Human Cell

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MicroRNA-498 inhibits the proliferation, migration and invasion of gastric cancer through targeting BMI-1 and suppressing AKT pathway

  • Dong You
  • Dawei Wang
  • Peiji Liu
  • Yuning Chu
  • Xueying Zhang
  • Xueli Ding
  • Xiaoyu Li
  • Tao Mao
  • Xue Jing
  • Zibin Tian
  • Yinghua PanEmail author
Research Article


Recently, microRNA-498 (miR-498) plays important effect in human cancers. Nonetheless, the role of miR-498 is still unclear in gastric cancer (GC). Therefore, this study was designed to investigate the function of miR-498 in GC tissues and cell lines (SGC-7901, BGC-823, MGC-803). The expressions of miR-498 and BMI-1 were examined in GC tissues via the RT-qPCR assay. The function of miR-498 was investigated through MTT and transwell assays. The relationship between miR-498 and BMI-1 was testified by dual luciferase assay. The protein expression of EMT markers, AKT pathway markers and BMI-1 was measured through western blot. The expression of miR-498 was decreased in GC tissues which predicted poor prognosis of GC patients. Moreover, functional analyses show that the overexpression of miR-498 inhibited the progression of GC. Furthermore, BMI-1 was a direct target of miR-498 which was upregulated in GC. Especially, the upregulation of BMI-1 recovered the suppressive effect of miR-498 in GC. In addition, miR-498 inhibited the metastasis and proliferation of GC cells through blocking EMT and AKT pathway. MiR-498, by targeting BMI-1, presents a plethora of tumor suppressor activities in GC cells.


AKT pathway BMI-1 Gastric cancer MiR-498 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interests.

Ethical approval

This study was approved by the Institutional Ethics Committee of The Affiliated Hospital of Qingdao University (Qingdao, China) and was performed according to the guidelines of the Declaration of Helsinki. Informed consent was obtained from all patients.

Supplementary material

13577_2019_313_MOESM1_ESM.xlsx (25 kb)
Supplementary material 1 (XLSX 24 kb)


  1. 1.
    Piazuelo MB, Correa P. Gastric cancer: overview. Colomb Med. 2013;44(3):192–201.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29. Scholar
  3. 3.
    Yang L. Incidence and mortality of gastric cancer in China. World J Gastroenterol. 2006;12(1):17–20.CrossRefGoogle Scholar
  4. 4.
    Jing JJ, Liu HY, Hao JK, Wang LN, Wang YP, Sun LH, et al. Gastric cancer incidence and mortality in Zhuanghe, China, between 2005 and 2010. World J Gastroenterol. 2012;18(11):1262–9. Scholar
  5. 5.
    Fujita T. Gastric cancer. Lancet. 2009;374(9701):1593–4. reply 4–5).CrossRefPubMedGoogle Scholar
  6. 6.
    Kim JG, Ryoo BY, Park YH, Kim BS, Kim TY, Im YH, et al. Prognostic factors for survival of patients with advanced gastric cancer treated with cisplatin-based chemotherapy. Cancer Chemother Pharmacol. 2008;61(2):301–7. Scholar
  7. 7.
    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108. Scholar
  8. 8.
    Choi YY, Noh SH, Cheong JH. Evolution of gastric cancer treatment: from the golden age of surgery to an era of precision medicine. Yonsei Med J. 2015;56(5):1177–85. Scholar
  9. 9.
    Cervantes A, Rosello S, Roda D, Rodriguez-Braun E. The treatment of advanced gastric cancer: current strategies and future perspectives. Ann Oncol. 2008;19(Suppl 5):v103–7. Scholar
  10. 10.
    Kloosterman WP, Plasterk RH. The diverse functions of microRNAs in animal development and disease. Dev Cell. 2006;11(4):441–50. Scholar
  11. 11.
    Cui HB, Ge HE, Wang YS, Bai XY. MiR-208a enhances cell proliferation and invasion of gastric cancer by targeting SFRP1 and negatively regulating MEG3. Int J Biochem Cell Biol. 2018;102:31–9. Scholar
  12. 12.
    Gao W, Cao Y, Guo P, Bao X, Zhu H, Zheng J, et al. Downregulation of MiR-1297 predicts poor prognosis and enhances gastric cancer cell growth by targeting CREB1. Biomed Pharmacother. 2018;105:413–9. Scholar
  13. 13.
    An JX, Ma MH, Zhang CD, Shao S, Zhou NM, Dai DQ. MiR-1236-3p inhibits invasion and metastasis in gastric cancer by targeting MTA2. Cancer Cell Int. 2018;18:66. Scholar
  14. 14.
    Yan Q, Li W, Tang Q, Yao S, Lv Z, Feng N, et al. Cellular microRNAs 498 and 320d regulate herpes simplex virus 1 induction of Kaposi’s sarcoma-associated herpesvirus lytic replication by targeting RTA. PLoS One. 2013;8(2):e55832. Scholar
  15. 15.
    Liu R, Liu F, Li L, Sun M, Chen K. MiR-498 regulated FOXO3 expression and inhibited the proliferation of human ovarian cancer cells. Biomed Pharmacother. 2015;72:52–7. Scholar
  16. 16.
    Yang L, Wei N, Wang L, Wang X, Liu QH. MiR-498 promotes cell proliferation and inhibits cell apoptosis in retinoblastoma by directly targeting CCPG1. Child’s Nerv Syst. 2018;34(3):417–22. Scholar
  17. 17.
    Montanini L, Lasagna L, Barili V, Jonstrup SP, Murgia A, Pazzaglia L, et al. MicroRNA cloning and sequencing in osteosarcoma cell lines: differential role of miR-93. Cell Oncol. 2012;35(1):29–41. Scholar
  18. 18.
    Tu Y, Gao X, Li G, Fu H, Cui D, Liu H, et al. MicroRNA-218 inhibits glioma invasion, migration, proliferation, and cancer stem-like cell self-renewal by targeting the polycomb group gene Bmi1. Cancer Res. 2013;73(19):6046–55. Scholar
  19. 19.
    Qi X, Li J, Zhou C, Lv C, Tian M. MicroRNA-320a inhibits cell proliferation, migration and invasion by targeting BMI-1 in nasopharyngeal carcinoma. FEBS Lett. 2014;588(20):3732–8. Scholar
  20. 20.
    Gong XF, Yu AL, Tang J, Wang CL, He JR, Chen GQ, et al. MicroRNA-630 inhibits breast cancer progression by directly targeting BMI1. Exp Cell Res. 2018;362(2):378–85. Scholar
  21. 21.
    Luo H, Yang R, Li C, Tong Y, Fan L, Liu X, et al. MicroRNA-139-5p inhibits bladder cancer proliferation and self-renewal by targeting the Bmi1 oncogene. Tumour Biol. 2017;39(7):1010428317718414. Scholar
  22. 22.
    Zhou L, Zhang WG, Wang DS, Tao KS, Song WJ, Dou KF. MicroRNA-183 is involved in cell proliferation, survival and poor prognosis in pancreatic ductal adenocarcinoma by regulating Bmi-1. Oncol Rep. 2014;32(4):1734–40. Scholar
  23. 23.
    Dong P, Kaneuchi M, Watari H, Hamada J, Sudo S, Ju J, et al. MicroRNA-194 inhibits epithelial to mesenchymal transition of endometrial cancer cells by targeting oncogene BMI-1. Mol Cancer. 2011;10:99. Scholar
  24. 24.
    Wu DM, Hong XW, Wang LL, Cui XF, Lu J, Chen GQ, et al. MicroRNA-17 inhibition overcomes chemoresistance and suppresses epithelial-mesenchymal transition through a DEDD-dependent mechanism in gastric cancer. Int J Biochem Cell Biol. 2018. Scholar
  25. 25.
    Bellacosa A, Kumar CC, Di Cristofano A, Testa JR. Activation of AKT kinases in cancer: implications for therapeutic targeting. Adv Cancer Res. 2005;94:29–86. Scholar
  26. 26.
    Cheng F, Yang Z, Huang F, Yin L, Yan G, Gong G. MicroRNA-107 inhibits gastric cancer cell proliferation and metastasis by targeting PI3K/AKT pathway. Microb Pathog. 2018;121:110–4. Scholar
  27. 27.
    Porta C, Paglino C, Mosca A. Targeting PI3K/Akt/mTOR signaling in cancer. Front Oncol. 2014;4:64. Scholar
  28. 28.
    He Y, Ge Y, Jiang M, Zhou J, Luo D, Fan H, et al. MiR-592 promotes gastric cancer proliferation, migration, and invasion through the PI3K/AKT and MAPK/ERK signaling pathways by targeting Spry2. Cell Physiol Biochem. 2018;47(4):1465–81. Scholar
  29. 29.
    Tian L, Zhao Z, Xie L, Zhu J. MiR-361-5p inhibits the mobility of gastric cancer cells through suppressing epithelial-mesenchymal transition via the Wnt/beta-catenin pathway. Gene. 2018. Scholar
  30. 30.
    Zhao T, Chen Y, Sheng S, Wu Y, Zhang T. Upregulating microRNA-498 inhibits gastric cancer proliferation invasion and chemoresistance through inverse interaction of Bmi1. Cancer Gene Ther. 2018. Scholar
  31. 31.
    Kang Y, Massague J. Epithelial-mesenchymal transitions: twist in development and metastasis. Cell. 2004;118(3):277–9. Scholar
  32. 32.
    Gupta GP, Massague J. Cancer metastasis: building a framework. Cell. 2006;127(4):679–95. Scholar
  33. 33.
    Li D, Tian B, Jin X. MiR-630 inhibits epithelial-to-mesenchymal transition (EMT) by regulating Wnt/betacatenin pathway in gastric cancer cells. Oncol Res. 2018. Scholar
  34. 34.
    Gopalan V, Smith RA, Lam AK. Downregulation of microRNA-498 in colorectal cancers and its cellular effects. Exp Cell Res. 2015;330(2):423–8. Scholar
  35. 35.
    Cong J, Liu R, Wang X, Wang J, Wang H, Hou J. Low miR-498 expression levels are associated with poor prognosis in ovarian cancer. Eur Rev Med Pharmacol Sci. 2015;19(24):4762–5.PubMedGoogle Scholar
  36. 36.
    Farazi TA, Juranek SA, Tuschl T. The growing catalog of small RNAs and their association with distinct Argonaute/Piwi family members. Development. 2008;135(7):1201–14. Scholar
  37. 37.
    Gao N, Wang FX, Wang G, Zhao QS. Targeting the HMGA2 oncogene by miR-498 inhibits non-small cell lung cancer biological behaviors. Eur Rev Med Pharmacol Sci. 2018;22(6):1693–9. Scholar
  38. 38.
    Liu PW, Lin Y, Chen XY. Expression of B-cell-specific Moloney murine leukemia virus integration site 1 mRNA and protein in gastric cancer. J Dig Dis. 2014;15(4):166–73. Scholar
  39. 39.
    Gao FL, Li WS, Liu CL, Zhao GQ. Silencing Bmi-1 enhances the senescence and decreases the metastasis of human gastric cancer cells. World J Gastroenterol. 2013;19(46):8764–9. Scholar
  40. 40.
    Shan ZN, Tian R, Zhang M, Gui ZH, Wu J, Ding M, et al. MiR128-1 inhibits the growth of glioblastoma multiforme and glioma stem-like cells via targeting BMI1 and E2F3. Oncotarget. 2016;7(48):78813–26. Scholar
  41. 41.
    Wu SQ, Niu WY, Li YP, Huang HB, Zhan R. MiR-203 inhibits cell growth and regulates G1/S transition by targeting Bmi-1 in myeloma cells. Mol Med Rep. 2016;14(5):4795–801. Scholar
  42. 42.
    Deng Y, Xiong Y, Liu Y. MiR-376c inhibits cervical cancer cell proliferation and invasion by targeting BMI1. Int J Exp Pathol. 2016;97(3):257–65. Scholar
  43. 43.
    Li F, Liang A, Lv Y, Liu G, Jiang A, Liu P. MicroRNA-200c inhibits epithelial-mesenchymal transition by targeting the BMI-1 gene through the phospho-AKT pathway in endometrial carcinoma cells in vitro. Med Sci Monit. 2017;23:5139–49.CrossRefGoogle Scholar
  44. 44.
    Will M, Qin AC, Toy W, Yao Z, Rodrik-Outmezguine V, Schneider C, et al. Rapid induction of apoptosis by PI3K inhibitors is dependent upon their transient inhibition of RAS-ERK signaling. Cancer Discov. 2014;4(3):334–47. Scholar
  45. 45.
    Liu GL, Yang HJ, Liu B, Liu T. Effects of MicroRNA-19b on the proliferation, apoptosis, and migration of wilms’ tumor cells via the PTEN/PI3K/AKT signaling pathway. J Cell Biochem. 2017;118(10):3424–34. Scholar
  46. 46.
    Long ZW, Wu JH, Cai H, Wang YN, Zhou Y. MiR-374b promotes proliferation and inhibits apoptosis of human GIST cells by inhibiting PTEN through activation of the PI3K/Akt pathway. Mol Cells. 2018;41(6):532–44. Scholar
  47. 47.
    Xiao F, Cheng Z, Wang P, Gong B, Huang H, Xing Y, et al. MicroRNA-28-5p inhibits the migration and invasion of gastric cancer cells by suppressing AKT phosphorylation. Oncol Lett. 2018;15(6):9777–85. Scholar

Copyright information

© Japan Human Cell Society and Springer Japan KK, part of Springer Nature 2020

Authors and Affiliations

  1. 1.Department of RadiotherapyYantai Yuhuangding Hospital Affiliated to Qingdao UniversityYantaiChina
  2. 2.Qingdao University Medical CollegeQingdaoChina
  3. 3.Department of GastroenterologyThe Affiliated Hospital of Qingdao UniversityQingdaoChina
  4. 4.Department of RadiologyYantai Yuhuangding Hospital Affiliated to Qingdao UniversityYantaiChina

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