Tumor Biology

, Volume 35, Issue 2, pp 1357–1363 | Cite as

Significance and prognostic value of Gli-1 and Snail/E-cadherin expression in progressive gastric cancer

  • Zhan-shan Wang
  • Yang Shen
  • Xu Li
  • Chong-zhi Zhou
  • Yu-gang Wen
  • Yu-biao Jin
  • Ji-kun Li
Research Article


Abnormal activation of the hedgehog (Hh) signaling pathway has been found to be involved in the occurrence, invasion, and metastasis of cancers. Epithelial–mesenchymal transition (EMT) also plays an important role in the invasion and metastasis of cancers. However, the significance of the Hh signaling pathway and EMT in the invasion and metastasis of gastric cancer is still unclear. This study aimed to investigate the significance and prognostic value of the Hh signaling pathway and EMT in progressive gastric cancer. Immunohistochemistry was performed to detect the expression of the Hh-induced transcriptional factor Gli-1 and the EMT-related molecules Snail and E-cadherin in 121 patients with progressive gastric cancer. Histological type, depth of invasion, lymph node metastasis, and pTNM stage were also recorded. In progressive gastric cancer, Gli-1 expression increased markedly, and was closely associated with increased Snail expression and decreased E-cadherin expression. Diffuse type cancer, lymph node metastasis, and abnormal expression of E-cadherin were independent factors influencing the prognosis of patients with progressive gastric cancer. These findings suggest that abnormal activation of the Hh signaling pathway is closely related to the presence of EMT and is an important factor influencing the prognosis of patients with diffuse progressive gastric cancer.


Gastric cancer Hedgehog signaling pathway Epithelial–mesenchymal transition Prognosis 


Conflicts of interest



  1. 1.
    Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.PubMedCrossRefGoogle Scholar
  2. 2.
    Lin Y, Ueda J, Kikuchi S, Totsuka Y, Wei W, Qiao Y, et al. Comparative epidemiology of gastric cancer between Japan and China. World J Gastroenterol. 2011;17:4421–8.PubMedCrossRefGoogle Scholar
  3. 3.
    Tsugane S, Sasazuki S. Diet and the risk of gastric cancer: review of epidemiological evidence. Gastric Cancer. 2007;10:75–83.PubMedCrossRefGoogle Scholar
  4. 4.
    Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E, et al. Cancer statistics, 2004. CA Cancer J Clin. 2004;54:8–29.PubMedCrossRefGoogle Scholar
  5. 5.
    Beachy PA, Karhadkar SS, Berman DM. Tissue repair and stem cell renewal in carcinogenesis. Nature. 2004;432(7015):324–31.PubMedCrossRefGoogle Scholar
  6. 6.
    Wicking C, Smyt HI, Bale A. The hedgehog signaling pathway in tumorigenesis and development. Oncogene. 1999;18(55):7844–51.PubMedCrossRefGoogle Scholar
  7. 7.
    Yoo YA, Kang MH, Kim JS, Oh C. 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.PubMedCrossRefGoogle Scholar
  8. 8.
    Thiery JP. Epithelial−mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2:442–54.PubMedCrossRefGoogle Scholar
  9. 9.
    Hugo H, Ackland ML, Blick T, Lawrence MG, Clements JA, Williams ED, et al. Epithelial–mesenchymal and mesenchymal–epithelial transitions in carcinoma progression. J Cell Physiol. 2007;213(2):374–83.PubMedCrossRefGoogle Scholar
  10. 10.
    Chaffer CL, Brennan JP, Slavin JL, Blick T, Thompson EW, Williams ED. Mesenchymal-to-epithelial transition facilitates bladder cancer metastasis: role of fibroblast growth factor receptor-2. Cancer Res. 2006;66:11271–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, editors. AJCC cancer staging manual. 7th ed. Chicago: Springer; 2010. p. 117–26.Google Scholar
  12. 12.
    Ohno T, Aihara R, Kamiyama Y, Mochiki E, Asao T, Kuwano H. Prognostic significance of combined expression of MUC1 and adhesion molecules in advanced gastric cancer. Eur J Cancer. 2006;42(2):256–63.PubMedCrossRefGoogle Scholar
  13. 13.
    Yoshikawa R, Nakano Y, Tao L, Koishi K, Matsumoto T, Sasako M, et al. Hedgehog signal activation in oesophageal cancer patients undergoing neoadjuvant chemoradiotherapy. Br J Cancer. 2008;98:1670–4.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Rosivatz E, Becker I, Specht K, Fricke E, Luber B, Busch R, et al. Differential expression of the epithelial−mesenchymal transition regulators snail, SIP-1, and twist in gastric cancer. Am J Pathol. 2002;161(5):1881–91.PubMedCrossRefGoogle Scholar
  15. 15.
    Dessaud E, McMahon AP, Briscoe J. Pattern formation in the vertebrate neural tube: a sonic hedgehog morphogen-regulated transcriptional network. Development. 2008;135(15):2489–503.PubMedCrossRefGoogle Scholar
  16. 16.
    Gupta S, Takebe N, LoRusso P. Targeting the hedgehog pathway in cancer. Ther Adv Med Oncol. 2010;2:237–50.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Katoh Y, Katoh M. Hedgehog signaling pathway and gastric cancer. Cancer Biol Ther. 2005;4:1050–4.PubMedCrossRefGoogle Scholar
  18. 18.
    Ma X, Chen K, Huang S, Zhang X, Adegboyega PA, Evers BM, et al. Frequent activation of the hedgehog pathway in advanced gastric adenocardinomas. Carcinogenesis. 2005;26:1698–705.PubMedCrossRefGoogle Scholar
  19. 19.
    Kim JY, Ko GH, Lee YJ, Ha WS, Choi SK, Jung EJ, et al. Prognostic value of hedgehog protein expression in gastric cancer. Jpn J Clin Oncol. 2012;42:1054–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Kamikihara T, Ishigami S, Arigami T, Matsumoto M, Okumura H, Uchikado Y, et al. Clinical implications of N-cadherin expression in gastric cancer. Pathol Int. 2012;62:161–6.PubMedCrossRefGoogle Scholar
  21. 21.
    Ohta H, Aoyagi K, Fukaya M, Danjoh I, Ohta A, Isohata N, et al. Cross talk between hedgehog and epithelial−mesenchymal transition pathways in gastric pit cells and in diffuse-type gastric cancers. Br J Cancer. 2009;100:389–98.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Yoo YA, Kang MH, Lee HJ, Kim BH, Park JK, Kim HK, et al. Sonic hedgehog pathway promotes metastasis and lymphangiogenesis via activation of Akt, EMT, and MM-9 pathway in gastric cancer. Cancer Res. 2011;71:7061–70.PubMedCrossRefGoogle Scholar
  23. 23.
    Kim MA, Lee HS, Lee HE, Kim JH, Yang HK, Kim WH. Prognostic importance of epithelial−mesenchymal transition-related protein expression in gastric carcinoma. Histopathology. 2009;54(4):442–51.PubMedCrossRefGoogle Scholar
  24. 24.
    Katoh Y, Katoh M. Hedgehog signaling, epithelial-to-mesenchymal transition and miRNA (review). Int J Mol Med. 2008;22(3):271–5. Review.PubMedGoogle Scholar
  25. 25.
    Katoh M. Epithelial−mesenchymal transition in gastric cancer. Int J Oncol. 2005;27:1677–83.PubMedGoogle Scholar
  26. 26.
    Matsumura T, Makino R, Mitamura K. Frequent down-regulation of E-cadherin by genetic and epigenetic changes in the malignant progress of hepatocellular carcinomas. Clin Cancer Res. 2001;7(3):594–9.PubMedGoogle Scholar
  27. 27.
    Saze Z, Terashima M, Kogure M, Ohsuka F, Suzuki H, Gotoh M. Activation of the sonic hedgehog pathway and its prognostic impact in patients with gastric cancer. Dig Surg. 2012;29(2):115–23.PubMedCrossRefGoogle Scholar
  28. 28.
    Wei L, Xu Z. Cross-signaling among phosphoinositide 3-kinase, mitogen-activated protein kinase and sonic hedgehog pathways in esophageal cancer. Int J Cancer. 2011;129:275–84.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  • Zhan-shan Wang
    • 1
  • Yang Shen
    • 1
  • Xu Li
    • 1
  • Chong-zhi Zhou
    • 1
  • Yu-gang Wen
    • 1
  • Yu-biao Jin
    • 2
  • Ji-kun Li
    • 1
  1. 1.Department of General SurgeryShanghai Jiaotong University Affiliated First People’s HospitalShanghaiChina
  2. 2.Department of PathologyShanghai Jiaotong University Affiliated First People’s HospitalShanghaiChina

Personalised recommendations