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Human Cell

pp 1–10 | Cite as

MiR-125b-5p suppresses the bladder cancer progression via targeting HK2 and suppressing PI3K/AKT pathway

  • Shuo LiuEmail author
  • Qin Chen
  • Yue Wang
Research Article
  • 21 Downloads

Abstract

Bladder cancer (BCa) is identified as the most common malignant solid cancer in the urogenital tract. Recently, dysregulation of miRNAs has received more attention because of its extensive role in the carcinogenesis of BCa. This research was designed to verify how miR-125b-5p be involved in BCa development. The expression of miR-125b-5p was detected in 52 pairs of BCa specimens and adjacent normal bladder specimens. The effects of miR-125b-5p on BCa viability, migration, and apoptosis in vitro were examined. We then examined directly target gene(s) of miR-125b-5p in BCa cells. Our data demonstrated that miR-125b-5p was decreased in BCa tissues and cell lines. Patients with low miR-125b-5p expression had obviously shorter 5-year survival time. Lower miR-125b-5p expression was significant correlated with distant metastasis, tumor size and lymph node metastasis. Ectopic expression of miR-125b-5p inhibited the BCa cell viability and migration and induced cell apoptosis. Furthermore, HK2 was confirmed regulated by miR-125b-5p. HK2 recovered miR-125b-5p-mediated suppression of BCa cell viability and migration. In addition, miR-125b-5p also exhibited suppressive effect on PI3K/AKT pathway. Overall, these data indicate that miR-125b-5p played a role in the suppressive effect on BCa by targeting HK2 through suppressing PI3K/AKT pathway and offer a potential therapeutic target for BCa.

Keywords

MiR-125b-5p Bladder cancer HK2 PI3K/AKT pathway 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval and consent to participate

Ethics Committee of Liaoning Cancer Hospital and Institute (20180415) approved the research, and written informed consent was given by all participants.

References

  1. 1.
    Burger M, Catto JW, Dalbagni G, Grossman HB, Herr H, Karakiewicz P, et al. Epidemiology and risk factors of urothelial bladder cancer. Eur Urol. 2013;63(2):234–41.  https://doi.org/10.1016/j.eururo.2012.07.033.CrossRefGoogle Scholar
  2. 2.
    Ploeg M, Aben KK, Kiemeney LA. The present and future burden of urinary bladder cancer in the world. World J Urol. 2009;27(3):289–93.  https://doi.org/10.1007/s00345-009-0383-3.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Fung C, Pandya C, Guancial E, Noyes K, Sahasrabudhe DM, Messing EM, et al. Impact of bladder cancer on health related quality of life in 1,476 older Americans: a cross-sectional study. J Urol. 2014;192(3):690–5.  https://doi.org/10.1016/j.juro.2014.03.098.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Andrew AS, Marsit CJ, Schned AR, Seigne JD, Kelsey KT, Moore JH, et al. Expression of tumor suppressive microRNA-34a is associated with a reduced risk of bladder cancer recurrence. Int J Cancer. 2015;137(5):1158–66.  https://doi.org/10.1002/ijc.29413.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Blick CG, Nazir SA, Mallett S, Turney BW, Onwu NN, Roberts IS, et al. Evaluation of diagnostic strategies for bladder cancer using computed tomography (CT) urography, flexible cystoscopy and voided urine cytology: results for 778 patients from a hospital haematuria clinic. BJU Int. 2012;110(1):84–94.  https://doi.org/10.1111/j.1464-410X.2011.10664.x.CrossRefPubMedGoogle Scholar
  6. 6.
    Chen JQ, Papp G, Szodoray P, Zeher M. The role of microRNAs in the pathogenesis of autoimmune diseases. Autoimmun Rev. 2016;15(12):1171–80.  https://doi.org/10.1016/j.autrev.2016.09.003.CrossRefPubMedGoogle Scholar
  7. 7.
    Homami A, Ghazi F. MicroRNAs as biomarkers associated with bladder cancer. Med J Islam Repub Iran. 2016;30:475.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Guancial EA, Bellmunt J, Yeh S, Rosenberg JE, Berman DM. The evolving understanding of microRNA in bladder cancer. Urol Oncol. 2014;32(1):41.  https://doi.org/10.1016/j.urolonc.2013.04.014 (e31–40).CrossRefPubMedGoogle Scholar
  9. 9.
    Braicu C, Cojocneanu-Petric R, Chira S, Truta A, Floares A, Petrut B, et al. Clinical and pathological implications of miRNA in bladder cancer. Int J Nanomed. 2015;10:791–800.  https://doi.org/10.2147/IJN.S72904.CrossRefGoogle Scholar
  10. 10.
    Ratert N, Meyer HA, Jung M, Lioudmer P, Mollenkopf HJ, Wagner I, et al. miRNA profiling identifies candidate mirnas for bladder cancer diagnosis and clinical outcome. J Mol Diagn. 2013;15(5):695–705.  https://doi.org/10.1016/j.jmoldx.2013.05.008.CrossRefPubMedGoogle Scholar
  11. 11.
    Inamoto T, Uehara H, Akao Y, Ibuki N, Komura K, Takahara K, et al. A panel of MicroRNA signature as a tool for predicting survival of patients with urothelial carcinoma of the bladder. Dis Markers. 2018;2018:5468672.  https://doi.org/10.1155/2018/5468672.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Li Y, Wang Y, Fan H, Zhang Z, Li N. miR-125b-5p inhibits breast cancer cell proliferation, migration and invasion by targeting KIAA1522. Biochem Biophys Res Commun. 2018;504(1):277–82.  https://doi.org/10.1016/j.bbrc.2018.08.172.CrossRefPubMedGoogle Scholar
  13. 13.
    Tao YC, Wang ML, Wang M, Ma YJ, Bai L, Feng P, et al. Quantification of circulating miR-125b-5p predicts survival in chronic hepatitis B patients with acute-on-chronic liver failure. Dig Liver Dis. 2018.  https://doi.org/10.1016/j.dld.2018.08.030.CrossRefPubMedGoogle Scholar
  14. 14.
    Canturk KM, Ozdemir M, Can C, Oner S, Emre R, Aslan H, et al. Investigation of key miRNAs and target genes in bladder cancer using miRNA profiling and bioinformatic tools. Mol Biol Rep. 2014;41(12):8127–35.  https://doi.org/10.1007/s11033-014-3713-5.CrossRefPubMedGoogle Scholar
  15. 15.
    Zhong JT, Zhou SH. Warburg effect, hexokinase-II, and radioresistance of laryngeal carcinoma. Oncotarget. 2017;8(8):14133–46.  https://doi.org/10.18632/oncotarget.13044.CrossRefPubMedGoogle Scholar
  16. 16.
    Lis P, Dylag M, Niedzwiecka K, Ko YH, Pedersen PL, Goffeau A, et al. The HK2 dependent “Warburg Effect” and mitochondrial oxidative phosphorylation in cancer: targets for effective therapy with 3-bromopyruvate. Molecules. 2016.  https://doi.org/10.3390/molecules21121730.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Jiao L, Zhang HL, Li DD, Yang KL, Tang J, Li X, et al. Regulation of glycolytic metabolism by autophagy in liver cancer involves selective autophagic degradation of HK2 (hexokinase 2). Autophagy. 2018;14(4):671–84.  https://doi.org/10.1080/15548627.2017.1381804.CrossRefPubMedGoogle Scholar
  18. 18.
    Wilson JE. Isozymes of mammalian hexokinase: structure, subcellular localization and metabolic function. J Exp Biol. 2003;206(Pt 12):2049–57.CrossRefGoogle Scholar
  19. 19.
    Li LQ, Yang Y, Chen H, Zhang L, Pan D, Xie WJ. MicroRNA-181b inhibits glycolysis in gastric cancer cells via targeting hexokinase 2 gene. Cancer Biomark. 2016;17(1):75–81.  https://doi.org/10.3233/CBM-160619.CrossRefPubMedGoogle Scholar
  20. 20.
    Wei L, Zhou Y, Dai Q, Qiao C, Zhao L, Hui H, et al. Oroxylin A induces dissociation of hexokinase II from the mitochondria and inhibits glycolysis by SIRT3-mediated deacetylation of cyclophilin D in breast carcinoma. Cell Death Dis. 2013;4:e601.  https://doi.org/10.1038/cddis.2013.131.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Zhang Z, Huang S, Wang H, Wu J, Chen D, Peng B, et al. High expression of hexokinase domain containing 1 is associated with poor prognosis and aggressive phenotype in hepatocarcinoma. Biochem Biophys Res Commun. 2016;474(4):673–9.  https://doi.org/10.1016/j.bbrc.2016.05.007.CrossRefPubMedGoogle Scholar
  22. 22.
    Mukherjee A, Ma Y, Yuan F, Gong Y, Fang Z, Mohamed EM, et al. Lysophosphatidic acid up-regulates hexokinase II and glycolysis to promote proliferation of ovarian cancer cells. Neoplasia. 2015;17(9):723–34.  https://doi.org/10.1016/j.neo.2015.09.003.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Xi F, Ye J. Inhibition of lung carcinoma A549 cell growth by knockdown of hexokinase 2 in situ and in vivo. Oncol Res. 2016;23(1–2):53–9.  https://doi.org/10.3727/096504015X14459480491740.CrossRefPubMedGoogle Scholar
  24. 24.
    Hui L, Zhang J, Guo X. MiR-125b-5p suppressed the glycolysis of laryngeal squamous cell carcinoma by down-regulating hexokinase-2. Biomed Pharmacother. 2018;103:1194–201.  https://doi.org/10.1016/j.biopha.2018.04.098.CrossRefPubMedGoogle Scholar
  25. 25.
    Tang H, Li RP, Liang P, Zhou YL, Wang GW. miR-125a inhibits the migration and invasion of liver cancer cells via suppression of the PI3K/AKT/mTOR signaling pathway. Oncol Lett. 2015;10(2):681–6.  https://doi.org/10.3892/ol.2015.3264.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Baer C, Claus R, Plass C. Genome-wide epigenetic regulation of miRNAs in cancer. Can Res. 2013;73(2):473–7.  https://doi.org/10.1158/0008-5472.CAN-12-3731.CrossRefGoogle Scholar
  27. 27.
    Tan M, Mu X, Liu Z, Tao L, Wang J, Ge J, et al. microRNA-495 promotes bladder cancer cell growth and invasion by targeting phosphatase and tensin homolog. Biochem Biophys Res Commun. 2017;483(2):867–73.  https://doi.org/10.1016/j.bbrc.2017.01.019.CrossRefPubMedGoogle Scholar
  28. 28.
    Yang X, Shi L, Yi C, Yang Y, Chang L, Song D. MiR-210-3p inhibits the tumor growth and metastasis of bladder cancer via targeting fibroblast growth factor receptor-like 1. Am J Cancer Res. 2017;7(8):1738–53.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Hu G, Zhao X, Wang J, Lv L, Wang C, Feng L, et al. miR-125b regulates the drug-resistance of breast cancer cells to doxorubicin by targeting HAX-1. Oncol Lett. 2018;15(2):1621–9.  https://doi.org/10.3892/ol.2017.7476.CrossRefPubMedGoogle Scholar
  30. 30.
    Wein SA, Laviano A, Wolffram S. Quercetin induces hepatic gamma-glutamyl hydrolase expression in rats by suppressing hepatic microRNA rno-miR-125b-3p. J Nutr Biochem. 2015;26(12):1660–3.  https://doi.org/10.1016/j.jnutbio.2015.08.010.CrossRefPubMedGoogle Scholar
  31. 31.
    Mathupala SP, Ko YH, Pedersen PL. Hexokinase-2 bound to mitochondria: cancer’s stygian link to the “Warburg Effect” and a pivotal target for effective therapy. Semin Cancer Biol. 2009;19(1):17–24.  https://doi.org/10.1016/j.semcancer.2008.11.006.CrossRefPubMedGoogle Scholar
  32. 32.
    Jiang S, Zhang LF, Zhang HW, Hu S, Lu MH, Liang S, et al. A novel miR-155/miR-143 cascade controls glycolysis by regulating hexokinase 2 in breast cancer cells. EMBO J. 2012;31(8):1985–98.  https://doi.org/10.1038/emboj.2012.45.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Liu H, Liu N, Cheng Y, Jin W, Zhang P, Wang X, et al. Hexokinase 2 (HK2), the tumor promoter in glioma, is downregulated by miR-218/Bmi1 pathway. PLoS One. 2017;12(12):e0189353.  https://doi.org/10.1371/journal.pone.0189353.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Zhu W, Huang Y, Pan Q, Xiang P, Xie N, Yu H. MicroRNA-98 suppress warburg effect by targeting HK2 in colon cancer cells. Dig Dis Sci. 2017;62(3):660–8.  https://doi.org/10.1007/s10620-016-4418-5.CrossRefPubMedGoogle Scholar
  35. 35.
    Challouf S, Ziadi S, Zaghdoudi R, Ksiaa F, Ben Gacem R, Trimeche M. Patterns of aberrant DNA hypermethylation in nasopharyngeal carcinoma in Tunisian patients. Clinica Chimica Acta Int J Clin Chem. 2012;413(7–8):795–802.  https://doi.org/10.1016/j.cca.2012.01.018.CrossRefGoogle Scholar

Copyright information

© Japan Human Cell Society and Springer Japan KK, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmacy, Cancer Hospital of China Medical UniversityLiaoning Cancer Hospital & InstituteShenyangPeople’s Republic of China

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