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β-catenin downregulates Dicer to promote ovarian cancer metastasis

Oncogene volume 36, pages 5927–5938 (2017)Cite this article

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Abstract

Ovarian cancer is a nearly uniform lethal disease and its highly aggressive metastatic phenotype portends a poor prognosis. Lack of a well-controlled, relevant experimental model has been a major obstacle to identifying key molecules causing metastasis. Here we describe the creation of a new isogenic model of spontaneous human ovarian cancer metastasis exhibiting opposite phenotypes—highly metastatic (HM) and non-metastatic (NM)—both in vitro and in vivo. HM was unique in its ability to metastasize consistently to the peritoneum, mimicking the major dissemination route of human ovarian cancer. In contrast, NM failed to form detectable metastases, although it was equally tumorigenic. Using comparative label-free quantitative liquid chromatography tandem mass spectrometry (LC-MS/MS), we identified β-catenin, which we demonstrated for the first time as having a direct role in the pathogenesis of ovarian cancer metastasis. Our studies also revealed a previously unrecognized role of β-catenin in the downregulation of multiple microRNAs (miRNAs) through attenuating miRNA biogenesis by targeting Dicer, a key component of the miRNA-processing machinery. One such downregulated miRNAs was miR-29s involved in epithelial-to-mesenchymal transition and subsequent stem cell traits. Silencing β-catenin or overexpressing Dicer or miR-29 mimics in HM significantly reduced the ability of these cells to migrate. β-catenin-knockdown cells also failed to metastasize in an orthotopic model of ovarian cancer. Meta-analysis revealed an increase in CTNNB1 and a decrease in DICER1 expression levels in the high-risk group. These results uncover β-catenin as a critical factor in promoting ovarian cancer aggressiveness and a new mechanism linking between β-catenin and miRNA downregulation underlying this process.

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Acknowledgements

We thank the assistance of the Faculty Core Facility of the Li Ka Shing Faculty of Medicine at the University of Hong Kong. The work described in this paper was supported by the Research Grant Council grant (17141216) and partially the Special Equipment Grant from the University Grants Committee of the Hong Kong Special Administrative Region, China (Project Code: SEG_HKU02). ASTW is a recipient of the Croucher Senior Research Fellowship.

Author contributions

SKYT, ASCM and S-SL conducted the in vitro and in vivo experiments and analyzed the results; YMEF performed LC-MS/MS; DW performed SKY analyses. BR and JZ performed analyses of the microarray and TCGA data sets. CMC and ASTW designed and supervised the study. All authors edited and approved the final manuscript.

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Author notes

  1. S K Y To, A S C Mak and Y M Eva Fung: These authors contributed equally to this work.

Authors and Affiliations

  1. School of Biological Sciences, University of Hong Kong, Hong Kong

    S K Y To, A S C Mak, S-S Li, B Ru, J Zhang & A S T Wong

  2. Department of Chemistry, Chemical Biology Centre, State Key Laboratory of Synthetic Chemistry, University of Hong Kong, Hong Kong

    Y M Eva Fung & C-M Che

  3. School of Nursing, University of Hong Kong, Hong Kong

    W Deng

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To, S., Mak, A., Eva Fung, Y. et al. β-catenin downregulates Dicer to promote ovarian cancer metastasis. Oncogene 36, 5927–5938 (2017). https://doi.org/10.1038/onc.2017.185

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