Tumor Biology

, Volume 37, Issue 1, pp 511–519 | Cite as

miR-125/Pokemon auto-circuit contributes to the progression of hepatocellular carcinoma

  • Jing Kong
  • Xiaoping Liu
  • Xiangqian Li
  • Jinsheng Wu
  • Ning Wu
  • Jun Chen
  • Fang Fang
Research Article

Abstract

Hepatocellular carcinoma (HCC) is a type of human malignant tumor occurring in hepatic tissues with high mortality. Patients benefit little from current therapeutic modalities, at least partially due to the lack of complete elucidation of molecular network regulating HCC. miR-125 and Pokemon are well-recognized tumor suppressor and oncogenes for HCC, respectively. However, the underlying mechanism by which the two genes exert their functions and the relationship between miR-125 and Pokemon is still unexplored yet. In this study, we found that there is an inverse association between miR-125 and Pokemon expression levels in HCC specimen and cell lines. Online database mining indicated that there are three putative mRNA recognition elements (MREs) of miR-125 within 3′ untranslated region (3′UTR) of Pokemon. MREs of miR-125 confer the expression of luciferase with a miR-125-dependent fashion. The alteration in miR-125 abundance regulates the expression of Pokemon at both protein and mRNA levels. Overexpression of Pokemon is able to abrogate the inhibitory effect of miR-125 on HCC progression. Further study showed that Pokemon inhibits the expression of miR-125 by binding of recognition sites within its promoter. In conclusion, we found that there is an auto-regulatory circuit consisting of miR-125 and Pokemon, which promotes the progression of HCC and may be a promising therapeutic target in clinical HCC treatment.

Keywords

miR-125 Pokemon HCC 

Notes

Acknowledgments

This study was funded by the Jiangsu Provincial Special Program of Medical Science (BL2013021) and Huai’an Science foundation (SN12037)

Conflicts of interest

None.

Disclosure of research involving human participants and informed consent

In this study, human cancer tissues were harvested from HCC patients during surgery with their written consents at the Department of Hepatopancreatobiliary Surgery, Huai’an First People’s Hospital (Huai’an, China).

References

  1. 1.
    Maeda T, Hobbs RM, Merghoub T, Guernah I, Zelent A, Cordon-Cardo C, et al. Role of the proto-oncogene Pokemon in cellular transformation and ARF repression. Nature. 2005;433(7023):278–85. doi: 10.1038/nature03203.CrossRefPubMedGoogle Scholar
  2. 2.
    Zhang QL, Tian DA, Xu XJ. Depletion of Pokemon gene inhibits hepatocellular carcinoma cell growth through inhibition of H-Ras. Onkologie. 2011;34(10):526–31. doi: 10.1159/000332141.CrossRefPubMedGoogle Scholar
  3. 3.
    Lin CC, Zhou JP, Liu YP, Liu JJ, Yang XN, Jazag A, et al. The silencing of Pokemon attenuates the proliferation of hepatocellular carcinoma cells in vitro and in vivo by inhibiting the PI3K/Akt pathway. PLoS One. 2012;7(12):e51916. doi: 10.1371/journal.pone.0051916.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Zhu X, Dai Y, Chen Z, Xie J, Zeng W, Lin Y. Knockdown of Pokemon protein expression inhibits hepatocellular carcinoma cell proliferation by suppression of Akt activity. Oncol Res. 2013;20(8):377–81. doi: 10.3727/096504013X13657689383012.CrossRefPubMedGoogle Scholar
  5. 5.
    Zhang YQ, Xiao CX, Lin BY, Shi Y, Liu YP, Liu JJ, et al. Silencing of Pokemon enhances caspase-dependent apoptosis via fas- and mitochondria-mediated pathways in hepatocellular carcinoma cells. PLoS One. 2013;8(7):e68981. doi: 10.1371/journal.pone.0068981.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Liu K, Liu F, Zhang N, Liu S, Jiang Y. Pokemon silencing leads to bim-mediated anoikis of human hepatoma cell QGY7703. Int J Mol Sci. 2012;13(5):5818–31. doi: 10.3390/ijms13055818.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Zhang NN, Sun QS, Chen Z, Liu F, Jiang YY. Homeostatic regulatory role of Pokemon in NF-κB signaling: stimulating both p65 and IκBα expression in human hepatocellular carcinoma cells. Mol Cell Biochem. 2013;372(1–2):57–64. doi: 10.1007/s11010-012-1445-1.CrossRefPubMedGoogle Scholar
  8. 8.
    Jin XL, Sun QS, Liu F, Yang HW, Liu M, Liu HX. microRNA 21-mediated suppression of Sprouty1 by Pokemon affects liver cancer cell growth and proliferation. J Cell Biochem. 2013;114(7):1625–33. doi: 10.1002/jcb.24504.CrossRefPubMedGoogle Scholar
  9. 9.
    Ding Y, Wang W, Feng M, Wang Y, Zhou J, Ding X, et al. A biomimetic nanovector-mediated targeted cholesterol-conjugated siRNA delivery for tumor gene therapy. Biomaterials. 2012;33(34):8893–905. doi: 10.1016/j.biomaterials.2012.08.057.CrossRefPubMedGoogle Scholar
  10. 10.
    Ma L, Liu J, Liu L, Duan G, Wang Q, Xu Y, et al. Overexpression of the transcription factor MEF2D in hepatocellular carcinoma sustains malignant character by suppressing G2-M transition genes. Cancer Res. 2014;74(5):1452–62. doi: 10.1158/0008-5472.CAN-13-2171.CrossRefPubMedGoogle Scholar
  11. 11.
    Wang Y, Lu Y, Toh ST, Sung WK, Tan P, Chow P, et al. Lethal-7 is down-regulated by the hepatitis B virus x protein and targets signal transducer and activator of transcription 3. J Hepatol. 2010;53(1):57–66. doi: 10.1016/j.jhep.2009.12.043.CrossRefPubMedGoogle Scholar
  12. 12.
    Jiang JX, Gao S, Pan YZ, Yu C, Sun CY. Overexpression of microRNA-125b sensitizes human hepatocellular carcinoma cells to 5-fluorouracil through inhibition of glycolysis by targeting hexokinase II. Molec Med Rep. 2014;10(2):995–1002. doi: 10.3892/mmr.2014.2271.Google Scholar
  13. 13.
    Liang L, Wong CM, Ying Q, Fan DN, Huang S, Ding J, et al. MicroRNA-125b suppressesed human liver cancer cell proliferation and metastasis by directly targeting oncogene LIN28B2. Hepatology. 2010;52(5):1731–40. doi: 10.1002/hep.23904.CrossRefPubMedGoogle Scholar
  14. 14.
    Bi Q, Tang S, Xia L, Du R, Fan R, Gao L, et al. Ectopic expression of MiR-125a inhibits the proliferation and metastasis of hepatocellular carcinoma by targeting MMP11 and VEGF. PLoS One. 2012;7(6):e40169. doi: 10.1371/journal.pone.0040169.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    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
  16. 16.
    Yuan S, Tang H, Xing J, Fan X, Cai X, Li Q, et al. Methylation by NSun2 represses the levels and function of microRNA 125b. Mol Cell Biol. 2014;34(19):3630–41. doi: 10.1128/MCB.00243-14.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Yu W, Huang C, Wang Q, Huang T, Ding Y, Ma C, et al. MEF2 transcription factors promotes EMT and invasiveness of hepatocellular carcinoma through TGF-β1 autoregulation circuitry. Tumour Biol : J Int Soc Oncodev Biol Med. 2014;35(11):10943–51. doi: 10.1007/s13277-014-2403-1.CrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Jing Kong
    • 1
  • Xiaoping Liu
    • 1
  • Xiangqian Li
    • 1
  • Jinsheng Wu
    • 2
  • Ning Wu
    • 3
  • Jun Chen
    • 1
  • Fang Fang
    • 1
  1. 1.Faculty of Life Science and Chemical EngineeringHuaiyin Institute of TechnologyHuai’anPeople’s Republic of China
  2. 2.Department of Hepatopancreatobiliary Surgery, Huai’an First People’s HospitalNanjing Medical UniversityHuai’anPeople’s Republic of China
  3. 3.Institute of OceanologyChinese Academy of SciencesQingdaoPeople’s Republic of China

Personalised recommendations