Tumor Biology

, Volume 35, Issue 11, pp 11137–11145 | Cite as

MicroRNA-486-5p targeting PIM-1 suppresses cell proliferation in breast cancer cells

  • Guoqiang Zhang
  • Zengyan Liu
  • Guanghe Cui
  • Xiaohong Wang
  • Zhenlin Yang
Research Article


MicroRNAs (miRNAs) are emerging as critical regulators in carcinogenesis and tumor progression. Recently, miR-486-5p has been proved to play an important role in several cancers, but its functions in the context of breast cancer (BC) remain unknown. In this study, we found that miR-486-5p expression is significantly downregulated in BC tissues and cell lines. Overexpression of miR-486-5p dramatically suppressed BC cell proliferation in vitro and in vivo, induced G0/G1 arrest, and promoted apoptosis. We subsequently identified the oncogene PIM-1 as a direct target of miR-486-5p in BC. Overexpression of PIM-1 attenuated the function of miR-486-5p in BC cells. Together, we conclude that miR-486-5p exerts its antiproliferative function by directly downregulating PIM-1 expression. This novel miR-486-5p/PIM-1 axis provides insight into the pathogenesis of BC and might be therapeutic targets for prevention or treatment of BC.


miR-486-5p PIM-1 Breast cancer Proliferation 



This work was supported by the National Natural Science Foundation of China (nos. 30973932 and 81173601) and Binzhou Science and Technology Development Plan (no. 2013ZC1708).

Conflicts of interest



  1. 1.
    Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics. CA Cancer J Clin. 2009;59:225–49.PubMedCrossRefGoogle Scholar
  2. 2.
    Guarneri V, Conte P. Metastatic breast cancer: therapeutic options according to molecular subtypes and prior adjuvant therapy. Oncologist. 2009;14:645–56.PubMedCrossRefGoogle Scholar
  3. 3.
    Van Kouwenhove M, Kedde M, Agami R. MicroRNA regulation by RNA-binding proteins and its implications for cancer. Nat Rev Cancer. 2011;11:644–56.PubMedCrossRefGoogle Scholar
  4. 4.
    Körner C, Keklikoglou I, Bender C, Wörner A, Münstermann 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.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Elgamal OA, Park JK, Gusev Y, Azevedo-Pouly AC, Jiang J, Roopra A, et al. Tumor suppressive function of mir-205 in breast cancer is linked to HMGB3 regulation. PLoS One. 2013;8:e76402.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Png KJ, Yoshida M, Zhang XH, Shu W, Lee H, Rimner A, et al. MicroRNA-335 inhibits tumor reinitiation and is silenced through genetic and epigenetic mechanisms in human breast cancer. Genes Dev. 2011;25:226–31.PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Gravgaard KH, Lyng MB, Laenkholm AV, Søkilde R, Nielsen BS, Litman T, et al. The miRNA-200 family and miRNA-9 exhibit differential expression in primary versus corresponding metastatic tissue in breast cancer. Breast Cancer Res Treat. 2012;134:207–17.PubMedCrossRefGoogle Scholar
  8. 8.
    Li L, Luo J, Wang B, Wang D, Xie X, Yuan L, et al. Microrna-124 targets flotillin-1 to regulate proliferation and migration in breast cancer. Mol Cancer. 2013;12:163.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Wu ZS, Wu Q, Wang CQ, Wang XN, Huang J, Zhao JJ, et al. miR-340 inhibition of breast cancer cell migration and invasion through targeting of oncoprotein c-Met. Cancer. 2011;117:2842–52.PubMedCrossRefGoogle Scholar
  10. 10.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Han X, Yan S, Weijie Z, Feng W, Liuxing W, Mengquan L, et al. Critical role of miR-10b in transforming growth factor-β1-induced epithelial-mesenchymal transition in breast cancer. Cancer Gene Ther. 2014;21:60–7.PubMedCrossRefGoogle Scholar
  12. 12.
    Yan GR, Xu SH, Tan ZL, Liu L, He QY. Global identification of miR-373-regulated genes in breast cancer by quantitative proteomics. Proteomics. 2011;11:912–20.PubMedCrossRefGoogle Scholar
  13. 13.
    Huang Q, Gumireddy K, Schrier M, le Sage C, Nagel R, Nair S, et al. The microRNAs miR-373 and miR-520c promote tumour invasion and metastasis. Nat Cell Biol. 2008;10:202–10.PubMedCrossRefGoogle Scholar
  14. 14.
    Selcuklu SD, Donoghue MT, Rehmet K, de Souza Gomes M, Fort A, Kovvuru P, et al. MicroRNA-9 inhibition of cell proliferation and identification of novel miR-9 targets by transcriptome profiling in breast cancer cells. J Biol Chem. 2012;287:29516–28.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Hwang MS, Yu N, Stinson SY, Yue P, Newman RJ, Allan BB, et al. miR-221/222 targets adiponectin receptor 1 to promote the epithelial-to-mesenchymal transition in breast cancer. PLoS One. 2013;8:e66502.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Navon R, Wang H, Steinfeld I, Tsalenko A, Ben-Dor A, Yakhini Z. Novel rank-based statistical methods reveal microRNAs with differential expression in multiple cancer types. PLoS One. 2009;4:e8003.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Dhanasekaran SM, Barrette TR, Ghosh D, Shah R, Varambally S, Kurachi K, et al. Delineation of prognostic biomarkers in prostate cancer. Nature. 2001;412:822–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Valdman A, Fang X, Pang ST, Ekman P, Egevad L. Pim-1 expression in prostatic intraepithelial neoplasia and human prostate cancer. Prostate. 2004;60:367–71.PubMedCrossRefGoogle Scholar
  19. 19.
    Bachmann M, Moroy T. The serine/threonine kinase Pim-1. Int J Biochem Cell Biol. 2005;37:726–30.PubMedCrossRefGoogle Scholar
  20. 20.
    Roh M, Gary B, Song C, Said-Al-Naief N, Tousson A, Kraft A, et al. Overexpression of the oncogenic kinase Pim-1 leads to genomic instability. Cancer Res. 2003;63:8079–84.PubMedGoogle Scholar
  21. 21.
    Roh M, Song C, Kim J, Abdulkadir SA. Chromosomal instability induced by Pim-1 is passage-dependent and associated with dysregulation of cyclin B1. J Biol Chem. 2005;280:40568–77.PubMedCrossRefGoogle Scholar
  22. 22.
    Roh M, Franco OE, Hayward SW, van der Meer R, Abdulkadir SA. A role for polyploidy in the tumorigenicity of Pim-1-expressing human prostate and mammary epithelial cells. PLoS One. 2008;3:e2572.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Smigal C, Jemal A, Ward E, Cokkinides V, Smith R, Howe HL, et al. Trends in breast cancer by race and ethnicity: update 2006. CA Cancer J Clin. 2006;56:168–83.PubMedCrossRefGoogle Scholar
  24. 24.
    Shen J, Liu Z, Todd NW, Zhang H, Liao J, Yu L, et al. Diagnosis of lung cancer in individuals with solitary pulmonary nodules by plasma microRNA biomarkers. BMC Cancer. 2011;11:374.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Tan X, Qin W, Zhang L, Hang J, Li B, Zhang C, et al. A 5-microRNA signature for lung squamous cell carcinoma diagnosis and hsa-miR-31 for prognosis. Clin Cancer Res. 2011;17:6802–11.PubMedCrossRefGoogle Scholar
  26. 26.
    Bansal A, Lee IH, Hong X, Anand V, Mathur SC, Gaddam S, et al. Feasibility of microRNAs as biomarkers for Barrett’s esophagus progression: a pilot cross-sectional, phase 2 biomarker study. Am J Gastroenterol. 2011;106:1055–63.PubMedCrossRefGoogle Scholar
  27. 27.
    Ragusa M, Majorana A, Statello L, Maugeri M, Salito L, Barbagallo D, et al. Specific alterations of microRNA transcriptome and global network structure in colorectal carcinoma after cetuximab treatment. Mol Cancer Ther. 2010;9:3396–409.PubMedCrossRefGoogle Scholar
  28. 28.
    Wang J, Tian X, Han R, Zhang X, Wang X, Shen H, et al. Downregulation of miR-486-5p contributes to tumor progression and metastasis by targeting protumorigenic ARHGAP5 in lung cancer. Oncogene. 2014;33:1181–9.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Oh HK, Tan AL, Das K, Ooi CH, Deng NT, Tan IB, et al. Genomic loss of miR-486 regulates tumor progression and the OLFM4 antiapoptotic factor in gastric cancer. Clin Cancer Res. 2011;17:2657–67.PubMedCrossRefGoogle Scholar
  30. 30.
    Midorikawa Y, Yamamoto S, Tsuji S, Kamimura N, Ishikawa S, Igarashi H, et al. Allelic imbalances and homozygous deletion on 8p23.2 for stepwise progression of hepatocarcinogenesis. Hepatology. 2009;49:513–22.PubMedCrossRefGoogle Scholar
  31. 31.
    Jiang F, Yin Z, Caraway NP, Li R, Katz RL. Genomic profiles in stage I primary non small cell lung cancer using comparative genomic hybridization analysis of cDNA microarrays. Neoplasia. 2004;6:623–35.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J, et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature. 2005;433:769–73.PubMedCrossRefGoogle Scholar
  33. 33.
    Small EM, O’Rourke JR, Moresi V, Sutherland LB, McAnally J, Gerard RD, et al. Regulation of PI3-kinase/Akt signaling by muscle-enriched microRNA-486. Proc Natl Acad Sci U S A. 2010;107:4218–23.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Thomas M, Lange-Grunweller K, Weirauch U, Gutsch D, Aigner A, Grunweller A, et al. The proto-oncogene Pim-1 is a target of miR-33a. Oncogene. 2012;33:918–28.CrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Guoqiang Zhang
    • 1
  • Zengyan Liu
    • 2
  • Guanghe Cui
    • 3
  • Xiaohong Wang
    • 1
  • Zhenlin Yang
    • 1
  1. 1.Department of Thyroid and Breast SurgeryAffiliated Hospital of Binzhou Medical CollegeBinzhouChina
  2. 2.Department of HematologyAffiliated Hospital of Binzhou Medical CollegeBinzhouChina
  3. 3.Department of Ultrasonic MedicineAffiliated Hospital of Binzhou Medical CollegeBinzhouChina

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