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Dual strands of the miR-145 duplex (miR-145-5p and miR-145-3p) regulate oncogenes in lung adenocarcinoma pathogenesis

Abstract

Our original microRNA (miRNA) expression signatures (based on RNA sequencing) revealed that both strands of the miR-145 duplex (miR-145-5p, the guide strand, and miR-145-3p, the passenger strand) were downregulated in several types of cancer tissues. Involvement of passenger strands of miRNAs in cancer pathogenesis is a new concept in miRNA biogenesis. In our continuing analysis of lung adenocarcinoma (LUAD) pathogenesis, we aimed here to identify important oncogenes that were controlled by miR-145-5p and miR-145-3p. Downregulation of miR-145-5p and miR-145-3p was confirmed in LUAD clinical specimens. Functional assays showed that miR-145-3p significantly blocked the malignant abilities in LUAD cells, e.g., cancer cell proliferation, migration and invasion. Thus, the data showed that expression of the passenger strand of the miR-145-duplex acted as an anti-tumor miRNA. In LUAD cells, we identified four possible target genes (LMNB2, NLN, SIX4, and DDC) that might be regulated by both strands of miR-145. Among the possible targets, high expression of LMNB2 predicted a significantly poorer prognosis of LUAD patients (disease-free survival, p = 0.0353 and overall survival, p = 0.0017). Overexpression of LMNB2 was detected in LUAD clinical specimens and its aberrant expression promoted malignant transformation of LUAD cells. Genes regulated by anti-tumor miR-145-5p and miR-145-3p are closely involved in the molecular pathogenesis of LUAD. We suggest that they are promising prognostic markers for this disease. Our approach, based on the roles of anti-tumor miRNAs, will contribute to improved understanding of the molecular pathogenesis of LUAD.

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References

  1. 1.

    Global Burden of Disease Cancer Consortium. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: A systematic analysis for the global burden of disease study. JAMA Oncol. 2017;3:524–48.

    Article  Google Scholar 

  2. 2.

    Travis WD. Pathology of lung cancer. Clin Chest Med. 2011;32:669–92.

    Article  PubMed  Google Scholar 

  3. 3.

    Arai T, Kuroishi T, Saito Y, Kurita Y, Naruke T, Kaneko M. Tumor doubling time and prognosis in lung cancer patients: evaluation from chest films and clinical follow-up study. Jpn J Clin Oncol. 1994;24:199–204.

    PubMed  CAS  Google Scholar 

  4. 4.

    Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018;553:446.

    PubMed  CAS  Google Scholar 

  5. 5.

    Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136:215–33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. 6.

    Gulyaeva LF, Kushlinskiy NE. Regulatory mechanisms of microRNA expression. J Transl Med. 2016;14:143.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. 7.

    Peng Y, Croce CM. The role of microRNAs in human cancer. Signal Transduct Target Ther. 2016;1:15004.

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Ramassone A, Pagotto S, Veronese A, Visone R. Epigenetics and microRNAs in cancer. Int J Mol Sci. 2018;19:E459.

    Article  PubMed  Google Scholar 

  9. 9.

    Koshizuka K, Nohata N, Hanazawa T, Kikkawa N, Arai T, Okato A, et al. Deep sequencing-based microRNA expression signatures in head and neck squamous cell carcinoma: dual strands of pre-miR-150 as antitumor miRNAs. Oncotarget. 2017;8:30288–304.

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Mizuno K, Mataki H, Arai T, Okato A, Kamikawaji K, Kumamoto T, et al. The microRNA expression signature of small cell lung cancer: tumor suppressors of miR-27a-5p and miR-34b-3p and their targeted oncogenes. J Hum Genet. 2017;62:671–8.

    Article  PubMed  CAS  Google Scholar 

  11. 11.

    Arai T, Okato A, Yamada Y, Sugawara S, Kurozumi A, Kojima S, et al. Regulation of NCAPG by miR-99a-3p (passenger strand) inhibits cancer cell aggressiveness and is involved in CRPC. Cancer Med. 2018;7:1988–2002.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. 12.

    Goto Y, Kurozumi A, Arai T, Nohata N, Kojima S, Okato A, et al. Impact of novel miR-145-3p regulatory networks on survival in patients with castration-resistant prostate cancer. Br J Cancer. 2017;117:409–20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. 13.

    Koshizuka K, Hanazawa T, Kikkawa N, Arai T, Okato A, Kurozumi A, et al. Regulation of ITGA3 by the anti-tumor miR-199 family inhibits cancer cell migration and invasion in head and neck cancer. Cancer Sci. 2017;108:1681–92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. 14.

    Okato A, Arai T, Kojima S, Koshizuka K, Osako Y, Idichi T, et al. Dual strands of pre-miR150 (miR1505p and miR1503p) act as antitumor miRNAs targeting SPOCK1 in naive and castration-resistant prostate cancer. Int J Oncol. 2017;51:245–56.

    Article  PubMed  CAS  Google Scholar 

  15. 15.

    Yamada Y, Koshizuka K, Hanazawa T, Kikkawa N, Okato A, Idichi T, et al. Passenger strand of miR-145-3p acts as a tumor-suppressor by targeting MYO1B in head and neck squamous cell carcinoma. Int J Oncol. 2018;52:166–78.

    PubMed  CAS  Google Scholar 

  16. 16.

    Yonemori K, Seki N, Idichi T, Kurahara H, Osako Y, Koshizuka K, et al. The microRNA expression signature of pancreatic ductal adenocarcinoma by RNA sequencing: anti-tumour functions of the microRNA-216 cluster. Oncotarget. 2017;8:70097–115.

    Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Mataki H, Seki N, Mizuno K, Nohata N, Kamikawaji K, Kumamoto T, et al. Dual-strand tumor-suppressor microRNA-145 (miR-145-5p and miR-145-3p) coordinately targeted MTDH in lung squamous cell carcinoma. Oncotarget. 2016;7:72084–98.

    Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Matsushita R, Yoshino H, Enokida H, Goto Y, Miyamoto K, Yonemori M, et al. Regulation of UHRF1 by dual-strand tumor-suppressor microRNA-145 (miR-145-5p and miR-145-3p): Inhibition of bladder cancer cell aggressiveness. Oncotarget. 2016;7:28460–87.

    Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Kamikawaji K, Seki N, Watanabe M, Mataki H, Kumamoto T, Takagi K, et al. Regulation of LOXL2 and SERPINH1 by antitumor microRNA-29a in lung cancer with idiopathic pulmonary fibrosis. J Hum Genet. 2016;61:985–93.

    Article  PubMed  CAS  Google Scholar 

  20. 20.

    Suetsugu T, Koshizuka K, Seki N, Mizuno K, Okato A, Arai T, et al. Downregulation of matrix metalloproteinase 14 by the antitumor miRNA, miR-150-5p, inhibits the aggressiveness of lung squamous cell carcinoma cells. Int J Oncol. 2018;52:913–24.

    PubMed  Google Scholar 

  21. 21.

    Mataki H, Enokida H, Chiyomaru T, Mizuno K, Matsushita R, Goto Y, et al. Downregulation of the microRNA-1/133a cluster enhances cancer cell migration and invasion in lung-squamous cell carcinoma via regulation of Coronin1C. J Hum Genet. 2015;60:53–61.

    Article  PubMed  CAS  Google Scholar 

  22. 22.

    Mizuno K, Seki N, Mataki H, Matsushita R, Kamikawaji K, Kumamoto T, et al. Tumor-suppressive microRNA-29 family inhibits cancer cell migration and invasion directly targeting LOXL2 in lung squamous cell carcinoma. Int J Oncol. 2016;48:450–60.

    Article  PubMed  CAS  Google Scholar 

  23. 23.

    Osako Y, Seki N, Koshizuka K, Okato A, Idichi T, Arai T, et al. Regulation of SPOCK1 by dual strands of pre-miR-150 inhibit cancer cell migration and invasion in esophageal squamous cell carcinoma. J Hum Genet. 2017;62:935–44.

    Article  PubMed  CAS  Google Scholar 

  24. 24.

    Kumamoto T, Seki N, Mataki H, Mizuno K, Kamikawaji K, Samukawa T, et al. Regulation of TPD52 by antitumor microRNA-218 suppresses cancer cell migration and invasion in lung squamous cell carcinoma. Int J Oncol. 2016;49:1870–80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. 25.

    Anaya J. OncoLnc: linking TCGA survival data to mRNAs, miRNAs, and lncRNAs. PeerJ Comput Sci. 2016;2:e67.

  26. 26.

    Kent OA, McCall MN, Cornish TC, Halushka MK. Lessons from miR-143/145: the importance of cell-type localization of miRNAs. Nucleic Acids Res. 2014;42:7528–38.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. 27.

    Morgado AL, Rodrigues CM, Sola S. MicroRNA-145 regulates neural stem cell differentiation through the Sox2-Lin28/let-7 signaling pathway. Stem Cells. 2016;34:1386–95.

    Article  PubMed  CAS  Google Scholar 

  28. 28.

    Xu N, Papagiannakopoulos T, Pan G, Thomson JA, Kosik KS. MicroRNA-145 regulates OCT4, SOX2, and KLF4 and represses pluripotency in human embryonic stem cells. Cell. 2009;137:647–58.

    Article  PubMed  CAS  Google Scholar 

  29. 29.

    Kano M, Seki N, Kikkawa N, Fujimura L, Hoshino I, Akutsu Y, et al. miR-145, miR-133a and miR-133b: tumor-suppressive miRNAs target FSCN1 in esophageal squamous cell carcinoma. Int J Cancer. 2010;127:2804–14.

    Article  PubMed  CAS  Google Scholar 

  30. 30.

    Liu SY, Li XY, Chen WQ, Hu H, Luo B, Shi YX, et al. Demethylation of the MIR145 promoter suppresses migration and invasion in breast cancer. Oncotarget. 2017;8:61731–41.

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    Mei LL, Wang WJ, Qiu YT, Xie XF, Bai J, Shi ZZ. miR-145-5p suppresses tumor cell migration, invasion and epithelial to mesenchymal transition by regulating the Sp1/NF-kappaB signaling pathway in esophageal squamous cell carcinoma. Int J Mol Sci. 2017;18:E1833.

    Article  PubMed  CAS  Google Scholar 

  32. 32.

    Sachdeva M, Zhu S, Wu F, Wu H, Walia V, Kumar S, et al. p53 represses c-Myc through induction of the tumor suppressor miR-145. Proc Natl Acad Sci USA. 2009;106:3207–12.

    Article  PubMed  Google Scholar 

  33. 33.

    Chendrimada TP, Gregory RI, Kumaraswamy E, Norman J, Cooch N, Nishikura K, et al. TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature. 2005;436:740–4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. 34.

    Hutvagner G, Zamore PD. A microRNA in a multiple-turnover RNAi enzyme complex. Science. 2002;297:2056–60.

    Article  PubMed  CAS  Google Scholar 

  35. 35.

    Matranga C, Tomari Y, Shin C, Bartel DP, Zamore PD. Passenger-strand cleavage facilitates assembly of siRNA into Ago2-containing RNAi enzyme complexes. Cell. 2005;123:607–20.

    Article  PubMed  CAS  Google Scholar 

  36. 36.

    Kojima S, Enokida H, Yoshino H, Itesako T, Chiyomaru T, Kinoshita T, et al. The tumor-suppressive microRNA-143/145 cluster inhibits cell migration and invasion by targeting GOLM1 in prostate cancer. J Hum Genet. 2014;59:78–87.

    Article  PubMed  CAS  Google Scholar 

  37. 37.

    Yoshino H, Enokida H, Itesako T, Kojima S, Kinoshita T, Tatarano S, et al. Tumor-suppressive microRNA-143/145 cluster targets hexokinase-2 in renal cell carcinoma. Cancer Sci. 2013;104:1567–74.

    Article  PubMed  CAS  Google Scholar 

  38. 38.

    Prokocimer M, Davidovich M, Nissim-Rafinia M, Wiesel-Motiuk N, Bar DZ, Barkan R, et al. Nuclear lamins: key regulators of nuclear structure and activities. J Cell Mol Med. 2009;13:1059–85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. 39.

    Broers JL, Ramaekers FC. The role of the nuclear lamina in cancer and apoptosis. Adv Exp Med Biol. 2014;773:27–48.

    Article  PubMed  CAS  Google Scholar 

  40. 40.

    Butin-Israeli V, Adam SA, Goldman AE, Goldman RD. Nuclear lamin functions and disease. Trends Genet. 2012;28:464–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. 41.

    Irianto J, Pfeifer CR, Ivanovska IL, Swift J, Discher DE. Nuclear lamins in cancer. Cell Mol Bioeng. 2016;9:258–67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. 42.

    Kong L, Schafer G, Bu H, Zhang Y, Zhang Y, Klocker H. Lamin A/C protein is overexpressed in tissue-invading prostate cancer and promotes prostate cancer cell growth, migration and invasion through the PI3K/AKT/PTEN pathway. Carcinogenesis. 2012;33:751–9.

    Article  PubMed  CAS  Google Scholar 

  43. 43.

    Sakthivel KM, Sehgal P. A novel role of lamins from genetic disease to cancer biomarkers. Oncol Rev. 2016;10:309.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. 44.

    Deng W, Yan M, Yu T, Ge H, Lin H, Li J, et al. Quantitative proteomic analysis of the metastasis-inhibitory mechanism of miR-193a-3p in non-small cell lung cancer. Cell Physiol Biochem. 2015;35:1677–88.

    Article  PubMed  CAS  Google Scholar 

  45. 45.

    Ma Y, Fei L, Zhang M, Zhang W, Liu X, Wang C, et al. Lamin B2 binding to minichromosome maintenance complex component 7 promotes non-small cell lung carcinogenesis. Oncotarget. 2017;8:104813–30.

    PubMed  PubMed Central  Google Scholar 

  46. 46.

    Liu YZ, Wang BS, Jiang YY, Cao J, Hao JJ, Zhang Y, et al. MCMs expression in lung cancer: implication of prognostic significance. J Cancer. 2017;8:3641–7.

    Article  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Nishihara K, Shomori K, Fujioka S, Tokuyasu N, Inaba A, Osaki M, et al. Minichromosome maintenance protein 7 in colorectal cancer: implication of prognostic significance. Int J Oncol. 2008;33:245–51.

    PubMed  CAS  Google Scholar 

  48. 48.

    Simon NE, Schwacha A. The Mcm2-7 replicative helicase: a promising chemotherapeutic target. Biomed Res Int. 2014;2014:549719.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

The present study was supported by KAKENHI grants 17K09660 and 18K09338.

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Correspondence to Naohiko Seki.

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Misono, S., Seki, N., Mizuno, K. et al. Dual strands of the miR-145 duplex (miR-145-5p and miR-145-3p) regulate oncogenes in lung adenocarcinoma pathogenesis. J Hum Genet 63, 1015–1028 (2018). https://doi.org/10.1038/s10038-018-0497-9

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