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A mutant p53/let-7i-axis-regulated gene network drives cell migration, invasion and metastasis

Oncogene volume 34, pages 1094–1104 (2015)Cite this article

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Abstract

Most p53 mutations in human cancers are missense mutations resulting in a full-length mutant p53 protein. Besides losing tumor suppressor activity, some hotspot p53 mutants gain oncogenic functions. This effect is mediated in part, through gene expression changes due to inhibition of p63 and p73 by mutant p53 at their target gene promoters. Here, we report that the tumor suppressor microRNA let-7i is downregulated by mutant p53 in multiple cell lines expressing endogenous mutant p53. In breast cancer patients, significantly decreased let-7i levels were associated with missense mutations in p53. Chromatin immunoprecipitation and promoter luciferase assays established let-7i as a transcriptional target of mutant p53 through p63. Introduction of let-7i to mutant p53 cells significantly inhibited migration, invasion and metastasis by repressing a network of oncogenes including E2F5, LIN28B, MYC and NRAS. Our findings demonstrate that repression of let-7i expression by mutant p53 has a key role in enhancing migration, invasion and metastasis.

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Acknowledgements

This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. Sudha Sharma was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number SC1GM093999. We thank K Prasanth, W Bodmer, B Hassel, M Thomas, J Lieberman and M Gorospe for their comments on this manuscript. We thank B Vogelstein for the DLD1 isogenic cell lines, K Vousden for the H1299-EV and H1299-p53R273H cells, S O’Hara for the pGL4-let-7i and Z Mourelators for the Ago2 (2A8) antibody.

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Authors and Affiliations

  1. Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    M Subramanian, P Francis, S Bilke, X L Li, T Hara, M F Jones, R L Walker, Y Zhu, M Pineda, P S Meltzer & A Lal

  2. Department of Biochemistry and Molecular Biology, College of Medicine, Howard University, Washington, DC, USA

    X Lu & S Sharma

  3. Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    C Lee & J Luo

  4. Department of Biochemistry, University of Mississippi Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA

    L Varanasi & L A Martinez

  5. Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Y Yang & L M Wakefield

  6. Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    S Ambs

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Subramanian, M., Francis, P., Bilke, S. et al. A mutant p53/let-7i-axis-regulated gene network drives cell migration, invasion and metastasis. Oncogene 34, 1094–1104 (2015). https://doi.org/10.1038/onc.2014.46

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