 2007; Tazawa et al., 424 Cell 137, May 1, 2009 ©2009 Elsevier…”
A microRNA DNA methylation signature for human cancer metastasis (2008, result): “These latter results relate to the different predicted targeting scores of each miR-34b and miR-34c for the corresponding proteins, as has also been recently described in ovarian cancer cells (34).”