Phosphodiesterase 7b/microrna-200c relationship regulates triple-negative breast cancer cell growth

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ABSTRACT Members of microRNA-200 (miRNA-200) family have a regulatory role in epithelial to mesenchymal transition (EMT) by suppressing Zeb1 and Zeb2 expression. Consistent with its role in


suppressing EMT, Hsa-miR-200c-3p (miR-200c), a member of miR-200 family is poorly expressed in mesenchymal-like triple-negative breast cancer (TNBC) cells and ectopic miR-200c expression


suppresses cell migration. In this study, we demonstrated that miR-200c potently inhibited TNBC cell growth and tumor development in a mechanism distinct from its ability to downregulate


Zeb1 and Zeb2 expression, because silencing them only marginally affected TNBC cell growth. We identified phosphodiesterase 7B (PDE7B) as a bona fide miR-200c target. Importantly,


miR-200c-led inhibition in cell growth and tumor development was prevented by forcing PDE7B transgene expression, while knockdown of PDE7B effectively inhibited cell growth. These results


suggest that miR-200c inhibits cell growth by targeting PDE7B mRNA. To elucidate mechanism underlying miR-200c/PDE7B regulation of TNBC cell growth, we showed that cAMP concentration was


lower in TNBC cells compared with estrogen receptor-positive (ER + ) cells, and that both miR-200c and PDE7B siRNAs were able to increase cAMP concentration in TNBC cells. High level of


cellular cAMP has been shown to induce cell cycle arrest and apoptosis in TNBC cells. Our observation that ectopic expression of miR-200c triggered apoptosis indicates that it does so by


elevating level of cellular cAMP. Analysis of breast tumor gene expression datasets revealed an inverse association between miR-200c and PDE7B expression. Especially, both low miR-200c and


high PDE7B expression were correlated with poor survival of breast cancer patients. Our study supports a critical role of miR-200c/PDE7B relationship in TNBC tumorigenesis. Access through


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This work was supported by funding from NSF of China 81773946, 81573673, 81001666 (DZ), NIH CA187152 (SH), and Florida Breast Cancer Foundation (SH). AUTHOR INFORMATION AUTHORS AND


AFFILIATIONS * Institute of Interdisciplinary Integrative Medical Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China Dan-Dan Zhang, Yuan Xu & Shuang


Huang * Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL, 32608, USA Yue Li & Shuang Huang * Department of Statistics, Sungkyunkwan


University, Seoul, 03063, South Korea Jaejik Kim Authors * Dan-Dan Zhang View author publications You can also search for this author inPubMed Google Scholar * Yue Li View author


publications You can also search for this author inPubMed Google Scholar * Yuan Xu View author publications You can also search for this author inPubMed Google Scholar * Jaejik Kim View


author publications You can also search for this author inPubMed Google Scholar * Shuang Huang View author publications You can also search for this author inPubMed Google Scholar


CORRESPONDING AUTHORS Correspondence to Dan-Dan Zhang or Shuang Huang. ETHICS DECLARATIONS CONFLICT OF INTEREST The authors declare that they have no conflict of interest. ELECTRONIC


SUPPLEMENTARY MATERIAL SUPPLEMENTAL INFORMATION RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Zhang, DD., Li, Y., Xu, Y. _et al._ Phosphodiesterase


7B/microRNA-200c relationship regulates triple-negative breast cancer cell growth. _Oncogene_ 38, 1106–1120 (2019). https://doi.org/10.1038/s41388-018-0499-2 Download citation * Received: 07


February 2018 * Revised: 27 July 2018 * Accepted: 31 July 2018 * Published: 12 September 2018 * Issue Date: 14 February 2019 * DOI: https://doi.org/10.1038/s41388-018-0499-2 SHARE THIS


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