miR-142 acts as a tumor suppressor in osteosarcoma cell lines by targeting Rac1

  • Authors:
    • Zhonghui Zheng
    • Muliang Ding
    • Jiangdong Ni
    • Deye Song
    • Jun Huang
    • Junjie Wang
  • View Affiliations

  • Published online on: December 22, 2014     https://doi.org/10.3892/or.2014.3687
  • Pages: 1291-1299
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Abstract

Although the 5-year survival rate of osteosarcoma (OS) has risen to ~60-70%, a substantial portion of patients still respond poorly to chemotherapy and have a high risk of relapse or metastasis even after curative resection. In this study, we found that the expression of miR-142 was significantly reduced in OS tissues and OS cell lines, while Ras-related C3 botulinum toxin substrate 1 (Rac1) expression was increased in the OS tissues and OS cell lines compared with expression in the controls. We then demonstrated that miR-142 regulated Rac1 expression at the transcriptional and translational levels by directly targeting its 3'-untranslated region (3'UTR). In addition, by loss- and gain-of function experiments, we investigated the role of miR-142 in OS cell lines and found that miR-142 acted as a tumor suppressor in the OS cell lines and inhibited cell proliferation and cell invasion and arrested cell cycle in the S phase. Furthermore, miR-142 inhibited osteosarcoma cell invasion by inducing E-cadherin expression and reducing expression of matrix metalloproteinase 2 (MMP2) and MMP9. Thus, overexpression of miR-142 and/or knockdown of Rac1 would be a novel target for OS therapy in the future.

References

1 

Kobayashi E, Hornicek FJ and Duan Z: MicroRNA involvement in osteosarcoma. Sarcoma. 2012:3597392012. View Article : Google Scholar : PubMed/NCBI

2 

Bennani-Baiti IM: Epigenetic and epigenomic mechanisms shape sarcoma and other mesenchymal tumor pathogenesis. Epigenomics. 3:715–732. 2011. View Article : Google Scholar : PubMed/NCBI

3 

Geller DS and Gorlick R: Osteosarcoma: a review of diagnosis, management, and treatment strategies. Clin Adv Hematol Oncol. 8:705–718. 2010.

4 

Maire G, Martin JW, Yoshimoto M, Chilton-MacNeill S, Zielenska M and Squire JA: Analysis of miRNA-gene expression-genomic profiles reveals complex mechanisms of microRNA deregulation in osteosarcoma. Cancer Genet. 204:138–146. 2011. View Article : Google Scholar : PubMed/NCBI

5 

Lewis BP, Burge CB and Bartel DP: Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 120:15–20. 2005. View Article : Google Scholar : PubMed/NCBI

6 

Croce CM: Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet. 10:704–714. 2009. View Article : Google Scholar : PubMed/NCBI

7 

Qian S, Ding JY, Xie R, et al: MicroRNA expression profile of bronchioalveolar stem cells from mouse lung. Biochem Biophys Res Commun. 377:668–673. 2008. View Article : Google Scholar : PubMed/NCBI

8 

Lin RJ, Xiao DW, Liao LD, et al: MiR-142–3p as a potential prognostic biomarker for esophageal squamous cell carcinoma. J Surg Oncol. 105:175–182. 2012. View Article : Google Scholar

9 

Namløs HM, Meza-Zepeda LA, Barøy T, et al: Modulation of the osteosarcoma expression phenotype by microRNAs. PLoS One. 7:e480862012. View Article : Google Scholar : PubMed/NCBI

10 

Bid HK, Roberts RD, Manchanda PK and Houghton PJ: RAC1: an emerging therapeutic option for targeting cancer angiogenesis and metastasis. Mol Cancer Ther. 12:1925–1934. 2013. View Article : Google Scholar : PubMed/NCBI

11 

Yukinaga H, Shionyu C, Hirata E, et al: Fluctuation of Rac1 activity is associated with the phenotypic and transcriptional heterogeneity of glioma cells. J Cell Sci. 127:1805–1815. 2014. View Article : Google Scholar : PubMed/NCBI

12 

Zhang H, An F, Tang L and Qiu R: Multiple effects of a novel epothilone analog on cellular processes and signaling pathways regulated by Rac1 GTPase in the human breast cancer cells. Korean J Physiol Pharmacol. 18:109–120. 2014. View Article : Google Scholar : PubMed/NCBI

13 

Chen R, Fu M, Zhang G, et al: Rac1 regulates skin tumors by regulation of keratin 17 through recruitment and interaction with CD11b+Gr1+ cells. Oncotarget. 5:4406–4417. 2014.PubMed/NCBI

14 

Wu L, Cai C, Wang X, Liu M, Li X and Tang H: MicroRNA-142-3p, a new regulator of RAC1, suppresses the migration and invasion of hepatocellular carcinoma cells. FEBS Lett. 585:1322–1330. 2011. View Article : Google Scholar : PubMed/NCBI

15 

Nugent M: MicroRNA function and dysregulation in bone tumors: the evidence to date. Cancer Manag Res. 6:15–25. 2014. View Article : Google Scholar : PubMed/NCBI

16 

Miao J, Wu S, Peng Z, Tania M and Zhang C: MicroRNAs in osteosarcoma: diagnostic and therapeutic aspects. Tumour Biol. 34:2093–2098. 2013. View Article : Google Scholar : PubMed/NCBI

17 

Chai S, Tong M, Ng KY, et al: Regulatory role of miR-142-3p on the functional hepatic cancer stem cell marker CD133. Oncotarget. 5:5725–5735. 2014.PubMed/NCBI

18 

Su YH, Zhou Z, Yang KP, Wang XG, Zhu Y and Fa XE: MIR-142-5p and miR-9 may be involved in squamous lung cancer by regulating cell cycle related genes. Eur Rev Med Pharmacol Sci. 17:3213–3220. 2013.PubMed/NCBI

19 

Dou L, Li J, Zheng D, et al: MicroRNA-142-3p inhibits cell proliferation in human acute lymphoblastic leukemia by targeting the MLL-AF4 oncogene. Mol Biol Rep. 40:6811–6819. 2013. View Article : Google Scholar : PubMed/NCBI

20 

Lin CW, Sun MS, Liao MY, et al: Podocalyxin-like 1 promotes invadopodia formation and metastasis through activation of Rac1/Cdc42/cortactin signaling in breast cancer cells. Carcinogenesis. 35:2425–2435. 2014. View Article : Google Scholar : PubMed/NCBI

21 

Kwanhian W, Lenze D, Alles J, et al: MicroRNA-142 is mutated in ~20% of diffuse large B-cell lymphoma. Cancer Med. 1:141–155. 2012. View Article : Google Scholar

22 

Chen HH, Yu HI, Cho WC and Tarn WY: DDX3 modulates cell adhesion and motility and cancer cell metastasis via Rac1-mediated signaling pathway. Oncogene. Jul 21–2014.(Epub ahead of print). View Article : Google Scholar

23 

Geng S, Zhang X, Chen J, et al: The tumor suppressor role of miR-124 in osteosarcoma. PLoS One. 9:e915662014. View Article : Google Scholar : PubMed/NCBI

24 

Lane J, Martin T, Weeks HP and Jiang WG: Structure and role of WASP and WAVE in Rho GTPase signalling in cancer. Cancer Genomics Proteomics. 11:155–165. 2014.PubMed/NCBI

25 

Yang H, Zhang Y, Zhou Z, Jiang X and Shen A: Transcription factor Snai1-1 induces osteosarcoma invasion and metastasis by inhibiting E-cadherin expression. Oncol Lett. 8:193–197. 2014.PubMed/NCBI

26 

Dong S, Zhao J, Wei J, et al: F-box protein complex FBXL19 regulates TGFβ1-induced E-cadherin downregulation by mediating Rac3 ubiquitination and degradation. Mol Cancer. 13:762014. View Article : Google Scholar

27 

Lee SJ, Jung YH, Oh SY, Yong MS, Ryu JM and Han HJ: Netrin-1 induces MMP-12-dependent E-cadherin degradation via the distinct activation of PKCα and FAK/Fyn in promoting mesenchymal stem cell motility. Stem Cells Dev. 23:1870–1882. 2014. View Article : Google Scholar : PubMed/NCBI

28 

Wen X, Liu H, Yu K and Liu Y: Matrix metalloproteinase 2 expression and survival of patients with osteosarcoma: a meta-analysis. Tumour Biol. 35:845–848. 2014. View Article : Google Scholar

29 

Gyurkó DM, Veres DV, Módos D, Lenti K, Korcsmáros T and Csermely P: Adaptation and learning of molecular networks as a description of cancer development at the systems-level: potential use in anticancer therapies. Semin Cancer Biol. 23:262–269. 2013. View Article : Google Scholar

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March 2015
Volume 33 Issue 3

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APA
Zheng, Z., Ding, M., Ni, J., Song, D., Huang, J., & Wang, J. (2015). miR-142 acts as a tumor suppressor in osteosarcoma cell lines by targeting Rac1. Oncology Reports, 33, 1291-1299. https://doi.org/10.3892/or.2014.3687
MLA
Zheng, Z., Ding, M., Ni, J., Song, D., Huang, J., Wang, J."miR-142 acts as a tumor suppressor in osteosarcoma cell lines by targeting Rac1". Oncology Reports 33.3 (2015): 1291-1299.
Chicago
Zheng, Z., Ding, M., Ni, J., Song, D., Huang, J., Wang, J."miR-142 acts as a tumor suppressor in osteosarcoma cell lines by targeting Rac1". Oncology Reports 33, no. 3 (2015): 1291-1299. https://doi.org/10.3892/or.2014.3687