Tumor Biology

, Volume 36, Issue 8, pp 5807–5814 | Cite as

Thermo-chemotherapy Induced miR-218 upregulation inhibits the invasion of gastric cancer via targeting Gli2 and E-cadherin

  • Qiang Ruan
  • Zhi-yuan Fang
  • Shu-zhong Cui
  • Xiang-liang Zhang
  • Yin-bing Wu
  • Hong-sheng Tang
  • Yi-nuo Tu
  • Yan Ding
Research Article


Thermo-chemotherapy has been proven to reduce the invasion capability of cancer cells. However, the molecular mechanism underlying this anti-invasion effect is still unclear. In this study, the role of thermo-chemotherapy in the inhibition of tumor invasion was studied. The results demonstrated that expression of miR-218 was downregulated in gastric cancer tissues, which had a positive correlation with tumor invasion and metastasis. In vitro thermo-chemotherapy increased miR-218 expression in SGC7901 cells and inhibited both proliferation and invasion of cancer cells. Gli2 was identified as a downstream target of miR-218, and its expression was negatively regulated by miR-218. The thermo-chemotherapy induced miR-218 upregulation was also accompanied by increasing of E-cadherin expression. In conclusion, the present study indicates that thermo-chemotherapy can effectively decrease the invasion capability of cancer cells and increase cell-cell adhesion. miR-218 and its downstream target Gli2, as well as E-cadherin, participate in the anti-invasion process.


Thermo-chemotherapy miR-218 Gli2 Tumor invasion Gastric cancer E-cadherin 



This work was supported by Grants from the PhD Start-up Funds of Guangzhou Medical College, Guangdong Province, China (Nos. 2012C66 and 2012C69), Guangdong Province Natural Science Fund(No S2013010016662), and the National Natural Science Foundation of China (Nos.81201932 and 81372493).

Conflicts of interest



  1. 1.
    Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol. 2006;24(14):2137–50.CrossRefPubMedGoogle Scholar
  2. 2.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90. doi: 10.3322/caac.20107.CrossRefPubMedGoogle Scholar
  3. 3.
    Oue N, Aung PP, Mitani Y, Kuniyasu H, Nakayama H, Yasui W. Genes involved in invasion and metastasis of gastric cancer identified by array-based hybridization and serial analysis of gene expression. Oncology. 2005;69 Suppl 1:17–22.CrossRefPubMedGoogle Scholar
  4. 4.
    Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 2005;120(1):15–20.CrossRefPubMedGoogle Scholar
  5. 5.
    Lai EC. Micro RNAs are complementary to 3' UTR sequence motifs that mediate negative post-transcriptionalregulation. Nat Genet. 2002;30(4):363–4.CrossRefPubMedGoogle Scholar
  6. 6.
    Nicoloso MS, Spizzo R, Shimizu M, Rossi S, Calin GA. MicroRNAs—the micro steering wheel of tumour metastases. Nat Rev Cancer. 2009;9(4):293–302. doi: 10.1038/nrc2619.CrossRefPubMedGoogle Scholar
  7. 7.
    Tie J, Pan Y, Zhao L, Wu K, Liu J, Sun S, et al. MiR-218 inhibits invasion and metastasis of gastric cancer by targeting the Robo1 receptor. PLoS Genet. 2010;6(3):e1000879. doi: 10.1371/journal.pgen.1000879.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Zhang XL, Shi HJ, Wang JP, Tang HS, Wu YB, Fang ZY, et al. MicroRNA-218 is upregulated in gastric cancer after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy and increases chemosensitivity to cisplatin. World J Gastroenterol. 2014;20(32):11347–55. doi: 10.3748/wjg.v20.i32.11347.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Yoo YA, Kang MH, Kim JS, Oh SC. Sonic hedgehog signaling promotes motility and invasiveness of gastric cancer cells through TGF-beta-mediated activation of the ALK5-Smad 3 pathway. Carcinogenesis. 2008;29(3):480–90. doi: 10.1093/carcin/bgm281.CrossRefPubMedGoogle Scholar
  10. 10.
    Bai R, Zhao H, Zhang X, Du S. Characterization of sonic hedgehog inhibition in gastric carcinoma cells. Oncol Lett. 2014;7(5):1381–4.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Grzelak CA, Sigglekow ND, McCaughan GW. GLI2 as a marker of Hedgehog-responsive cells. Hepatology. 2014. doi: 10.1002/hep.27432.Google Scholar
  12. 12.
    Alexaki VI, Javelaud D, Van Kempen LC, Mohammad KS, Dennler S, Luciani F, et al. GLI2-mediated melanoma invasion and metastasis. J Natl Cancer Inst. 2010;102(15):1148–59. doi: 10.1093/jnci/djq257.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Golse N, Bakrin N, Passot G, Mohamed F, Vaudoyer D, Gilly FN, et al. Iterative procedures combining cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for peritoneal recurrence: postoperative and long-term results. J Surg Oncol. 2012;106(2):197–203. doi: 10.1002/jso.23062.CrossRefPubMedGoogle Scholar
  14. 14.
    Airoldi M, Gabriele P, Brossa PC, Pedani F, Tseroni V, D'Alberto M, et al. Serum thyroid hormone changes in head and neck cancer patients treated with microwave hyperthermia on lymph node metastasis. Cancer. 1990;65(4):901–7.CrossRefPubMedGoogle Scholar
  15. 15.
    Hamaguchi S, Tohnai I, Ito A, Mitsudo K, Shigetomi T, Ito M, et al. Selective hyperthermia using magnetoliposomes to target cervical lymph node metastasis in a rabbit tongue tumor model. Cancer Sci. 2003;94(9):834–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Huhnt W, Lubbe AS. Growth, microvessel density and tumor cell invasion of human colon adenocarcinoma under repeated treatment with hyperthermia and serotonin. J Cancer Res Clin Oncol. 1995;121(7):423–8.CrossRefPubMedGoogle Scholar
  17. 17.
    Gao X, Jin W. The emerging role of tumor-suppressive microRNA-218 in targeting glioblastoma stemness. Cancer Lett. 2014;353(1):25–31. doi: 10.1016/j.canlet.2014.07.011.CrossRefPubMedGoogle Scholar
  18. 18.
    Xin SY, Feng XS, Zhou LQ, Sun JJ, Gao XL, Yao GL. Reduced expression of circulating microRNA-218 in gastric cancer and correlation with tumor invasion and prognosis. World J Gastroenterol. 2014;20(22):6906–11. doi: 10.3748/wjg.v20.i22.6906.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Wei Y, Du Y, Chen X, Li P, Wang Y, Zang W, et al. Expression patterns of microRNA-218 and its potential functions by targeting CIP2A and BMI1 genes in melanoma. Tumour Biol. 2014;35(8):8007–15. doi: 10.1007/s13277-014-2079-6.CrossRefPubMedGoogle Scholar
  20. 20.
    Zhang C, Ge S, Hu C, Yang N, Zhang J. MiRNA-218, a new regulator of HMGB1, suppresses cell migration and invasion in non-small cell lung cancer. Acta Biochim Biophys Sin (Shanghai). 2013;45(12):1055–61. doi: 10.1093/abbs/gmt109.CrossRefGoogle Scholar
  21. 21.
    Jin J, Cai L, Liu ZM, Zhou XS. miRNA-218 inhibits osteosarcoma cell migration and invasion by down-regulating of TIAM1, MMP2 and MMP9. Asian Pac J Cancer Prev. 2013;14(6):3681–4.CrossRefPubMedGoogle Scholar
  22. 22.
    Peng B, Li D, Qin M, Luo D, Zhang X, Zhao H, et al. MicroRNA218 inhibits glioma migration and invasion via inhibiting glioma-associated oncogene homolog 1 expression at N terminus. Tumour Biol. 2014;35(4):3831–7. doi: 10.1007/s13277-013-1507-3.CrossRefPubMedGoogle Scholar
  23. 23.
    Ruiz i Altaba A, Sanchez P, Dahmane N. Gli and hedgehog in cancer: tumours, embryos and stem cells. Nat Rev Cancer. 2002;2(5):361–72.CrossRefPubMedGoogle Scholar
  24. 24.
    Varjosalo M, Taipale J. Hedgehog: functions and mechanisms. Genes Dev. 2008;22(18):2454–72. doi: 10.1101/gad.1693608.CrossRefPubMedGoogle Scholar
  25. 25.
    Kasper M, Regl G, Frischauf AM, Aberger F. GLI transcription factors: mediators of oncogenic Hedgehog signalling. Eur J Cancer. 2006;42(4):437–45.CrossRefPubMedGoogle Scholar
  26. 26.
    Mechlin CW, Tanner MJ, Chen M, Buttyan R, Levin RM, Mian BM. Gli2 expression and human bladder transitional carcinoma cell invasiveness. J Urol. 2010;184(1):344–51. doi: 10.1016/j.juro.2010.03.007.CrossRefPubMedGoogle Scholar
  27. 27.
    Zeng C, Wang Y, Lu Q, Chen J, Zhang J, Liu T, et al. SPOP suppresses tumorigenesis by regulating hedgehog/Gli2 signaling pathway in gastric cancer. J Exp Clin Cancer Res. 2014;33(1):75.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Liu X, Chu KM. E-cadherin and gastric cancer: cause, consequence, and applications. Biomed Res Int. 2014;2014:637308. doi: 10.1155/2014/637308.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Xu W, Hu X, Chen Z, Zheng X, Zhang C, Wang G, et al. Normal fibroblasts induce E-cadherin loss and increase lymph node metastasis in gastric cancer. PLoS One. 2014;9(5):e97306. doi: 10.1371/journal.pone.0097306.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Zhang D, Cao L, Li Y, Lu H, Yang X, Xue P. Expression of glioma-associated oncogene 2 (Gli 2) is correlated with poor prognosis in patients with hepatocellular carcinoma undergoing hepatectomy. World J Surg Oncol. 2013;11:25. doi: 10.1186/1477-7819-11-25.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Chou CH, Lieu AS, Wu CH, Chang LK, Loh JK, Lin RC, et al. Differential expression of hedgehog signaling components and Snail/E-cadherin in human brain tumors. Oncol Rep. 2010;24(5):1225–32.PubMedGoogle Scholar
  32. 32.
    Fendrich V, Waldmann J, Esni F, Ramaswamy A, Mullendore M, Buchholz M, et al. Snail and Sonic Hedgehog activation in neuroendocrine tumors of the ileum. Endocr Relat Cancer. 2007;14(3):865–74.CrossRefPubMedGoogle Scholar
  33. 33.
    Berx G, van Roy F. Involvement of members of the cadherin superfamily in cancer. Cold Spring Harb Perspect Biol. 2009;1(6):a003129. doi: 10.1101/cshperspect.a003129.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Niessen CM, Leckband D, Yap AS. Tissue organization by cadherin adhesion molecules: dynamic molecular and cellular mechanisms of morphogenetic regulation. Physiol Rev. 2011;91(2):691–731. doi: 10.1152/physrev.00004.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Qiang Ruan
    • 1
  • Zhi-yuan Fang
    • 1
  • Shu-zhong Cui
    • 1
  • Xiang-liang Zhang
    • 1
  • Yin-bing Wu
    • 1
  • Hong-sheng Tang
    • 1
  • Yi-nuo Tu
    • 1
  • Yan Ding
    • 1
  1. 1.Department of Hepatobiliary Surgery, Cancer Institute and HospitalGuangzhou Medical UniversityGuangzhouChina

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