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.
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References
Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.
Ma L, Teruya-Feldstein J, Weinberg RA. Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature. 2007;449:682–8.
Korner C, Keklikoglou I, Bender C, Worner A, Munstermann E, Wiemann S. MicroRNA-31 sensitizes human breast cells to apoptosis by direct targeting of protein kinase C epsilon (PKCepsilon). J Biol Chem. 2013;288:8750–61.
Sossey-Alaoui K, Downs-Kelly E, Das M, Izem L, Tubbs R, Plow EF. WAVE3, an actin remodeling protein, is regulated by the metastasis suppressor microRNA, miR-31, during the invasion-metastasis cascade. Int J Cancer. 2011;129:1331–43.
Luo D, Wilson JM, Harvel N, Liu J, Pei L, Huang S, et al. A systematic evaluation of miRNA:mRNA interactions involved in the migration and invasion of breast cancer cells. J Transl Med. 2013;11:57.
Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol. 2008;10:593–601.
Hong S, Noh H, Teng Y, Shao J, Rehmani H, Ding HF, et al. SHOX2 is a direct miR-375 target and a novel epithelial-to-mesenchymal transition inducer in breast cancer cells. Neoplasia. 2014;16:279–90 e5.
Shimono Y, Zabala M, Cho RW, Lobo N, Dalerba P, Qian D, et al. Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell. 2009;138:592–603.
Cochrane DR, Spoelstra NS, Howe EN, Nordeen SK, Richer JK. MicroRNA-200c mitigates invasiveness and restores sensitivity to microtubule-targeting chemotherapeutic agents. Mol Cancer Ther. 2009;8:1055–66.
Knezevic J, Pfefferle AD, Petrovic I, Greene SB, Perou CM, Rosen JM. Expression of miR-200c in claudin-low breast cancer alters stem cell functionality, enhances chemosensitivity and reduces metastatic potential. Oncogene. 2015;34:5997–6006.
Jones R, Watson K, Bruce A, Nersesian S, Kitz J, Moorehead R. Re-expression of miR-200c suppresses proliferation, colony formation and in vivo tumor growth of murine claudin-low mammary tumor cells. Oncotarget. 2017;8:23727–49.
Bender AT, Beavo JA. Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev. 2006;58:488–520.
Maurice DH, Ke H, Ahmad F, Wang Y, Chung J, Manganiello VC. Advances in targeting cyclic nucleotide phosphodiesterases. Nat Rev Drug Discov. 2014;13:290–314.
Levy I, Horvath A, Azevedo M, de Alexandre RB, Stratakis CA. Phosphodiesterase function and endocrine cells: links to human disease and roles in tumor development and treatment. Curr Opin Pharmacol. 2011;11:689–97.
Shimizu K, Murata T, Watanabe Y, Sato C, Morita H, Tagawa T. Characterization of phosphodiesterase 1 in human malignant melanoma cell lines. Anticancer Res. 2009;29:1119–22.
Zhang L, Murray F, Zahno A, Kanter JR, Chou D, Suda R, et al. Cyclic nucleotide phosphodiesterase profiling reveals increased expression of phosphodiesterase 7B in chronic lymphocytic leukemia. Proc Natl Acad Sci USA. 2008;105:19532–7.
Zhang L, Murray F, Rassenti LZ, Pu M, Kelly C, Kanter JR, et al. Cyclic nucleotide phosphodiesterase 7B mRNA: an unfavorable characteristic in chronic lymphocytic leukemia. Int J Cancer. 2011;129:1162–9.
Drees M, Zimmermann R, Eisenbrand G. 3’,5’-Cyclic nucleotide phosphodiesterase in tumor cells as potential target for tumor growth inhibition. Cancer Res. 1993;53:3058–61.
Cho-Chung YS, Nesterova MV. Tumor reversion: protein kinase A isozyme switching. Ann N Y Acad Sci. 2005;1058:76–86.
Savai R, Pullamsetti SS, Banat GA, Weissmann N, Ghofrani HA, Grimminger F, et al. Targeting cancer with phosphodiesterase inhibitors. Expert Opin Investig Drugs. 2010;19:117–31.
Li Y, Zhang M, Chen H, Dong Z, Ganapathy V, Thangaraju M, et al. Ratio of miR-196s to HOXC8 messenger RNA correlates with breast cancer cell migration and metastasis. Cancer Res. 2010;70:7894–904.
Dicitore A, Grassi ES, Caraglia M, Borghi MO, Gaudenzi G, Hofland LJ, et al. The cAMP analogs have potent anti-proliferative effects on medullary thyroid cancer cell lines. Endocrine. 2016;51:101–12.
McEwan DG, Brunton VG, Baillie GS, Leslie NR, Houslay MD, Frame MC. Chemoresistant KM12C colon cancer cells are addicted to low cyclic AMP levels in a phosphodiesterase 4-regulated compartment via effects on phosphoinositide 3-kinase. Cancer Res. 2007;67:5248–57.
Wang W, Li Y, Zhu JY, Fang D, Ding HF, Dong Z, et al. Triple negative breast cancer development can be selectively suppressed by sustaining an elevated level of cellular cyclic AMP through simultaneously blocking its efflux and decomposition. Oncotarget. 2016;7:87232–45.
Chen H, Zhu G, Li Y, Padia RN, Dong Z, Pan ZK, et al. Extracellular signal-regulated kinase signaling pathway regulates breast cancer cell migration by maintaining slug expression. Cancer Res. 2009;69:9228–35.
Hu Q, Lu YY, Noh H, Hong S, Dong Z, Ding HF, et al. Interleukin enhancer-binding factor 3 promotes breast tumor progression by regulating sustained urokinase-type plasminogen activator expression. Oncogene. 2013;32:3933–43.
Wolfrum C, Shi S, Jayaprakash KN, Jayaraman M, Wang G, Pandey RK, et al. Mechanisms and optimization of in vivo delivery of lipophilic siRNAs. Nat Biotechnol. 2007;25:1149–57.
Naviglio S, Di Gesto D, Romano M, Sorrentino A, Illiano F, Sorvillo L, et al. Leptin enhances growth inhibition by cAMP elevating agents through apoptosis of MDA-MB-231 breast cancer cells. Cancer Biol Ther. 2009;8:1183–90.
Naviglio S, Di Gesto D, Illiano F, Chiosi E, Giordano A, Illiano G, et al. Leptin potentiates antiproliferative action of cAMP elevation via protein kinase A down-regulation in breast cancer cells. J Cell Physiol. 2010;225:801–9.
Song C, Liu LZ, Pei XQ, Liu X, Yang L, Ye F, et al. miR-200c inhibits breast cancer proliferation by targeting KRAS. Oncotarget. 2015;6:34968–78.
Hurteau GJ, Carlson JA, Spivack SD, Brock GJ. Overexpression of the microRNA hsa-miR-200c leads to reduced expression of transcription factor 8 and increased expression of E-cadherin. Cancer Res. 2007;67:7972–6.
Radisky DC. miR-200c at the nexus of epithelial-mesenchymal transition, resistance to apoptosis, and the breast cancer stem cell phenotype. Breast Cancer Res. 2011;13:110.
Howe EN, Cochrane DR, Richer JK. Targets of miR-200c mediate suppression of cell motility and anoikis resistance. Breast Cancer Res. 2011;13:R45.
Feng ZM, Qiu J, Chen XW, Liao RX, Liao XY, Zhang LP, et al. Essential role of miR-200c in regulating self-renewal of breast cancer stem cells and their counterparts of mammary epithelium. BMC Cancer. 2015;15:645.
Lim YY, Wright JA, Attema JL, Gregory PA, Bert AG, Smith E, et al. Epigenetic modulation of the miR-200 family is associated with transition to a breast cancer stem-cell-like state. J Cell Sci. 2013;126(Pt 10):2256–66.
Lin J, Liu C, Gao F, Mitchel RE, Zhao L, Yang Y, et al. miR-200c enhances radiosensitivity of human breast cancer cells. J Cell Biochem. 2013;114:606–15.
Sun Q, Liu T, Yuan Y, Guo Z, Xie G, Du S, et al. MiR-200c inhibits autophagy and enhances radiosensitivity in breast cancer cells by targeting UBQLN1. Int J Cancer. 2015;136:1003–12.
Kopp F, Oak PS, Wagner E, Roidl A. miR-200c sensitizes breast cancer cells to doxorubicin treatment by decreasing TrkB and Bmi1 expression. PLoS One. 2012;7:e50469.
Liu J, Meng T, Yuan M, Wen L, Cheng B, Liu N, et al. MicroRNA-200c delivered by solid lipid nanoparticles enhances the effect of paclitaxel on breast cancer stem cell. Int J Nanomed. 2016;11:6713–25.
Damiano V, Brisotto G, Borgna S, di Gennaro A, Armellin M, Perin T, et al. Epigenetic silencing of miR-200c in breast cancer is associated with aggressiveness and is modulated by ZEB1. Genes Chromosomes Cancer. 2017;56:147–58.
Park SM, Gaur AB, Lengyel E, Peter ME. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev. 2008;22:894–907.
Li JH, Liu S, Zhou H, Qu LH, Yang JH. starBasev2.0: decoding miRNA-ceRNA, miRNA-ncRNA and protein-RNA interaction networks from large-scale CLIP-Seq data. Nucleic Acids Res. 2014;42(Database issue):D92–7.
Karagkouni D, Paraskevopoulou MD, Chatzopoulos S, Vlachos IS, Tastsoglou S, Kanellos I, et al. DIANA-TarBasev8: a decade-long collection of experimentally supported miRNA-gene interactions. Nucleic Acids Res. 2018;46(D1):D239–D45.
Yi Y, Zhao Y, Li C, Zhang L, Huang H, Li Y, et al. RAID v2.0: an updated resource of RNA-associated interactions across organisms. Nucleic Acids Res. 2017;45(D1):D115–D8.
Kopp F, Wagner E, Roidl A. The proto-oncogene KRAS is targeted by miR-200c. Oncotarget. 2014;5:185–95.
Tamura M, Sasaki Y, Kobashi K, Takeda K, Nakagaki T, Idogawa M, et al. CRKL oncogene is downregulated by p53 through miR-200s. Cancer Sci. 2015;106:1033–40.
Fang C, Dong HJ, Zou ZJ, Fan L, Wang L, Zhang R, et al. High expression of cyclic nucleotide phosphodiesterase 7B mRNA predicts poor prognosis in mantle cell lymphoma. Leuk Res. 2013;37:536–40.
Brooks MD, Jackson E, Warrington NM, Luo J, Forys JT, Taylor S, et al. PDE7B is a novel, prognostically significant mediator of glioblastoma growth whose expression is regulated by endothelial cells. PLoS ONE. 2014;9:e107397.
Cho-Chung YS, Clair T, Bodwin JS, Berghoffer B. Growth arrest and morphological change of human breast cancer cells by dibutyryl cyclic AMP and L-arginine. Science (New York, NY). 1981;214:77–9.
Kim SN, Ahn YH, Kim SG, Park SD, Cho-Chung YS, Hong SH. 8-Cl-cAMP induces cell cycle-specific apoptosis in human cancer cells. Int J Cancer J Int du Cancer. 2001;93:33–41.
Pattabiraman DR, Bierie B, Kober KI, Thiru P, Krall JA, Zill C, et al. Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability. Sci (New York, NY). 2016;351:aad3680.
Zheng Q, Zhang D, Yang YU, Cui X, Sun J, Liang C, et al. MicroRNA-200c impairs uterine receptivity formation by targeting FUT4 andalpha1,3-fucosylation. Cell Death Differ. 2017;24:2161–72.
Hong S, Noh H, Chen H, Padia R, Pan ZK, Su SB, et al. Signaling by p38 MAPK stimulates nuclear localization of the microprocessor component p68 for processing of selected primary microRNAs. Sci Signal. 2013;6:ra16.
Yang L, Fang D, Chen H, Lu Y, Dong Z, Ding HF, et al. Cyclin-dependent kinase 2 is an ideal target for ovary tumors with elevated cyclin E1 expression. Oncotarget. 2015;6:20801–12.
Budczies J, Klauschen F, Sinn BV, Gyorffy B, Schmitt WD, Darb-Esfahani S, et al. Cutoff Finder: a comprehensive and straightforward Web application enabling rapid biomarker cutoff optimization. PLoS ONE. 2012;7:e51862.
Acknowledgements
This work was supported by funding from NSF of China 81773946, 81573673, 81001666 (DZ), NIH CA187152 (SH), and Florida Breast Cancer Foundation (SH).
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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
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DOI: https://doi.org/10.1038/s41388-018-0499-2
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