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MicroRNA-185 suppresses tumor growth and progression by targeting the Six1 oncogene in human cancers

Oncogene volume 29, pages 4971–4979 (2010)Cite this article

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Abstract

Homeobox genes encode transcription factors that are essential for normal development and are often dysregulated in cancers. The molecular mechanisms that cause their misregulation in cancers are largely unknown. In this study, we investigate the mechanism by which the Six1 homeobox protein, which has a crucial role during development, is frequently deregulated in several poor outcome, aggressive, metastatic adult human cancers, including breast cancer, ovarian cancer, hepatocellular carcinoma and pediatric malignancies such as rhabdomyosarcoma and Wilms’ tumor. Our results reveal that miRNA-185 translationally represses Six1 by binding to its 3′-untranslated region. Analyses of ovarian cancers, pediatric renal tumors and multiple breast cancer cell lines showed decreased miR-185 expression, paralleling an increase in Six1 levels. Further investigation revealed that miR-185 impedes anchorage-independent growth and cell migration, in addition to suppressing tumor growth in vivo, implicating it to be a potent tumor suppressor. Our results indicate that miR-185 mediates its tumor suppressor function by regulating cell-cycle proteins and Six1 transcriptional targets c-myc and cyclin A1. Furthermore, we show that miR-185 sensitizes Six1-overexpressing resistant cancer cells to apoptosis in general and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in particular. Together, our findings suggest that the altered expression of the novel tumor suppressor miR-185 may be one of the central events that leads to dysregulation of oncogenic protein Six1 in human cancers.

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Acknowledgements

We thank Jennifer Rebeles and Tiffany Jones for their assistance in flow cytometry and data analysis; Dr Yao-Fu-Chang for his suggestions in the preparation of this paper; Drs James Garbe and Martha Stampfer of Lawrence Berkeley National Laboratory for kindly providing us normal HMEC RNA samples; the Children's Oncology Group for providing Wilms’ tumor and matched control kidney tissues; Dr Russell Broaddus and Ovarian Cancer Translational Research Tumor Bank, MD Anderson Cancer Center for normal and ovarian cancer tissues; and Dr Padmanabhan Swami, UT Health Science Center, San Antonio for recombinant human TRAIL. Financial support: This work was supported by San Antonio Area Foundation Grant (JSI and MKR) and GCCRI startup fund (MKR).

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Authors and Affiliations

  1. Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    J S Imam, K Buddavarapu, J S Lee-Chang, C Camosy & M K Rao

  2. Department of Radiation Oncology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    S Ganapathy

  3. Department of Epidemiology and Biostatistics, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Y Chen

  4. Department of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    M K Rao

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  1. J S Imam
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  2. K Buddavarapu
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Correspondence to M K Rao.

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Supplementary Information accompanies the paper on the Oncogene website

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Imam, J., Buddavarapu, K., Lee-Chang, J. et al. MicroRNA-185 suppresses tumor growth and progression by targeting the Six1 oncogene in human cancers. Oncogene 29, 4971–4979 (2010). https://doi.org/10.1038/onc.2010.233

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