Tumor Biology

, Volume 35, Issue 9, pp 8565–8572 | Cite as

miR-122/Wnt/β-catenin regulatory circuitry sustains glioma progression

Research Article

Abstract

Malignant glioma is the most common type of human intracranial cancer and has poor prognosis due to its high recurrence and invasiveness. However, the molecular mechanisms underlying its malignant phenotypes have still not been completely explored yet. miR-122 has been well documented to act as a tumor suppressor for hepatocellular carcinoma and breast cancer, but the implication of miR-122 in the progression of glioma is not clear yet. In this study, we found that miR-122 was underexpressed in glioma specimens and glioma cell lines, compared with normal brain tissues and cell lines. The expression of miR-122 levels is inversely correlated with the survival of patients after surgery. Overexpression of miR-122 by an adenoviral vector suppressed the proliferation and colony formation of glioma cells. The in vivo tumorigenicity of U-87 MG cells was also greatly compromised by restoring miR-122. miR-122 suppressed the activation of Wnt/β-catenin pathway in glioma cells. Interestingly, Wnt/β-catenin signaling conversely reduced the expression of miR-122 in glioma cells, maybe in a hepatocyte nuclear factor (HNF)-dependent mechanism. Taken together, we revealed that there is a miR-122/Wnt/β-catenin regulatory circuitry existing in glioma cells that contributes to glioma progression.

Keywords

Glioma miR-122 Wnt/β-catenin Adenovirus 

Notes

Conflicts of interest

None

Supplementary material

13277_2014_2089_MOESM1_ESM.pptx (71 kb)
Supplementary Fig. 1 The survival of patients with low or high level of miR-122 was subjected to Kaplan-Meier survival analysis. 21 patients with the highest miR-122 levels are defined as high miR-122 group, while 21 patients with the lowest miR-122 levels as low miR-122 group. (PPTX 71 kb)
13277_2014_2089_MOESM2_ESM.pptx (45 kb)
Supplementary Fig. 2 Apoptosis of U-87 MG and U-251 MG cells was determined at the indicated time points by cytometrical analysis when Ad-miR122 or Ad-EGFP (10 MOI) was used. The data were shown as means ± SD of three independent experiments. (PPTX 44 kb)
13277_2014_2089_MOESM3_ESM.pptx (57 kb)
Supplementary Fig. 3 miR-122 suppressed the expression of WNT1 by binding its 3UTR. U-87 MG cells were transfected with psiCheck2, psiCheck2-WNT1-3UTR and psiCheck2-WNT1-3UTR-mut. After 12 h, the cells were infected with Ad-miR122 or Ad-EGFP (10 MOI) for 48 h. Relative luciferase expression was assessed and shown as means ± SD of three independent experiments. (PPTX 56 kb)
13277_2014_2089_MOESM4_ESM.pptx (1.8 mb)
Supplementary Fig. 4 Nuclear accumulation of β-catenin was diminished in U-87 MG and U-251 MG cells transfected with Ad-miR122 or Ad-EGFP (10 MOI) for 48 h. (PPTX 1878 kb)

References

  1. 1.
    Goodenberger ML, Jenkins RB. Genetics of adult glioma. Cancer Genet. 2012;205(12):613–21.CrossRefPubMedGoogle Scholar
  2. 2.
    Meister G. miRNAs get an early start on translational silencing. Cell. 2007;131(1):25–8.CrossRefPubMedGoogle Scholar
  3. 3.
    Croce CM, Calin GA. miRNAs, cancer, and stem cell division. Cell. 2005;122(1):6–7.CrossRefPubMedGoogle Scholar
  4. 4.
    Besse A, Sana J, Fadrus P, Slaby O. MicroRNAs involved in chemo- and radioresistance of high-grade gliomas. Tumour Biol. 2013;34(4):1969–78. doi: 10.1007/s13277-013-0772-5.CrossRefPubMedGoogle Scholar
  5. 5.
    Li M, Li J, Liu L, Li W, Yang Y, Yuan J. MicroRNA in human glioma. Cancers (Basel). 2013;5(4):1306–31.CrossRefGoogle Scholar
  6. 6.
    Peng B, Hu S, Jun Q, Luo D, Zhang X, Zhao H, et al. MicroRNA-200b targets CREB1 and suppresses cell growth in human malignant glioma. Mol Cell Biochem. 2013;379(1–2):51–8. doi: 10.1007/s11010-013-1626-6.CrossRefPubMedGoogle Scholar
  7. 7.
    Filipowicz W, Grosshans H. The liver-specific microRNA miR-122: biology and therapeutic potential. Prog Drug Res. 2011;67:221–38.PubMedGoogle Scholar
  8. 8.
    Ma L, Liu J, Liu L, Duan G, Wang Q, Xu Y, et al. Overexpression of the transcription factor MEF2D in hepatocellular cancer sustains malignant character by suppressing G2/M transition genes. Cancer Res. 2014. doi: 10.1158/0008-5472.CAN-13-2171.Google Scholar
  9. 9.
    Ma L, Liu J, Shen J, Liu L, Wu J, Li W, et al. Expression of miR-122 mediated by adenoviral vector induces apoptosis and cell cycle arrest of cancer cells. Cancer Biol Ther. 2010;9(7):554–61.CrossRefPubMedGoogle Scholar
  10. 10.
    Wang B, Wang H, Yang Z. MiR-122 inhibits cell proliferation and tumorigenesis of breast cancer by targeting IGF1R. PLoS One. 2012;7(10):e47053.PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Kanaan Z, Rai SN, Eichenberger MR, Barnes C, Dworkin AM, Weller C, et al. Differential microRNA expression tracks neoplastic progression in inflammatory bowel disease-associated colorectal cancer. Hum Mutat. 2012;33(3):551–60.PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Kunte DP, DelaCruz M, Wali RK, Menon A, Du H, Stypula Y, et al. Dysregulation of microRNAs in colonic field carcinogenesis: implications for screening. PLoS One. 2012;7(9):e45591.PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Qian J, Zhai A, Kao W, Li Y, Song W, Fu Y, et al. Modulation of miR-122 on persistently Borna disease virus infected human oligodendroglial cells. Antivir Res. 2010;87(2):249–56.CrossRefPubMedGoogle Scholar
  14. 14.
    Xu H, He JH, Xiao ZD, Zhang QQ, Chen YQ, Zhou H, et al. Liver-enriched transcription factors regulate microRNA-122 that targets CUTL1 during liver development. Hepatology. 2010;52(4):1431–42. doi: 10.1002/hep.23818.CrossRefPubMedGoogle Scholar
  15. 15.
    Gramantieri L, Ferracin M, Fornari F, Veronese A, Sabbioni S, Liu CG, et al. Cyclin G1 is a target of miR-122a, a microRNA frequently down-regulated in human hepatocellular carcinoma. Cancer Res. 2007;67(13):6092–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Lin CJ, Gong HY, Tseng HC, Wang WL, Wu JL. miR-122 targets an anti-apoptotic gene, Bcl-w, in human hepatocellular carcinoma cell lines. Biochem Biophys Res Commun. 2008;375(3):315–20.CrossRefPubMedGoogle Scholar
  17. 17.
    Tsai WC, Hsu PW, Lai TC, Chau GY, Lin CW, Chen CM, et al. MicroRNA-122, a tumor suppressor microRNA that regulates intrahepatic metastasis of hepatocellular carcinoma. Hepatology. 2009;49(5):1571–82.CrossRefPubMedGoogle Scholar
  18. 18.
    Zeng C, Wang R, Li D, Lin XJ, Wei QK, Yuan Y, et al. A novel GSK-3 beta-C/EBP alpha-miR-122-insulin-like growth factor 1 receptor regulatory circuitry in human hepatocellular carcinoma. Hepatology. 2010;52(5):1702–12.CrossRefPubMedGoogle Scholar
  19. 19.
    Xu J, Zhu X, Wu L, Yang R, Yang Z, Wang Q, et al. MicroRNA-122 suppresses cell proliferation and induces cell apoptosis in hepatocellular carcinoma by directly targeting Wnt/beta-catenin pathway. Liver Int. 2012;32(5):752–60.CrossRefPubMedGoogle Scholar
  20. 20.
    Wang B, Hsu SH, Wang X, Kutay H, Bid HK, Yu J et al. Reciprocal regulation of miR-122 and c-Myc in hepatocellular cancer: role of E2F1 and TFDP2. Hepatology. 2013.Google Scholar
  21. 21.
    Manfe V, Biskup E, Rosbjerg A, Kamstrup M, Skov AG, Lerche CM, et al. miR-122 regulates p53/Akt signalling and the chemotherapy-induced apoptosis in cutaneous T-cell lymphoma. PLoS One. 2012;7(1):e29541.PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Lian JH, Wang WH, Wang JQ, Zhang YH, Li Y. MicroRNA-122 promotes proliferation, invasion and migration of renal cell carcinoma cells through the PI3K/Akt signaling pathway. Asian Pac J Cancer Prev. 2013;14(9):5017–21.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  1. 1.Department of NeurosurgeryHarbin Medical University Second Affiliated HospitalHarbinChina

Personalised recommendations