miR-29b inhibits non-small cell lung cancer progression by targeting STRN4

Abstract

Non-small cell lung cancer (NSCLC) is a malignant tumor with a high fatality, low overall cure, and survival rates worldwide. When only palliative therapy is available, the disease leads to malignant proliferation. Previous studies showed miR-29b serves as an NSCLC suppressor by inhibiting cells proliferation, migration, and invasion. However, the mechanism underlying NSCLC progression remains elusive. In this study, we identified Striatin 4 (STRN4), a target of miR-29b, which serves as a pro-oncogenic protein by promoting cells proliferation, migration, and invasion in NSCLC. Besides, the STRN4 was highly expressed in NSCLC and negatively regulated by miR-29b. Down-regulation of STRN4 inhibits NSCLC cells proliferation, migration, invasion, and promotes apoptosis in vitro, whereas overexpression-induced enhanced cell migration and invasion could be reverved by miR-29b. Notably, overexpression of miR-29b and down-regulation of STRN4 by shRNA suppressed cellular proliferation and delayed tumor progression in vivo. Together, these findings identify a miR-29b/STRN4 regulatory pathway in NSCLC progression, which may provide a new sight for the treatment of NSCLC.

This is a preview of subscription content, access via your institution.

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

Data accessibility

All data necessary to understand and assess the conclusions of this study are available in the main text. There are no restrictions on data availability in the manuscript.

References

  1. 1.

    Torre LA, et al. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.

    Article  PubMed  Google Scholar 

  2. 2.

    Herbst RS, et al. The biology and management of non-small cell lung cancer. Nature. 2018;553(7689):446–54.

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Ambros V. MicroRNA pathways in flies and worms: growth, death, fat, stress, and timing. Cell. 2003;113(6):673–6.

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Volinia S, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci. 2006;103(7):2257–61.

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Jiang H, et al. Diverse roles of miR-29 in cancer. Oncol Rep. 2014;31(4):1509–16.

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Wang Y, et al. The role of miRNA-29 family in cancer. Eur J Cell Biol. 2013;92(3):123–8.

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Suda K, et al. Biological and clinical significance of KRAS mutations in lung cancer: an oncogenic driver that contrasts with EGFR mutation. Cancer Metastasis Rev. 2010;29(1):49–60.

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Thakur S, Brenner C. KRAS-driven miR-29b expression is required for tumor suppressor gene silencing. Oncotarget. 2017;8(43):74755–66.

    PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Ling Q, et al. Special suppressive role of miR-29b in HER2-positive breast cancer cells by targeting Stat3. Am J Transl Res. 2015;7(5):878–90.

    Google Scholar 

  10. 10.

    Zhang L, et al. The relationship between microRNAs and the STAT3-related signaling pathway in cancer. Tumor Biol. 2017;39(7):1–11.

    Google Scholar 

  11. 11.

    Li Y, et al. Chemotherapy-mediated miR-29b expression inhibits the invasion and angiogenesis of cervical cancer. Oncotarget. 2017;8(9):14655–65.

    PubMed  PubMed Central  Google Scholar 

  12. 12.

    Wang H, et al. MicroRNA-29b attenuates non-small cell lung cancer metastasis by targeting matrix metalloproteinase 2 and PTEN. J Exp Clin cancer Res. 2015;34(59):1–12.

    Google Scholar 

  13. 13.

    Chen B, et al. A regulatory circuitry comprising TP53, miR-29 family, and SETDB1 in non-small cell lung cancer. Biosci Rep. 2018;38(5):1–10.

    Google Scholar 

  14. 14.

    Tang Y, et al. Radiation-induced miR-208a increases the proliferation and radioresistance by targeting p21 in human lung cancer cells. J Exp Clin cancer Res. 2016;35(7):1–14.

    Google Scholar 

  15. 15.

    Mizuno K, 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(2):450–60.

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Bartoli M, et al. Interaction of calmodulin with striatin, a WD-repeat protein present in neuronal dendritic spines. J Biol Chem. 1998;273(35):22248–53.

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Gaillard S, et al. Targeting of proteins of the striatin family to dendritic spines: role of the coiled-coil domain. Traffic. 2006;7(1):74–84.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Gaillard S, et al. Striatin, a calmodulin-dependent scaffolding protein, directly binds caveolin-1. FEBS Lett. 2001;508(1):49–52.

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Castets F, et al. Zinedin, SG2NA, and striatin are calmodulin-binding, WD repeat proteins principally expressed in the brain. J Biol Chem. 2000;275(26):19970–7.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Bartoli M, et al. Down-regulation of striatin, a neuronal calmodulin-binding protein, impairs rat locomotor activity. J Neurobiol. 1999;40(2):234–43.

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Kachidian P, et al. Relationships between striatin-containing neurons and cortical or thalamic afferent fibres in the rat striatum. An ultrastructural study by dual labelling. Neuroscience. 1998;85(1):111–22.

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Salin P, et al. Distribution of Striatin, a newly identified calmodulin-binding protein in the rat brain: an in situ hybridization and immunocytochemical study. J Comp Neurol. 1998;397(1):41–59.

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Wong M, et al. Silencing of STRN 4 suppresses the malignant characteristics of cancer cells. Cancer Sci. 2014;105(12):1526–32.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Collins CS, et al. A small interfering RNA screen for modulators of tumor cell motility identifies MAP4K4 as a promigratory kinase. Proc Natl Acad Sci. 2006;103(10):3775–80.

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Hyodo T, et al. Misshapen-like kinase 1 (MINK1) is a novel component of striatin-interacting phosphatase and kinase (STRIPAK) and is required for the completion of cytokinesis. J Biol Chem. 2012;287(30):25019–29.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Shitashige M, et al. Traf2-and Nck-interacting kinase is essential for Wnt signaling and colorectal cancer growth. Cancer Res. 2010;70(12):5024–33.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Fan C, et al. MicroRNA-873 inhibits colorectal cancer metastasis by targeting ELK1 and STRN4. Oncotarget. 2019;10(41):4192–204.

    PubMed  Article  Google Scholar 

  28. 28.

    Sartini D, et al. Pokemon proto-oncogene in oral cancer: potential role in the early phase of tumorigenesis. Oral Dis. 2015;21(4):462–9.

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Rheinbay E, et al. Recurrent and functional regulatory mutations in breast cancer. Nature. 2017;547(7661):55–60.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Molina JR et al., Non-small cell lung cancer epidemiology, risk factors, treatment, and survivorship, Mayo Clinic Proceedings. Amsterdam: Elsevier; 2008, pp. 584–594.

  31. 31.

    Fabbri M, et al. MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci. 2007;104(40):15805–10.

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136(2):215–33.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Fabian MR, et al. Regulation of mRNA translation and stability by microRNAs. Annu Rev Biochem. 2010;79:351–79.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Jiang F, et al. Pro-oncogene pokemon promotes prostate cancer progression by inducing STRN4 expression. J Cancer. 2019;10(8):1833–45.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Madsen CD, et al. STRIPAK components determine mode of cancer cell migration and metastasis. Nat Cell Biol. 2015;17(1):68–80.

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Gautschi O, et al. Cyclin D1 in non-small cell lung cancer: a key driver of malignant transformation. Lung Cancer. 2007;55(1):1–14.

    PubMed  Article  Google Scholar 

  37. 37.

    Li Y, et al. Curcumin inhibits human non-small cell lung cancer A549 cell proliferation through regulation of Bcl-2/Bax and cytochrome C. Asian Pac J Cancer Prev. 2013;14(8):4599–602.

    PubMed  Article  Google Scholar 

  38. 38.

    Jiang H, et al. Paris saponin I induces apoptosis via increasing the Bax/Bcl-2 ratio and caspase-3 expression in gefitinib-resistant non-small cell lung cancer in vitro and in vivo. Mol Med Rep. 2014;9(6):2265–72.

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Chakraborty S, et al. Restoration of p53/miR-34a regulatory axis decreases survival advantage and ensures Bax-dependent apoptosis of non-small cell lung carcinoma cells. FEBS Lett. 2014;588(4):549–59.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Jung O, et al. Timosaponin AIII inhibits migration and invasion of A549 human non-small-cell lung cancer cells via attenuations of MMP-2 and MMP-9 by inhibitions of ERK1/2, Src/FAK and β-catenin signaling pathways. Bioorg Med Chem Lett. 2016;26(16):3963–7.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Bae G-Y, et al. Loss of E-cadherin activates EGFR-MEK/ERK signaling, which promotes invasion via the ZEB1/MMP2 axis in non-small cell lung cancer. Oncotarget. 2013;4(12):2512–22.

    PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

We are grateful to the supporting from the Science and Technology Program for Public Wellbeing of Chengdu (2015-HM01-00224-SF). We thank LetPub (www.letpub.com) for its linguistic assistance during the preparation of this manuscript.

Author information

Affiliations

Authors

Contributions

YX participated in the research design. YX and FZ conducted the experiments. PZ and DP performed data analysis. YX and YS wrote the manuscript.

Corresponding author

Correspondence to Yangmei Shen.

Ethics declarations

Conflict of interest

The authors declare no potential conflicts of interest.

Ethical approval

Written informed consent was obtained from all the participants. The protocols for human specimen studies were approved by the Ethics Committee of the West China Second University Hospital of Sichuan University, and were conducted in agreement with the principles set forth in the Declaration of Helsinki. All animal protocols were approved by the Animal Care and Use Committee of the West China Second University Hospital of Sichuan University.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Xie, Y., Zhao, F., Zhang, P. et al. miR-29b inhibits non-small cell lung cancer progression by targeting STRN4. Human Cell 33, 220–231 (2020). https://doi.org/10.1007/s13577-019-00305-w

Download citation

Keywords

  • miR-29b
  • STRN4
  • Non-small cell lung cancer
  • Progression
  • Overexpression