MicroRNA-200b inhibits the growth and metastasis of glioma cells via targeting ZEB2

  • Authors:
    • Jian Li
    • Jian Yuan
    • Xianrui Yuan
    • Jie Zhao
    • Zhiping Zhang
    • Ling Weng
    • Jingping Liu
  • View Affiliations

  • Published online on: November 26, 2015     https://doi.org/10.3892/ijo.2015.3267
  • Pages: 541-550
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Abstract

MicroRNAs (miRs) have been found to play important roles in mediating a variety of biological processes in human cancers, including tumor cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT). In the present study, we aimed to investigate the putative role of miR‑200b in the progression of glioma. Real-time RT-PCR data showed that the miR‑200b levels were frequently reduced in primary glioma tissues (n=88) and cell lines, when compared to normal brain tissues (n=25). Moreover, decreased miR‑200b level was tightly associated with the malignant progression of glioma. Overexpression of miR‑200b significantly suppressed cell proliferation, migration, invasion and EMT in glioma U251 and U87 cells. Luciferase reporter assay data further identified ZEB2 as a direct target of miR‑200b, and the protein expression of ZEB2 was markedly reduced after overexpression of miR‑200b in U251 and U87 cells. Furthermore, restoration of ZEB2 effectively reversed the reduced expression of ZEB2, as well as the suppressive effects of miR‑200b overexpression on the proliferation, migration, invasion and EMT in glioma U251 and U87 cells. Moreover, in vivo study showed that overexpression of miR‑200b significantly inhibited tumorigenesis as well as the tumor growth of glioma cells, and effectively protected nude mice from tumor-induced death. Taken together these findings suggest that miR‑200b has suppressive effects on the proliferation, migration, invasion and EMT of glioma cells, partly at least, via targeting ZEB2. Therefore, miR‑200b acts as a novel tumor suppressor in glioma, and thus may become a promising therapeutic candidate for glioma.

References

1 

Goodenberger ML and Jenkins RB: Genetics of adult glioma. Cancer Genet. 205:613–621. 2012. View Article : Google Scholar : PubMed/NCBI

2 

Agarwal S, Sane R, Oberoi R, Ohlfest JR and Elmquist WF: Delivery of molecularly targeted therapy to malignant glioma, a disease of the whole brain. Expert Rev Mol Med. 13:e172011. View Article : Google Scholar : PubMed/NCBI

3 

Stewart LA: Chemotherapy in adult high-grade glioma: A systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet. 359:1011–1018. 2002. View Article : Google Scholar : PubMed/NCBI

4 

Zhu VF, Yang J, Lebrun DG and Li M: Understanding the role of cytokines in Glioblastoma Multiforme pathogenesis. Cancer Lett. 316:139–150. 2012. View Article : Google Scholar

5 

Pulkkanen KJ and Yla-Herttuala S: Gene therapy for malignant glioma: Current clinical status. Mol Ther. 12:585–598. 2005. View Article : Google Scholar : PubMed/NCBI

6 

Moss EG: MicroRNAs: Hidden in the genome. Curr Biol. 12:R138–R140. 2002. View Article : Google Scholar : PubMed/NCBI

7 

Choi E, Choi E and Hwang KC: MicroRNAs as novel regulators of stem cell fate. World J Stem Cells. 5:172–187. 2013. View Article : Google Scholar : PubMed/NCBI

8 

Lujambio A, Calin GA, Villanueva A, Ropero S, Sanchez-Cespedes M, Blanco D, Montuenga LM, Rossi S, Nicoloso MS, Faller WJ, et al: A microRNA DNA methylation signature for human cancer metastasis. Proc Natl Acad Sci USA. 105:13556–13561. 2008. View Article : Google Scholar : PubMed/NCBI

9 

Calin GA and Croce CM: MicroRNA signatures in human cancers. Nat Rev Cancer. 6:857–866. 2006. View Article : Google Scholar : PubMed/NCBI

10 

Men D, Liang Y and Chen L: Decreased expression of microRNA-200b is an independent unfavorable prognostic factor for glioma patients. Cancer Epidemiol. 38:152–156. 2014. View Article : Google Scholar : PubMed/NCBI

11 

Liu Q, Tang H, Liu X, Liao Y, Li H, Zhao Z, Yuan X and Jiang W: miR-200b as a prognostic factor targets multiple members of RAB family in glioma. Med Oncol. 31:8592014. View Article : Google Scholar : PubMed/NCBI

12 

Peng B, Hu S, Jun Q, Luo D, Zhang X, Zhao H and Li D: MicroRNA-200b targets CREB1 and suppresses cell growth in human malignant glioma. Mol Cell Biochem. 379:51–58. 2013. View Article : Google Scholar : PubMed/NCBI

13 

Remacle JE, Kraft H, Lerchner W, Wuytens G, Collart C, Verschueren K, Smith JC and Huylebroeck D: New mode of DNA binding of multi-zinc finger transcription factors: deltaEF1 family members bind with two hands to two target sites. EMBO J. 18:5073–5084. 1999. View Article : Google Scholar : PubMed/NCBI

14 

Beuran M, Negoi I, Paun S, Ion AD, Bleotu C, Negoi RI and Hostiuc S: The epithelial to mesenchymal transition in pancreatic cancer: A systematic review. Pancreatology. 15:217–225. 2015. View Article : Google Scholar : PubMed/NCBI

15 

Zielinska HA, Bahl A, Holly JM and Perks CM: Epithelialto-mesenchymal transition in breast cancer: A role for insulin-like growth factor I and insulin-like growth factor-binding protein 3? Breast Cancer (Dove Med Press). 7:9–19. 2015.

16 

Ye Y, Xiao Y, Wang W, Yearsley K, Gao JX, Shetuni B and Barsky SH: ERalpha signaling through slug regulates E-cadherin and EMT. Oncogene. 29:1451–1462. 2010. View Article : Google Scholar : PubMed/NCBI

17 

Nam EH, Lee Y, Park YK, Lee JW and Kim S: ZEB2 upregulates integrin alpha5 expression through cooperation with Sp1 to induce invasion during epithelial-mesenchymal transition of human cancer cells. Carcinogenesis. 33:563–571. 2012. View Article : Google Scholar : PubMed/NCBI

18 

Qi S, Song Y, Peng Y, Wang H, Long H, Yu X, Li Z, Fang L, Wu A, Luo W, et al: ZEB2 mediates multiple pathways regulating cell proliferation, migration, invasion, and apoptosis in glioma. PLoS One. 7:e388422012. View Article : Google Scholar : PubMed/NCBI

19 

Liu Z, Long X, Chao C, Yan C, Wu Q, Hua S, Zhang Y, Wu A and Fang W: Knocking down CDK4 mediates the elevation of let-7c suppressing cell growth in nasopharyngeal carcinoma. BMC Cancer. 14:2742014. View Article : Google Scholar : PubMed/NCBI

20 

Liu B, Che W, Xue J, Zheng C, Tang K, Zhang J, Wen J and Xu Y: SIRT4 prevents hypoxia-induced apoptosis in H9c2 cardiomyoblast cells. Cell Physiol Biochem. 32:655–662. 2013. View Article : Google Scholar : PubMed/NCBI

21 

An L, Liu Y, Wu A and Guan Y: microRNA-124 inhibits migration and invasion by down-regulating ROCK1 in glioma. PLoS One. 8:e694782013. View Article : Google Scholar : PubMed/NCBI

22 

Gabriely G, Wurdinger T, Kesari S, Esau CC, Burchard J, Linsley PS and Krichevsky AM: MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators. Mol Cell Biol. 28:5369–5380. 2008. View Article : Google Scholar : PubMed/NCBI

23 

Rani SB, Rathod SS, Karthik S, Kaur N, Muzumdar D and Shiras AS: MiR-145 functions as a tumor-suppressive RNA by targeting Sox9 and adducin 3 in human glioma cells. Neuro Oncol. 15:1302–1316. 2013. View Article : Google Scholar : PubMed/NCBI

24 

Ning X, Shi Z, Liu X, Zhang A, Han L, Jiang K, Kang C and Zhang Q: DNMT1 and EZH2 mediated methylation silences the microRNA-200b/a/429 gene and promotes tumor progression. Cancer Lett. 359:198–205. 2015. View Article : Google Scholar : PubMed/NCBI

25 

Williams LV, Veliceasa D, Vinokour E and Volpert OV: miR-200b inhibits prostate cancer EMT, growth and metastasis. PLoS One. 8:e839912013. View Article : Google Scholar

26 

Yu J, Lu Y, Cui D, Li E, Zhu Y, Zhao Y, Zhao F and Xia S: miR-200b suppresses cell proliferation, migration and enhances chemosensitivity in prostate cancer by regulating Bmi-1. Oncol Rep. 31:910–918. 2014.

27 

Yoneyama K, Ishibashi O, Kawase R, Kurose K and Takeshita T: miR-200a, miR-200b and miR-429 are onco-miRs that target the PTEN gene in endometrioid endometrial carcinoma. Anticancer Res. 35:1401–1410. 2015.PubMed/NCBI

28 

Zhang Z, Yang C, Gao W, Chen T, Qian T, Hu J and Tan Y: FOXA2 attenuates the epithelial to mesenchymal transition by regulating the transcription of E-cadherin and ZEB2 in human breast cancer. Cancer Lett. 361:240–250. 2015. View Article : Google Scholar : PubMed/NCBI

29 

Li H, Xu L, Zhao L, Ma Y, Zhu Z, Liu Y and Qu X: Insulin-like growth factor-I induces epithelial to mesenchymal transition via GSK-3beta and ZEB2 in the BGC-823 gastric cancer cell line. Oncol Lett. 9:143–148. 2015.

30 

Chen Z, Tang ZY, He Y, Liu LF, Li DJ and Chen X: miRNA-205 is a candidate tumor suppressor that targets ZEB2 in renal cell carcinoma. Oncol Res Treat. 37:658–664. 2014. View Article : Google Scholar : PubMed/NCBI

31 

Usova EV, Kopantseva MR, Kostina MB, Van'Kovich AN, Egorov VI and Kopantsev EP: Expression of the ZEB2 gene in pancreatic stromal cells in pancreatic ductal adenocarcinoma, pancreatitis, and normal state. Dokl Biol Sci. 448:61–64. 2013. View Article : Google Scholar : PubMed/NCBI

32 

Chu PY, Hu FW, Yu CC, Tsai LL, Yu CH, Wu BC, Chen YW, Huang PI and Lo WL: Epithelial-mesenchymal transition transcription factor ZEB1/ZEB2 co-expression predicts poor prognosis and maintains tumor-initiating properties in head and neck cancer. Oral Oncol. 49:34–41. 2013. View Article : Google Scholar

33 

Xia M, Hu M, Wang J, Xu Y, Chen X, Ma Y and Su L: Identification of the role of Smad interacting protein 1 (SIP1) in glioma. J Neurooncol. 97:225–232. 2010. View Article : Google Scholar

34 

Yang X, Wang J, Qu S, Zhang H, Ruan B, Gao Y, Ma B, Wang X, Wu N, Li X, et al: MicroRNA-200a suppresses metastatic potential of side population cells in human hepatocellular carcinoma by decreasing ZEB2. Oncotarget. 6:7918–7929. 2015. View Article : Google Scholar : PubMed/NCBI

35 

Guo F, Cogdell D, Hu L, Yang D, Sood AK, Xue F and Zhang W: miR-101 suppresses the epithelial-to-mesenchymal transition by targeting ZEB1 and ZEB2 in ovarian carcinoma. Oncol Rep. 31:2021–2028. 2014.PubMed/NCBI

36 

You J, Li Y, Fang N, Liu B, Zu L, Chang R, Li X and Zhou Q: MiR-132 suppresses the migration and invasion of lung cancer cells via targeting the EMT regulator ZEB2. PLoS One. 9:e918272014. View Article : Google Scholar : PubMed/NCBI

37 

Kurashige J, Kamohara H, Watanabe M, Hiyoshi Y, Iwatsuki M, Tanaka Y, Kinoshita K, Saito S, Baba Y and Baba H: MicroRNA-200b regulates cell proliferation, invasion, and migration by directly targeting ZEB2 in gastric carcinoma. Ann Surg Oncol. 19(Suppl 3): S656–S664. 2012. View Article : Google Scholar : PubMed/NCBI

38 

Fang S, Zeng X, Zhu W, Tang R, Chao Y and Guo L: Zinc finger E-box-binding homeobox 2 (ZEB2) regulated by miR-200b contributes to multi-drug resistance of small cell lung cancer. Exp Mol Pathol. 96:438–444. 2014. View Article : Google Scholar : PubMed/NCBI

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February 2016
Volume 48 Issue 2

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Copy and paste a formatted citation
APA
Li, J., Yuan, J., Yuan, X., Zhao, J., Zhang, Z., Weng, L., & Liu, J. (2016). MicroRNA-200b inhibits the growth and metastasis of glioma cells via targeting ZEB2. International Journal of Oncology, 48, 541-550. https://doi.org/10.3892/ijo.2015.3267
MLA
Li, J., Yuan, J., Yuan, X., Zhao, J., Zhang, Z., Weng, L., Liu, J."MicroRNA-200b inhibits the growth and metastasis of glioma cells via targeting ZEB2". International Journal of Oncology 48.2 (2016): 541-550.
Chicago
Li, J., Yuan, J., Yuan, X., Zhao, J., Zhang, Z., Weng, L., Liu, J."MicroRNA-200b inhibits the growth and metastasis of glioma cells via targeting ZEB2". International Journal of Oncology 48, no. 2 (2016): 541-550. https://doi.org/10.3892/ijo.2015.3267