Skip to main content
SpringerLink
Log in

MiR-142-3p suppresses the proliferation, migration and invasion through inhibition of NR2F6 in lung adenocarcinoma

  • Research Article
  • Published:
Human Cell Aims and scope Submit manuscript

Abstract

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide and lung adenocarcinoma is its main type. MicroRNAs are small, non-coding and single-strand RNAs that regulate gene expression in human cancers. The aim of our study is to investigate the underlying molecular mechanism of miR-142-3p in NSCLC. The expression of miR-142-3p in lung adenocarcinoma tissues and cells was detected by RT-qPCR. Next, cell proliferation, migration, invasion and apoptosis were examined by CCK-8, scratch assay, transwell assay and flow cytometry in A549 and HCC827 cells, respectively. Then, the target of miR-142-3p was predicted by targetscanHuman 7.2 and confirmed using dual-luciferase reporter assay. Additionally, RT-qPCR and western blot were used to detect the expression of NR2F6, MMP2, MMP9 and caspase-3. The results showed that miR-142-3p expression was significantly decreased in tumor tissues and cells. Overexpression of miR-142-3p inhibited the proliferation, migration, invasion and promoted cell apoptosis in vitro, while knockdown of miR-142-3p had reversed function. Furthermore, NR2F6 was identified as a direct target of miR-142-3p, which was negatively correlated with miR-142-3p expression. Finally, miR-142-3p overexpression suppressed the expression of NR2F6, MMP2 and MMP9, but improved caspase-3 expression, while miR-142-3p knockdown got the opposite expression results. Suppressing MMP2 and MMP9 activities inhibited cell invasion. In summary, these findings indicated that miR-142-3p inhibits lung adenocarcinoma cell proliferation, migration and invasion, and enhances cell apoptosis by targeting NR2F6, suggesting that miR-142-3p may be a novel therapeutic target for lung adenocarcinoma treatment.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

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

Similar content being viewed by others

References

  1. Dela Cruz CS, Tanoue LT, Matthay RA. Lung cancer: epidemiology, etiology, and prevention. Clin Chest Med. 2011;32:605–44.

    Article  Google Scholar 

  2. Koudelakova V, Kneblova M, Trojanec R, Drabek J, Hajduch M. Non-small cell lung cancer—genetic predictors. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2013;157:125–36.

    Article  CAS  Google Scholar 

  3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30.

    Article  Google Scholar 

  4. Miller KD, Siegel RL, Lin CC, et al. Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin. 2016;66:271–89.

    Article  Google Scholar 

  5. Bui KT, Cooper WA, Kao S, Boyer M. Targeted molecular treatments in non-small cell lung cancer: a clinical guide for oncologists. J Clin med. 2018;7:192.

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. Farazi TA, Hoell JI, Morozov P, Tuschl T. MicroRNAs in human cancer. Adv Exp Med Biol. 2013;774:1–20.

    Article  CAS  Google Scholar 

  8. Hime GR, Somers WG. Micro-RNA mediated regulation of proliferation, self-renewal and differentiation of mammalian stem cells. Cell Adh Migr. 2009;3:425–32.

    Article  Google Scholar 

  9. Vescovo VD, Grasso M, Barbareschi M, Denti MA. MicroRNAs as lung cancer biomarkers. World J Clin Oncol. 2014;5:604–20.

    Article  Google Scholar 

  10. Shrestha A, Mukhametshina RT, Taghizadeh S, et al. MicroRNA-142 is a multifaceted regulator in organogenesis, homeostasis, and disease. Dev Dyn. 2017;246:285–90.

    Article  CAS  Google Scholar 

  11. Liu X, Sempere LF, Galimberti F, et al. Uncovering growth-suppressive microRNAs in lung cancer. Clin Cancer Res. 2009;15:1177–83.

    Article  CAS  Google Scholar 

  12. Xiao P, Liu WL. MiR-142-3p functions as a potential tumor suppressor directly targeting HMGB1 in non-small-cell lung carcinoma. Int J Clin Exp Pathol. 2015;8:10800–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Cao XC, Yu Y, Hou LK, et al. MiR-142-3p inhibits cancer cell proliferation by targeting CDC25C. Cell Prolif. 2016;49:58–68.

    Article  CAS  Google Scholar 

  14. Nimmo R, Ciau-Uitz A, Ruiz-Herguido C, et al. MiR-142-3p controls the specification of definitive hemangioblasts during ontogeny. Dev Cell. 2013;26:237–49.

    Article  CAS  Google Scholar 

  15. Naqvi AR, Fordham JB, Nares S. MiR-24, miR-30b, and miR-142-3p regulate phagocytosis in myeloid inflammatory cells. J Immunol. 2015;194(4):1916–27.

    Article  CAS  Google Scholar 

  16. Carraro G, Shrestha A, Rostkovius J, et al. MiR-142-3p balances proliferation and differentiation of mesenchymal cells during lung development. Development. 2014;141:1272–81.

    Article  CAS  Google Scholar 

  17. Wu L, Cai C, Wang X, Liu M, Li X, Tang H. MicroRNA-142-3p, a new regulator of RAC1, suppresses the migration and invasion of hepatocellular carcinoma cells. FEBS Lett. 2011;585:1322–30.

    Article  CAS  Google Scholar 

  18. Schwickert A, Weghake E, Brüggemann K, et al. MicroRNA miR-142-3p inhibits breast cancer cell invasiveness by synchronous targeting of WASL, integrin alpha V, and additional cytoskeletal elements. PLoS One. 2015;10:e0143993.

    Article  Google Scholar 

  19. Shen WW, Zeng Z, Zhu WX, Fu GH. MiR-142-3p functions as a tumor suppressor by targeting CD133, ABCG2, and Lgr5 in colon cancer cells. J Mol Med (Berl). 2013;91:989–1000.

    Article  CAS  Google Scholar 

  20. Zhu J, Tian X, Zhang Y, Bai Y, Pei K. MiR-142-3p is a tumor promoter by directly targeting FOXO4 to promote gastric cancer cell growth and suppress cell apoptosis in gastric cancer. Int J Clin Exp Pathol. 2016;9:12079–87.

    CAS  Google Scholar 

  21. Gao X, Xu W, Lu T, Zhou J, Ge X, Hua D. MicroRNA-142-3p promotes cellular invasion of colorectal cancer cells by activation of RAC1. Technol Cancer Res Treat. 2018;17:1533033818790508.

    Article  Google Scholar 

  22. Li Y, Chen D, Jin L, et al. Oncogenic microRNA-142-3p is associated with cellular migration, proliferation and apoptosis in renal cell carcinoma. Oncol Lett. 2016;11:1235–41.

    Article  CAS  Google Scholar 

  23. Lei Z, Xu G, Wang L, et al. MiR-142-3p represses TGF-β-induced growth inhibition through repression of TGFβR1 in non-small cell lung cancer. FASEB J. 2014;28:2696–704.

    Article  CAS  Google Scholar 

  24. Giguère V. Orphan nuclear receptors: from gene to function. Endocr Rev. 1999;20:689–725.

    PubMed  Google Scholar 

  25. Hermann-Kleiter N, Klepsch V, Wallner S, et al. The nuclear orphan receptor NR2F6 is a central checkpoint for cancer immune surveillance. Cell Rep. 2015;12:2072–85.

    Article  CAS  Google Scholar 

  26. Niu C, Sun X, Zhang W, et al. NR2F6 expression correlates with pelvic lymph node metastasis and poor prognosis in early-stage cervical cancer. Int J Mol Sci. 2016;17:E1694.

    Article  Google Scholar 

  27. Li XB, Jiao S, Sun H, et al. The orphan nuclear receptor EAR2 is overexpressed in colorectal cancer and it regulates survivability of colon cancer cells. Cancer Lett. 2011;309:137–44.

    Article  CAS  Google Scholar 

  28. Muscat GE, Eriksson NA, Byth K, et al. Research resource: nuclear receptors as transcriptome: discriminant and prognostic value in breast cancer. Mol Endocrinol. 2013;27:350–65.

    Article  CAS  Google Scholar 

  29. Ichim CV, Atkins HL, Iscove NN, Wells RA. Identification of a role for the nuclear receptor EAR-2 in the maintenance of clonogenic status within the leukemia cell hierarchy. Leukemia. 2011;25:1687–96.

    Article  CAS  Google Scholar 

  30. Klepsch V, Hermann-Kleiter N, Do-Dinh P, et al. Nuclear receptor NR2F6 inhibition potentiates responses to PD-L1/PD-1 cancer immune checkpoint blockade. Nat Commun. 2018;9:1538.

    Article  Google Scholar 

  31. Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell. 2010;141:52–67.

    Article  CAS  Google Scholar 

  32. Jian H, Zhao Y, Liu B, Lu S. SEMA4b inhibits MMP9 to prevent metastasis of non-small cell lung cancer. Tumour Biol. 2014;35:11051–6.

    Article  CAS  Google Scholar 

  33. Wang H, Guan X, Tu Y, 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.

    Article  CAS  Google Scholar 

  34. Porter AG, Jänicke RU. Emerging roles of caspase-3 in apoptosis. Cell Death Differ. 1999;6:99–104.

    Article  CAS  Google Scholar 

  35. Cui R, Kim T, Fassan M, et al. MicroRNA-224 is implicated in lung cancer pathogenesis through targeting caspase-3 and caspase-7. Oncotarget. 2015;6:21802–15.

    PubMed  PubMed Central  Google Scholar 

  36. Sledge GW Jr, Qulali M, Goulet R, et al. Effect of matrix metalloproteinase inhibitor batimastat on breast cancer regrowth and metastasis in athymic mice. J Natl Cancer Inst. 1995;87:1546–50.

    Article  CAS  Google Scholar 

  37. Stamenkovic I. Matrix metalloproteinases in tumor invasion and metastasis. Semin Cancer Biol. 2000;10:415–33.

    Article  CAS  Google Scholar 

  38. Zhang K, Chen D, Jiao X, et al. Slug enhances invasion ability of pancreatic cancer cells through upregulation of matrixmetalloproteinase-9 and actin cytoskeleton remodeling. Lab Invest. 2011;91:426–38.

    Article  CAS  Google Scholar 

  39. Yang XC, Wang X, Luo L, et al. RNA interference suppression of A100A4 reduces the growth and metastatic phenotype of human renal cancer cells via NF-kB-dependent MMP-2 and bcl-2 pathway. Eur Rev Med Pharmacol Sci. 2013;17:1669–80.

    PubMed  Google Scholar 

Download references

Acknowledgements

The present study was funded by the Sanming Project of Shenzhen Health and Family Planning Commission (SZSM201512016), Sanming Project of Medicine in Shenzhen (SZSM201612027) and Shenzhen Science Foundation (JCYJ20170413161913429).

Author information

Author notes

  1. Chang’e Jin, Liang Xiao and Zeqiang Zhou contributed equally as the first authors.

Authors and Affiliations

  1. Department of Respiratory and Critical Care Medicine, Shenzhen People’s Hospital, Second Clinical Medical College of Jinan University, Shenzhen, 518020, Guangdong, China

    Chang’e Jin

  2. Department of Surgery and Oncology, Shenzhen Second People’s Hospital, First Affiliated Hospital to Shenzhen University, Shenzhen, 518035, Guangdong, China

    Liang Xiao, Zeqiang Zhou, Yan Zhu & Geng Tian

  3. Department of Thoracic Surgery, Tangshan Gongren Hospital, No. 27, Wenhua Road, Tangshan, 063000, Hebei, China

    Shuhua Ren

Authors
  1. Chang’e Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Liang Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zeqiang Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yan Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Geng Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shuhua Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shuhua Ren.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interest.

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

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jin, C., Xiao, L., Zhou, Z. et al. MiR-142-3p suppresses the proliferation, migration and invasion through inhibition of NR2F6 in lung adenocarcinoma. Human Cell 32, 437–446 (2019). https://doi.org/10.1007/s13577-019-00258-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13577-019-00258-0

Keywords

Search

Navigation