Medical Oncology

, 31:41 | Cite as

Sonic hedgehog signaling may promote invasion and metastasis of oral squamous cell carcinoma by activating MMP-9 and E-cadherin expression

  • Hai-Xia Fan
  • Shan Wang
  • Hong Zhao
  • Nian Liu
  • Dong Chen
  • Miao Sun
  • Jin-Hua Zheng
Original Paper


The aim of this study was to investigate sonic hedgehog (SHH) signaling pathway components (Shh and Gli-1), E-cadherin, and MMP-9 expression in human oral squamous cell carcinoma (OSCC) and to evaluate their role in prognosis. Expression of Shh, Gli-1, and MMP-9 was significantly upregulated in 74 OSCC samples compared with non-cancerous tissue samples (Shh IOD: 162.44 ± 29.35 and 608.82 ± 170.99; Gli-1 IOD: 203.50 ± 71.57 and 831.11 ± 242.352; MMP-9 IOD: 196.69 ± 64.48 and 721.64 ± 197.99 in non-cancerous and tumor tissues, respectively, P < 0.01), whereas E-cadherin expression was downregulated (E-cadherin IOD: 1,006.19 ± 230.42 and 442.20 ± 156.11; in non-cancerous and tumor tissues, respectively, P < 0.01). Highly expressed proteins were associated with lymph node metastasis; moreover, overexpression of Gli-1 was related to tumor recurrence and cancer clinical staging. Spearman’s analysis indicated that the expression of Gli-1 and MMP-9 was positively correlated, whereas expression of Shh/Gli-1 and E-cadherin was negatively correlated. Kaplan–Meier results revealed that patients with low Shh, Gli-1, and MMP-9 expression survived longer than those with high expression. In contrast, low E-cadherin expression was associated with poor prognosis (P < 0.01). In conclusions, transcription factor Gli-1 of the SHH signaling pathway may be an important mediator of invasion and metastasis of OSCC through induced expression of MMP-9 and E-cadherin and may serve as a new prognostic marker.


Oral squamous cell carcinoma Sonic hedgehog signaling MMP-9 E-cadherin Immunohistochemistry Prognosis 



This work was supported by grants from the National Natural Science Foundation of China (305400083).

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

12032_2014_41_MOESM1_ESM.ppt (2.8 mb)
Supplementary material 1 (PPT 2831 kb)


  1. 1.
    Byers RM, El-Naggar AK, Lee YY, Rao B, Fornage B, Terry NH, et al. Can we detect or predict the presence of occult nodal metastases in patients with squamous carcinoma of the oral tongue? Head Neck. 1998;20(2):138–44.PubMedCrossRefGoogle Scholar
  2. 2.
    Yang L, Su X, Xie J. Activation of Hedgehog pathway in gastrointestinal cancers. Vitam Horm. 2012;88:461–72. doi: 10.1016/B978-0-12-394622-5.00020-1.PubMedCrossRefGoogle Scholar
  3. 3.
    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 MMP-9 pathway in gastric cancer. Cancer Res. 2011;71(22):7061–70. doi: 10.1158/0008-5472.CAN-11-1338.PubMedCrossRefGoogle Scholar
  4. 4.
    Chen JS, Huang XH, Wang Q, Huang JQ, Zhang LJ, Chen XL, et al. Sonic hedgehog signaling pathway induces cell migration and invasion through focal adhesion kinase/AKT signaling-mediated activation of matrix metalloproteinase (MMP)-2 and MMP-9 in liver cancer. Carcinogenesis. 2013;34(1):10–9. doi: 10.1093/carcin/bgs274.PubMedCrossRefGoogle Scholar
  5. 5.
    Im S, Choi HJ, Yoo C, Jung JH, Jeon YW, Suh YJ, et al. Hedgehog related protein expression in breast cancer: gli-2 is associated with poor overall survival. Korean J Pathol. 2013;47(2):116–23. doi: 10.4132/KoreanJPathol.47.2.116.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Von Hoff DD, LoRusso PM, Rudin CM, Reddy JC, Yauch RL, Tibes R, et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med. 2009;361(12):1164–72. doi: 10.1056/NEJMoa0905360.CrossRefGoogle Scholar
  7. 7.
    Wang YF, Chang CJ, Lin CP, Chang SY, Chu PY, Tai SK, et al. Expression of hedgehog signaling molecules as a prognostic indicator of oral squamous cell carcinoma. Head Neck. 2012;34(11):1556–61. doi: 10.1002/hed.21958.PubMedCrossRefGoogle Scholar
  8. 8.
    Bailey JM, Mohr AM, Hollingsworth MA. Sonic hedgehog paracrine signaling regulates metastasis and lymphangiogenesis in pancreatic cancer. Oncogene. 2009;28(40):3513–25. doi: 10.1038/onc.2009.220.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    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. doi: 10.1038/nrc796.PubMedCrossRefGoogle Scholar
  10. 10.
    Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 2001;15(23):3059–87. doi: 10.1101/gad.938601.PubMedCrossRefGoogle Scholar
  11. 11.
    Feldmann G, Dhara S, Fendrich V, Bedja D, Beaty R, Mullendore M, et al. Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res. 2007;67(5):2187–96. doi: 10.1158/0008-5472.CAN-06-3281.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Tian T, Nan KJ, Guo H, Wang WJ, Ruan ZP, Wang SH, et al. PTEN inhibits the migration and invasion of HepG2 cells by coordinately decreasing MMP expression via the PI3K/Akt pathway. Oncol Rep. 2010;23(6):1593–600.PubMedGoogle Scholar
  13. 13.
    Chen JS, Wang Q, Fu XH, Huang XH, Chen XL, Cao LQ, et al. Involvement of PI3K/PTEN/AKT/mTOR pathway in invasion and metastasis in hepatocellular carcinoma: association with MMP-9. Hepatol Res. 2009;39(2):177–86. doi: 10.1111/j.1872-034X.2008.00449.x.PubMedCrossRefGoogle Scholar
  14. 14.
    Elia D, Madhala D, Ardon E, Reshef R, Halevy O. Sonic hedgehog promotes proliferation and differentiation of adult muscle cells: involvement of MAPK/ERK and PI3K/Akt pathways. Biochim Biophys Acta. 2007;1773(9):1438–46. doi: 10.1016/j.bbamcr.2007.06.006.PubMedCrossRefGoogle Scholar
  15. 15.
    Riobo NA, Lu K, Ai X, Haines GM, Emerson CP Jr. Phosphoinositide 3-kinase and Akt are essential for Sonic Hedgehog signaling. Proc Natl Acad Sci USA. 2006;103(12):4505–10. doi: 10.1073/pnas.0504337103.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Fan HX, Li HX, Chen D, Gao ZX, Zheng JH. Changes in the expression of MMP2, MMP9, and ColIV in stromal cells in oral squamous tongue cell carcinoma: relationships and prognostic implications. J Exp Clin Cancer Res. 2012;31:90. doi: 10.1186/1756-9966-31-90.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Katoh Y, Katoh M. Hedgehog signaling, epithelial-to-mesenchymal transition and miRNA (review). Int J Mol Med. 2008;22(3):271–5.PubMedGoogle Scholar
  18. 18.
    Zhang Z, Pan J, Li L, Wang Z, Xiao W, Li N. Survey of risk factors contributed to lymphatic metastasis in patients with oral tongue cancer by immunohistochemistry. J Oral Pathol Med. 2011;40(2):127–34. doi: 10.1111/j.1600-0714.2010.00953.x.PubMedCrossRefGoogle Scholar
  19. 19.
    Sobin LH, Fleming ID. TNM classification of malignant tumors, fifth edition (1997). Union Internationale Contre le Cancer and the American Joint Committee on Cancer. Cancer. 1997;80(9):1803–4. doi: 10.1002/(SICI)1097-0142(19971101)80:9<1803:AID-CNCR16>3.0.CO;2-9.PubMedCrossRefGoogle Scholar
  20. 20.
    Akdeniz O, Akduman D, Haksever M, Ozkarakas H, Muezzinoglu B. Relationships between clinical behavior of laryngeal squamous cell carcinomas and expression of VEGF, mmp-9 and e-cadherin. Asian Pac J Cancer Prev. 2013;14(9):5301–10.PubMedCrossRefGoogle Scholar
  21. 21.
    Vilen ST, Salo T, Sorsa T, Nyberg P. Fluctuating roles of matrix metalloproteinase-9 in oral squamous cell carcinoma. TheScientificWorldJournal. 2013;2013:920595. doi: 10.1155/2013/920595.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Huang X, Ketova T, Fleming JT, Wang H, Dey SK, Litingtung Y, et al. Sonic hedgehog signaling regulates a novel epithelial progenitor domain of the hindbrain choroid plexus. Development. 2009;136(15):2535–43. doi: 10.1242/dev.033795.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Leovic D, Sabol M, Ozretic P, Musani V, Car D, Marjanovic K, et al. Hh-Gli signaling pathway activity in oral and oropharyngeal squamous cell carcinoma. Head Neck. 2012;34(1):104–12. doi: 10.1002/hed.21696.PubMedCrossRefGoogle Scholar
  24. 24.
    Yan M, Wang L, Zuo H, Zhang Z, Chen W, Mao L, et al. HH/GLI signalling as a new therapeutic target for patients with oral squamous cell carcinoma. Oral Oncol. 2011;47(6):504–9. doi: 10.1016/j.oraloncology.2011.03.027.PubMedCrossRefGoogle Scholar
  25. 25.
    Lu JT, Zhao WD, He W, Wei W. Hedgehog signaling pathway mediates invasion and metastasis of hepatocellular carcinoma via ERK pathway. Acta Pharmacol Sin. 2012;33(5):691–700. doi: 10.1038/aps.2012.24.PubMedCrossRefGoogle Scholar
  26. 26.
    Asai J, Takenaka H, Kusano KF, Ii M, Luedemann C, Curry C, et al. Topical sonic hedgehog gene therapy accelerates wound healing in diabetes by enhancing endothelial progenitor cell-mediated microvascular remodeling. Circulation. 2006;113(20):2413–24. doi: 10.1161/CIRCULATIONAHA.105.603167.PubMedCrossRefGoogle Scholar
  27. 27.
    Chen JS, Huang XH, Wang Q, Chen XL, Fu XH, Tan HX, et al. FAK is involved in invasion and metastasis of hepatocellular carcinoma. Clin Exp Metastasis. 2010;27(2):71–82. doi: 10.1007/s10585-010-9306-3.PubMedCrossRefGoogle Scholar
  28. 28.
    Huber MA, Kraut N, Beug H. Molecular requirements for epithelial–mesenchymal transition during tumor progression. Curr Opin Cell Biol. 2005;17(5):548–58. doi: 10.1016/ Scholar
  29. 29.
    Matsumura T, Makino R, Mitamura K. Frequent down-regulation of E-cadherin by genetic and epigenetic changes in the malignant progression of hepatocellular carcinomas. Clin Cancer Res. 2001;7(3):594–9.PubMedGoogle Scholar
  30. 30.
    Choi Y, Lee HJ, Jang MH, Gwak JM, Lee KS, Kim EJ, et al. Epithelial–mesenchymal transition increases during the progression of in situ to invasive basal-like breast cancer. Hum Pathol. 2013;44(11):2581–9. doi: 10.1016/j.humpath.2013.07.003.PubMedCrossRefGoogle Scholar
  31. 31.
    Reddy P, Liu L, Ren C, Lindgren P, Boman K, Shen Y, et al. Formation of E-cadherin-mediated cell–cell adhesion activates AKT and mitogen activated protein kinase via phosphatidylinositol 3 kinase and ligand-independent activation of epidermal growth factor receptor in ovarian cancer cells. Mol Endocrinol. 2005;19(10):2564–78. doi: 10.1210/me.2004-0342.PubMedCrossRefGoogle Scholar
  32. 32.
    Bussink J, Kaanders JH, van der Kogel AJ. Microenvironmental transformations by VEGF- and EGF-receptor inhibition and potential implications for responsiveness to radiotherapy. Radiother Oncol. 2007;82(1):10–7. doi: 10.1016/j.radonc.2006.10.022.PubMedCrossRefGoogle Scholar
  33. 33.
    Qian X, Karpova T, Sheppard AM, McNally J, Lowy DR. E-cadherin-mediated adhesion inhibits ligand-dependent activation of diverse receptor tyrosine kinases. EMBO J. 2004;23(8):1739–48. doi: 10.1038/sj.emboj.7600136.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Fan CC, Wang TY, Cheng YA, Jiang SS, Cheng CW, Lee AY, et al. Expression of E-cadherin, Twist, and p53 and their prognostic value in patients with oral squamous cell carcinoma. J Cancer Res Clin Oncol. 2013;139(10):1735–44. doi: 10.1007/s00432-013-1499-9.PubMedCrossRefGoogle Scholar
  35. 35.
    Eriksen JG, Steiniche T, Sogaard H, Overgaard J. Expression of integrins and E-cadherin in squamous cell carcinomas of the head and neck. APMIS. 2004;112(9):560–8. doi: 10.1111/j.1600-0463.2004.apm1120902.x.PubMedCrossRefGoogle Scholar
  36. 36.
    Wang ZS, Shen Y, Li X, Zhou CZ, Wen YG, Jin YB et al. Significance and prognostic value of Gli-1 and Snail/E-cadherin expression in progressive gastric cancer. Tumour Biol. 2013. doi: 10.1007/s13277-013-1185-1.
  37. 37.
    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(2):389–98. doi: 10.1038/sj.bjc.6604846.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Bai CB, Auerbach W, Lee JS, Stephen D, Joyner AL. Gli2, but not Gli1, is required for initial Shh signaling and ectopic activation of the Shh pathway. Development. 2002;129(20):4753–61.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Hai-Xia Fan
    • 1
  • Shan Wang
    • 1
  • Hong Zhao
    • 1
  • Nian Liu
    • 1
  • Dong Chen
    • 2
  • Miao Sun
    • 2
  • Jin-Hua Zheng
    • 1
  1. 1.Department of Anatomy, Basic Medical Science CollegeHarbin Medical UniversityHarbinPeople’s Republic of China
  2. 2.Department of Oral and Maxillofacial Surgery, Stomatological HospitalHarbin Medical UniversityHarbinPeople’s Republic of China

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