Skip to main content

Advertisement

Log in

MiR-140-3p suppressed cell growth and invasion by downregulating the expression of ATP8A1 in non-small cell lung cancer

  • Research Article
  • Published:
Tumor Biology

Abstract

MicroRNAs (miRNAs) as a class of small noncoding RNA molecules regulate the expression of targeted gene. The dysregulation of microRNAs is reported to be involved in carcinogenesis and tumor progression. Here, we identified miR-140-3p as a downregulated microRNA in most cancer tissues including lung cancer tissues, compared with their normal counterparts. MiR-140-3p was observed to perform its tumor suppressor function via its inhibition on cell growth, migration and invasion but its induction of cell apoptosis. Furthermore, the growth of non-small-cell lung cancer (NSCLC) cells in nude mouse models were suppressed by overexpression of miR-140-3p. ATP8A1 was demonstrated as a novel direct target of miR-140-3p using a luciferase assay. The increased level of intracellular ATP8A1 protein attenuated the inhibitor role of miR-140-3p in the growth and mobility of NSCLC cell. A regulation mechanism of miR-140-3p for the development and progression of NSCLC through downregulating the ATP8A1 expression was first discovered in the present study.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA: A Cancer J Clini. 2011;61:212–36.

    Google Scholar 

  2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA: A Cancer J Clin. 2011;61:69–90.

    Google Scholar 

  3. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA: A Cancer J Clin. 2012;62:10–29.

    Article  Google Scholar 

  4. Asmis TR, Ding K, Seymour L, Shepherd FA, Leighl NB, Winton TL, et al. Age and comorbidity as independent prognostic factors in the treatment of non small-cell lung cancer: A review of national cancer institute of canada clinical trials group trials. J Clin Oncol: Off J Ame Soc Clin Oncol. 2008;26:54–9.

    Article  CAS  Google Scholar 

  5. Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, et al. Cancer statistics, 2005. CA: A Cancer J Clin. 2005;55:10–30.

    Google Scholar 

  6. Bartel DP. Micrornas: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.

    Article  CAS  PubMed  Google Scholar 

  7. Ambros V. The functions of animal micrornas. Nature. 2004;431:350–5.

    Article  CAS  PubMed  Google Scholar 

  8. Zanetti KA, Haznadar M, Welsh JA, et al. 3′-UTR and functional secretor haplotypes in mannose-binding lectin 2 are associated with increased colon cancer risk in African Americans. Cancer Res. 2012;72(6):1467–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kirigin FF et al. Dynamic microRNA gene transcription and processing during T cell development. J Immunol. 2012;188:3257–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zeng Y, Yi R, Cullen BR. Recognition and cleavage of primary microRNA precursors by the nuclear processing enzyme Drosha. EMBO J. 2005;24:138–48.

    Article  CAS  PubMed  Google Scholar 

  11. Macrae IJ et al. Structural basis for double-stranded RNA processing by Dicer. Science. 2006;311:195–8.

    Article  CAS  PubMed  Google Scholar 

  12. Lau PW, Guiley KZ, De N, Potter CS, Carragher B, MacRae IJ. The molecular architecture of human Dicer. Nat Struct Mol Biol. 2012;19:436–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Pasquinelli AE. MicroRNAs and their targets: recognition, regulation and an emerging reciprocal relationship. Nat Rev Genet. 2012;13:271–82.

    CAS  PubMed  Google Scholar 

  14. Calin GA, Croce CM. Microrna signatures in human cancers. Nat Rev Cancer. 2006;6:857–66.

    Article  CAS  PubMed  Google Scholar 

  15. Croce CM. Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet. 2009;10:704–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Tu Y et al. MicroRNA-218 inhibits glioma invasion, migration, proliferation, and cancer stem-like cell self-renewal by targeting the polycomb group gene Bmi1. Cancer Res. 2013;73(19):6046–55.

    Article  CAS  PubMed  Google Scholar 

  17. Hui W et al. MicroRNA-195 inhibits the proliferation of human glioma cells by directly targeting cyclin D1 and cyclin E1. PLoS One. 2013;8(1), e54932.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Guan S et al. Overexpressed miRNA-137 inhibits human glioma cells growth by targeting Rac1. Cancer Biother Radiopharm. 2013;28(4):327–34.

    Article  CAS  Google Scholar 

  19. Yang TQ et al. MicroRNA-16 inhibits glioma cell growth and invasion through suppression of BCL2 and the nuclear factor-kappaB1/MMP9 signaling pathway. Cancer Sci. 2014;105(3):265–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Rodriguez A, Griffiths-Jones S, Ashurst JL, Bradley A. Identification of mammalian microrna host genes and transcription units. Genome Res. 2004;14:1902–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Tardif G, Pelletier JP, Fahmi H, Hum D, Zhang Y, Kapoor M, et al. Nfat3 and tgf-beta/smad3 regulate the expression of mir-140 in osteoarthritis. Arthritis Res Ther. 2013;15:R197.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sand M, Skrygan M, Sand D, Georgas D, Hahn SA, Gambichler T, et al. Expression of micrornas in basal cell carcinoma. Br J Dermatol. 2012;167:847–55.

    Article  CAS  PubMed  Google Scholar 

  23. Iorio MV, Visone R, Di Leva G, Donati V, Petrocca F, Casalini P, et al. Microrna signatures in human ovarian cancer. Cancer Res. 2007;67:8699–707.

    Article  CAS  PubMed  Google Scholar 

  24. 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: Off J Am Assoc Cancer Res. 2011;17:6802–11.

    Article  CAS  Google Scholar 

  25. Song B, Wang Y, Xi Y, Kudo K, Bruheim S, Botchkina GI, et al. Mechanism of chemoresistance mediated by mir-140 in human osteosarcoma and colon cancer cells. Oncogene. 2009;28:4065–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kai Y, Peng W, Ling W, Jiebing H, Zhuan B. Reciprocal effects between microrna-140-5p and adam10 suppress migration and invasion of human tongue cancer cells. Biochem Biophys Res Commun. 2014;448:308–14.

    Article  CAS  PubMed  Google Scholar 

  27. Yang H, Fang F, Chang R, Yang L. Microrna-140-5p suppresses tumor growth and metastasis by targeting transforming growth factor beta receptor 1 and fibroblast growth factor 9 in hepatocellular carcinoma. Hepatology. 2013;58:205–17.

    Article  CAS  PubMed  Google Scholar 

  28. Yuan Y, Shen Y, Xue L, Fan H. Mir-140 suppresses tumor growth and metastasis of non-small cell lung cancer by targeting insulin-like growth factor 1 receptor. PLoS One. 2013;8, e73604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Usui A, Hoshino I, Akutsu Y, Sakata H, Nishimori T, Murakami K, et al. The molecular role of fra-1 and its prognostic significance in human esophageal squamous cell carcinoma. Cancer. 2012;118:3387–96.

    Article  CAS  PubMed  Google Scholar 

  30. Hu H, Li S, Liu J, Ni B. Microrna-193b modulates proliferation, migration, and invasion of non-small cell lung cancer cells. Acta Biochim Biophys Sin. 2012;44:424–30.

    Article  CAS  PubMed  Google Scholar 

  31. Chen LT, Xu SD, Xu H, Zhang JF, Ning JF, Wang SF. Microrna-378 is associated with non-small cell lung cancer brain metastasis by promoting cell migration, invasion and tumor angiogenesis. Med Oncol. 2012;29:1673–80.

    Article  CAS  PubMed  Google Scholar 

  32. Pai LM, Barcelo G, Schupbach T. D-cbl, a negative regulator of the EGFR pathway, is required for dorsoventral patterning in Drosophila oogenesis. Cell. 2000;103:51–61.

    Article  CAS  PubMed  Google Scholar 

  33. Ashkenazi A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat Rev Cancer. 2002;2:420–30.

    Article  CAS  PubMed  Google Scholar 

  34. Soupene E, Kuypers FA. Identification of an erythroid atp-dependent aminophospholipid transporter. Br J Haematol. 2006;133:436–8.

    Article  CAS  PubMed  Google Scholar 

  35. Soupene E, Kemaladewi DU, Kuypers FA. Atp8a1 activity and phosphatidylserine transbilayer movement. J Recept Ligand Channel Res. 2008;1:1–10.

    Article  CAS  Google Scholar 

  36. Kato U, Inadome H, Yamamoto M, Emoto K, Kobayashi T, Umeda M. Role for phospholipid flippase complex of ATP8A1 and CDC50A proteins in cell migration. J Biol Chem. 2013;288:4922–34.

    Article  CAS  PubMed  Google Scholar 

  37. Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M, et al. Unique microrna molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell. 2006;9:189–98.

    Article  CAS  PubMed  Google Scholar 

  38. Bandi N, Zbinden S, Gugger M, Arnold M, Kocher V, Hasan L, et al. Mir-15a and mir-16 are implicated in cell cycle regulation in a rb-dependent manner and are frequently deleted or down-regulated in non-small cell lung cancer. Cancer Res. 2009;69:5553–9.

    Article  CAS  PubMed  Google Scholar 

  39. Takahashi Y, Forrest AR, Maeno E, Hashimoto T, Daub CO, Yasuda J. Mir-107 and mir-185 can induce cell cycle arrest in human non small cell lung cancer cell lines. PLoS One. 2009;4, e6677.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Calin GA, Ferracin M, Cimmino A, Di Leva G, Shimizu M, Wojcik SE, et al. A microrna signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med. 2005;353:1793–801.

    Article  CAS  PubMed  Google Scholar 

  41. Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, et al. Frequent deletions and down-regulation of micro- rna genes mir15 and mir16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A. 2002;99:15524–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, et al. A microrna expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci U S A. 2006;103:2257–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Saito Y, Liang G, Egger G, Friedman JM, Chuang JC, Coetzee GA, et al. Specific activation of microrna-127 with downregulation of the proto-oncogene bcl6 by chromatin-modifying drugs in human cancer cells. Cancer Cell. 2006;9:435–43.

    Article  CAS  PubMed  Google Scholar 

  44. O’Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT. C-myc-regulated micrornas modulate e2f1 expression. Nature. 2005;435:839–43.

    Article  CAS  PubMed  Google Scholar 

  45. Zhang Y, Eades G, Yao Y, Li Q, Zhou Q. Estrogen receptor alpha signaling regulates breast tumor-initiating cells by down-regulating mir-140 which targets the transcription factor sox2. J Biol Chem. 2012;287:41514–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Daleke DL, Lyles JV. Identification and purification of aminophospholipid flippases. Biochim Biophys Acta. 2000;1486:108–27.

    Article  CAS  PubMed  Google Scholar 

  47. Levano K, Punia V, Raghunath M, Debata PR, Curcio GM, Mogha A, et al. Atp8a1 deficiency is associated with phosphatidylserine externalization in hippocampus and delayed hippocampus-dependent learning. J Neurochem. 2012;120:302–13.

    Article  CAS  PubMed  Google Scholar 

  48. Fadok VA, de Cathelineau A, Daleke DL, Henson PM, Bratton DL. Loss of phospholipid asymmetry and surface exposure of phosphatidylserine is required for phagocytosis of apoptotic cells by macrophages and fibroblasts. J Biol Chem. 2001;276:1071–7.

    Article  CAS  PubMed  Google Scholar 

  49. Martin SJ, Reutelingsperger CP, McGahon AJ, Rader JA, van Schie RC, LaFace DM, et al. Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of bcl-2 and abl. J Exp Med. 1995;182:1545–56.

    Article  CAS  PubMed  Google Scholar 

  50. Fadok VA, Bratton DL, Rose DM, Pearson A, Ezekewitz RA, Henson PM. A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature. 2000;405:85–90.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was support by The development of science and technology plan projects of Chinese medicine in Shandong, No. 2013-209.

Conflicts of interest

None

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Baosheng Li.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dong, W., Yao, C., Teng, X. et al. MiR-140-3p suppressed cell growth and invasion by downregulating the expression of ATP8A1 in non-small cell lung cancer. Tumor Biol. 37, 2973–2985 (2016). https://doi.org/10.1007/s13277-015-3452-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-015-3452-9

Keywords

Navigation