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Adam12 and lnc015192 act as ceRNAs in breast cancer by regulating miR-34a

Oncogene volume 37, pages 6316–6326 (2018)Cite this article

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Abstract

Long non-coding RNAs (lncRNAs) are reported to play vital roles in the progress of multiple cancers. However, the functions of lncRNAs in breast cancer remain to be discovered. We performed microarrays to identify the differentially expressed mRNAs and lncRNAs in breast tissues with or without miR-34a knockout. To explore the functions of the differentially expressed mRNA and lncRNA in breast cancer, we conducted a series of experiments. We found that Adam12 and lnc015192 were significantly upregulated in miR-34a knockout breast tissues. Knockdown of Adam12 and lnc015192 inhibited breast cancer cell migration, invasion, and epithelial–mesenchymal transition (EMT). Further experiments revealed that lnc015192 regulated Adam12 expression by functioning as a competing endogenous RNA (ceRNA) for miR-34a. In summary, our study demonstrate that Adam12 and lnc015192 promote breast cancer metastasis partly by sponging miR-34a through the ceRNA mechanism.

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References

  1. Kasinski AL, Slack FJ. Epigenetics and genetics. MicroRNAs en route to the clinic: progress in validating and targeting microRNAs for cancer therapy. Nat Rev Cancer. 2011;11:849–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Chang TC, Wentzel EA, Kent OA, Ramachandran K, Mullendore M, Lee KH, et al. Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol Cell. 2007;26:745–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Rokavec M, Oner MG, Li H, Jackstadt R, Jiang L, Lodygin D, et al. IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. J Clin Invest. 2014;124:1853–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Xiao X, Huang X, Ye F, Chen B, Song C, Wen J, et al. The miR-34a-LDHA axis regulates glucose metabolism and tumor growth in breast cancer. Sci Rep. 2016;6:21735.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Batista PJ, Chang HY. Long noncoding RNAs: cellular address codes in development and disease. Cell. 2013;152:1298–307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Huarte M. The emerging role of lncRNAs in cancer. Nat Med. 2015;21:1253–61.

    Article  CAS  Google Scholar 

  7. Tay Y, Rinn J, Pandolfi PP. The multilayered complexity of ceRNA crosstalk and competition. Nature. 2014;505:344–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Song YX, Sun JX, Zhao JH, Yang YC, Shi JX, Wu ZH, et al. Non-coding RNAs participate in the regulatory network of CLDN4 via ceRNA mediated miRNA evasion. Nat Commun. 2017;8:289.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wang J, Voellger B, Benzel J, Schlomann U, Nimsky C, Bartsch JW, et al. Metalloproteinases ADAM12 and MMP-14 are associated with cavernous sinus invasion in pituitary adenomas. Int J Cancer. 2016;139:1327–39.

    Article  CAS  PubMed  Google Scholar 

  10. Kong L, Zhang Y, Ye ZQ, Liu XQ, Zhao SQ, Wei L, et al. CPC: assess the protein-coding potential of transcripts using sequence features and support vector machine. Nucleic Acids Res. 2007;35:W345–9.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Wang L, Park HJ, Dasari S, Wang S, Kocher JP, Li W. CPAT: Coding-Potential Assessment Tool using an alignment-free logistic regression model. Nucleic Acids Res. 2013;41:e74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Qu L, Ding J, Chen C, Wu ZJ, Liu B, Gao Y, et al. Exosome-transmitted lncARSR promotes sunitinib resistance in renal cancer by acting as a competing endogenous RNA. Cancer Cell. 2016;29:653–68.

    Article  CAS  PubMed  Google Scholar 

  13. Liu C, Kelnar K, Liu B, Chen X, Calhoun-Davis T, Li H, et al. The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med. 2011;17:211–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yang P, Li QJ, Feng Y, Zhang Y, Markowitz GJ, Ning S, et al. TGF-beta-miR-34a-CCL22 signaling-induced Treg cell recruitment promotes venous metastases of HBV-positive hepatocellular carcinoma. Cancer Cell. 2012;22:291–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Krzeszinski JY, Wei W, Huynh H, Jin Z, Wang X, Chang TC, et al. miR-34a blocks osteoporosis and bone metastasis by inhibiting osteoclastogenesis and Tgif2. Nature. 2014;512:431–5.

    Article  CAS  PubMed  Google Scholar 

  16. Li L, Yuan L, Luo J, Gao J, Guo J, Xie X. MiR-34a inhibits proliferation and migration of breast cancer through down-regulation of Bcl-2 and SIRT1. Clin Exp Med. 2013;13:109–17.

    Article  CAS  PubMed  Google Scholar 

  17. Bouchie A. First microRNA mimic enters clinic. Nat Biotechnol. 2013;31:577.

    Article  CAS  PubMed  Google Scholar 

  18. Ling H, Fabbri M, Calin GA. MicroRNAs and other non-coding RNAs as targets for anticancer drug development. Nat Rev Drug Discov. 2013;12:847–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wiggins JF, Ruffino L, Kelnar K, Omotola M, Patrawala L, Brown D, et al. Development of a lung cancer therapeutic based on the tumor suppressor microRNA-34. Cancer Res. 2010;70:5923–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Jang E, Kim E, Son HY, Lim EK, Lee H, Choi Y, et al. Nanovesicle-mediated systemic delivery of microRNA-34a for CD44 overexpressing gastric cancer stem cell therapy. Biomaterials. 2016;105:12–24.

    Article  CAS  PubMed  Google Scholar 

  21. Li L, Xie X, Luo J, Liu M, Xi S, Guo J, et al. Targeted expression of miR-34a using the T-VISA system suppresses breast cancer cell growth and invasion. Mol Ther. 2012;20:2326–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Duffy MJ, McKiernan E, O’Donovan N, McGowan PM. Role of ADAMs in cancer formation and progression. Clin Cancer Res. 2009;15:1140–4.

    Article  CAS  PubMed  Google Scholar 

  23. Le Pabic H, Bonnier D, Wewer UM, Coutand A, Musso O, Baffet G, et al. ADAM12 in human liver cancers: TGF-beta-regulated expression in stellate cells is associated with matrix remodeling. Hepatology. 2003;37:1056–66.

    Article  CAS  PubMed  Google Scholar 

  24. Frohlich C, Albrechtsen R, Dyrskjot L, Rudkjaer L, Orntoft TF, Wewer UM. Molecular profiling of ADAM12 in human bladder cancer. Clin Cancer Res. 2006;12:7359–68.

    Article  CAS  PubMed  Google Scholar 

  25. Rao VH, Kandel A, Lynch D, Pena Z, Marwaha N, Deng C, et al. A positive feedback loop between HER2 and ADAM12 in human head and neck cancer cells increases migration and invasion. Oncogene. 2012;31:2888–98.

    Article  CAS  PubMed  Google Scholar 

  26. Roy R, Wewer UM, Zurakowski D, Pories SE, Moses MA. ADAM 12 cleaves extracellular matrix proteins and correlates with cancer status and stage. J Biol Chem. 2004;279:51323–30.

    Article  CAS  PubMed  Google Scholar 

  27. Eckert MA, Santiago-Medina M, Lwin TM, Kim J, Courtneidge SA, Yang J. ADAM12 induction by Twist1 promotes tumor invasion and metastasis via regulation of invadopodia and focal adhesions. J Cell Sci. 2017;130:2036–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kallen AN, Zhou XB, Xu J, Qiao C, Ma J, Yan L, et al. The imprinted H19 lncRNA antagonizes let-7 microRNAs. Mol Cell. 2013;52:101–12.

    Article  CAS  Google Scholar 

  29. Zhu M, Liu J, Xiao J, Yang L, Cai M, Shen H, et al. Lnc-mg is a long non-coding RNA that promotes myogenesis. Nat Commun. 2017;8:14718.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Grelet S, Link LA, Howley B, Obellianne C, Palanisamy V, Gangaraju VK, et al. A regulated PNUTS mRNA to lncRNA splice switch mediates EMT and tumour progression. Nat Cell Biol. 2017;19:1105–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wang L, Bu P, Ai Y, Srinivasan T, Chen HJ, Xiang K, et al. A long non-coding RNA targets microRNA miR-34a to regulate colon cancer stem cell asymmetric division. eLife. 2016;5:pii: e14620.

  32. Dong R, Liu GB, Liu BH, Chen G, Li K, Zheng S, et al. Targeting long non-coding RNA-TUG1 inhibits tumor growth and angiogenesis in hepatoblastoma. Cell Death Dis. 2016;7:e2278.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Liu L, Chen X, Zhang Y, Hu Y, Shen X, Zhu W. Long non-coding RNA TUG1 promotes endometrial cancer development via inhibiting miR-299 and miR-34a-5p | Liu. Oncotarget. 2017;8:31386–94.

    PubMed  PubMed Central  Google Scholar 

  34. Concepcion CP, Han YC, Mu P, Bonetti C, Yao E, D’Andrea A, et al. Intact p53-dependent responses in miR-34-deficient mice. PLoS Genet. 2012;8:e1002797.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by funds from the National Natural Science Foundation of China (81672598 and 81772961).

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  1. These authors contributed equally: Xiaojia Huang, Xinhua Xie, Peng Liu.

Authors and Affiliations

  1. Department of Breast Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 510060, Guangzhou, China

    Xiaojia Huang, Xinhua Xie, Peng Liu, Lu Yang, Bo Chen, Cailu Song, Hailin Tang & Xiaoming Xie

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  1. Xiaojia Huang
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Correspondence to Hailin Tang or Xiaoming Xie.

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Huang, X., Xie, X., Liu, P. et al. Adam12 and lnc015192 act as ceRNAs in breast cancer by regulating miR-34a. Oncogene 37, 6316–6326 (2018). https://doi.org/10.1038/s41388-018-0410-1

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