Open Access

Activation of sonic hedgehog signaling enhances cell migration and invasion by induction of matrix metalloproteinase-2 and -9 via the phosphoinositide-3 kinase/AKT signaling pathway in glioblastoma

Corrigendum in: /mmr/12/5/7815

  • Authors:
    • Liang Chang
    • Dan Zhao
    • Hui‑Bin Liu
    • Qiu‑Shi Wang
    • Ping Zhang
    • Chen‑Long Li
    • Wen‑Zhong Du
    • Hong‑Jun Wang
    • Xing Liu
    • Zhi‑Ren Zhang
    • Chuan‑Lu Jiang
  • View Affiliations

  • Published online on: August 18, 2015     https://doi.org/10.3892/mmr.2015.4229
  • Pages: 6702-6710
  • Copyright: © Chang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Aberrant hedgehog signaling contributes to the development of various malignancies, including glioblastoma (GBM). However, the potential mechanism of hedgehog signaling in GBM migration and invasion has remained to be elucidated. The present study showed that enhanced hedgehog signaling by recombinant human sonic hedgehog N‑terminal peptide (rhSHH) promoted the adhesion, invasion and migration of GBM cells, accompanied by increases in mRNA and protein levels of matrix metalloproteinase‑2 (MMP‑2) and MMP‑9. However, inhibition of hedgehog signaling with cyclopamine suppressed the adhesion, invasion and migration of GBM cells, accompanied by decreases in mRNA and protein levels of MMP‑2 and ‑9. Furthermore, it was found that MMP‑2- and MMP‑9-neutralizing antibodies or GAM6001 reversed the inductive effects of rhSHH on cell migration and invasion. In addition, enhanced hedgehog signaling by rhSHH increased AKT phosphorylation, whereas blockade of hedgehog signaling decreased AKT phosphorylations. Further experiments showed that LY294002, an inhibitor of phosphoinositide-3 kinase (PI3K), decreased rhSHH‑induced upregulation of MMP‑2 and ‑9. Finally, the protein expression of glioblastoma-associated oncogene 1 was positively correlated with levels of phosphorylated AKT as well as protein expressions of MMP‑2 and ‑9 in GBM tissue samples. In conclusion, the present study indicated that the hedgehog pathway regulates GBM-cell migration and invasion by increasing MMP-2 and MMP-9 production via the PI3K/AKT pathway.

References

1 

Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW and Kleihues P: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 114:97–109. 2007. View Article : Google Scholar : PubMed/NCBI

2 

DeAngelis LM: Brain tumors. N Engl J Med. 344:114–123. 2001. View Article : Google Scholar : PubMed/NCBI

3 

Matsumura H, Ohnishi T, Kanemura Y, Maruno M and Yoshimine T: Quantitative analysis of glioma cell invasion by confocal laser scanning microscopy in a novel brain slice model. Biochem Biophys Res Commun. 269:513–520. 2000. View Article : Google Scholar : PubMed/NCBI

4 

Zhou X, Zhan W, Bian W, Hua L, Shi Q, Xie S, Yang D, Li Y, Zhang X, Liu G and Yu R: GOLPH3 regulates the migration and invasion of glioma cells though RhoA. Biochem Biophys Res Commun. 433:338–344. 2013. View Article : Google Scholar : PubMed/NCBI

5 

Hao K, Tian XD, Qin CF, Xie XH and Yang YM: Hedgehog signaling pathway regulates human pancreatic cancer cell proliferation and metastasis. Oncol Rep. 29:1124–1132. 2013.PubMed/NCBI

6 

Qin CF, Hao K, Tian XD, Xie XH and Yang YM: Combined effects of EGFR and Hedgehog signaling pathway inhibition on the proliferation and apoptosis of pancreatic cancer cells. Oncol Rep. 28:519–526. 2012.PubMed/NCBI

7 

Fuller K, O'Connell JT, Gordon J, Mauti O and Eggenschwiler J: Rab23 regulates Nodal signaling in vertebrate left-right patterning independently of the Hedgehog pathway. Dev Biol. 391:182–195. 2014. View Article : Google Scholar : PubMed/NCBI

8 

Ju B, Chen W, Spitsbergen JM, Lu J, Vogel P, Peters JL, Wang YD, Orr BA, Wu J and Henson HE: Activation of Sonic hedgehog signaling in neural progenitor cells promotes glioma development in the zebrafish optic pathway. Oncogenesis. 3:e962014. View Article : Google Scholar : PubMed/NCBI

9 

Onishi H and Katano M: Hedgehog signaling pathway as a new therapeutic target in pancreatic cancer. World J Gastroenterol. 20:2335–2342. 2014. View Article : Google Scholar : PubMed/NCBI

10 

Matsushita S, Onishi H, Nakano K, Nagamatsu I, Imaizumi A, Hattori M, Oda Y, Tanaka M and Katano M: Hedgehog signaling pathway is a potential therapeutic target for gallbladder cancer. Cancer Sci. 105:272–280. 2014. View Article : Google Scholar : PubMed/NCBI

11 

Chen Q, Gao G and Luo S: Hedgehog signaling pathway and ovarian cancer. Chin J Cancer Res. 25:346–353. 2013.PubMed/NCBI

12 

Wan J, Zhou J, Zhao H, Wang M, Wei Z, Gao H, Wang Y and Cui H: Sonic hedgehog pathway contributes to gastric cancer cell growth and proliferation. Biores Open Access. 3:53–59. 2014. View Article : Google Scholar : PubMed/NCBI

13 

Zhu W, You Z, Li T, Yu C, Tao G, Hu M and Chen X: Correlation of hedgehog signal activation with chemoradiotherapy sensitivity and survival in esophageal squamous cell carcinomas. Jpn J Clin Oncol. 41:386–393. 2011. View Article : Google Scholar

14 

Aparna M, Rao L, Kunhikatta V and Radhakrishnan R: The role of MMP-2 and MMP-9 as prognostic markers in the early stages of tongue squamous cell carcinoma. J Oral Pathol Med. 44:345–352. 2015. View Article : Google Scholar

15 

Zhou M, Qin S, Chu Y, Wang F, Chen L and Lu Y: Immunolocalization of MMP-2 and MMP-9 in human rheumatoid synovium. Int J Clin Exp Pathol. 7:3048–3056. 2014.PubMed/NCBI

16 

Yang W, Li Q and Pan Z: Sphingosine-1-phosphate promotes extravillous trophoblast cell invasion by activating MEK/ERK/MMP-2 signaling pathways via S1P/S1PR1 axis activation. PLoS One. 9:e1067252014. View Article : Google Scholar : PubMed/NCBI

17 

Liu WH and Chang LS: Caffeine induces matrix metalloproteinase-2 (MMP-2) and MMP-9 down-regulation in human leukemia U937 cells via Ca2+/ROS-mediated suppression of ERK/c-fos pathway and activation of p38 MAPK/c-jun pathway. J Cell Physiol. 224:775–785. 2010. View Article : Google Scholar : PubMed/NCBI

18 

Kang MH, Oh SC, Lee HJ, Kang HN, Kim JL, Kim JS and Yoo YA: Metastatic function of BMP-2 in gastric cancer cells: The role of PI3K/AKT, MAPK, the NF-κB pathway, and MMP-9 expression. Exp Cell Res. 317:1746–1762. 2011. View Article : Google Scholar : PubMed/NCBI

19 

Du WZ, Feng Y, Wang XF, Piao XY, Cui YQ, Chen LC, Lei XH, Sun X, Liu X, Wang HB, et al: Curcumin suppresses malignant glioma cells growth and induces apoptosis by inhibition of SHH/GLI1 signaling pathway in vitro and vivo. CNS Neurosci Ther. 19:926–936. 2013. View Article : Google Scholar : PubMed/NCBI

20 

Wang Y, Chen L, Bao Z, Li S, You G, Yan W, Shi Z, Liu Y, Yang P, Zhang W, et al: Inhibition of STAT3 reverses alkylator resistance through modulation of the AKT and β-catenin signaling pathways. Oncol Rep. 26:1173–1180. 2011.PubMed/NCBI

21 

Morgenroth A, Vogg AT, Ermert K, Zlatopolskiy B and Mottaghy FM: Hedgehog signaling sensitizes glioma stem cells to endogenous nano-irradiation. Oncotarget. 5:5483–5493. 2014. View Article : Google Scholar : PubMed/NCBI

22 

Dixit D, Ghildiyal R, Anto NP, Ghosh S, Sharma V and Sen E: Guggulsterone sensitizes glioblastoma cells to Sonic hedgehog inhibitor SANT-1 induced apoptosis in a Ras/NFκB dependent manner. Cancer Lett. 336:347–358. 2013. View Article : Google Scholar : PubMed/NCBI

23 

Das G, Shiras A, Shanmuganandam K and Shastry P: Rictor regulates MMP-9 activity and invasion through Raf-1-MEK-ERK signaling pathway in glioma cells. Mol Carcinog. 50:412–423. 2011. View Article : Google Scholar : PubMed/NCBI

24 

Senft C, Priester M, Polacin M, Schröder K, Seifert V, Kögel D and Weissenberger J: Inhibition of the JAK-2/STAT3 signaling pathway impedes the migratory and invasive potential of human glioblastoma cells. J Neurooncol. 101:393–403. 2011. View Article : Google Scholar

25 

Zhao Y, Xiao A, Dipierro CG, Abdel-Fattah R, Amos S, Redpath GT, Carpenter JE, Pieper RO and Hussaini IM: H-Ras increases urokinase expression and cell invasion in genetically modified human astrocytes through Ras/Raf/MEK signaling pathway. Glia. 56:917–924. 2008. View Article : Google Scholar : PubMed/NCBI

26 

Porta C and Figlin RA: Phosphatidylinositol-3-kinase/Akt signaling pathway and kidney cancer and the therapeutic potential of phosphatidylinositol-3-kinase/Akt inhibitors. J Urol. 182:2569–2577. 2009. View Article : Google Scholar : PubMed/NCBI

27 

Zhang E, Feng X, Liu F, Zhang P2, Liang J and Tang X: Roles of PI3K/Akt and c-Jun signaling pathways in human papillomavirus type 16 oncoprotein-induced HIF-1α, VEGF and IL-8 expression and in vitro angiogenesis in non-small cell lung cancer cells. PLoS One. 9:e1034402014. View Article : Google Scholar

28 

Mazzoletti M and Broggini M: PI3K/AKT/mTOR inhibitors in ovarian cancer. Curr Med Chem. 17:4433–4447. 2010. View Article : Google Scholar : PubMed/NCBI

29 

Yoo YA, Kang MH, Lee HJ, Kim BH, Park JK, Kim HK, Kim JS and Oh SC: Sonic hedgehog pathway promotes metastasis and lymphangiogenesis via activation of Akt, EMT and MMP-9 pathway in gastric cancer. Cancer Res. 71:7061–7070. 2011. View Article : Google Scholar : PubMed/NCBI

30 

Morton JP, Mongeau ME, Klimstra DS, Morris JP, Lee YC, Kawaguchi Y, Wright CV, Hebrok M and Lewis BC: Sonic hedgehog acts at multiple stages during pancreatic tumorigenesis. Proc Natl Acad Sci USA. 104:5103–5108. 2007. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

November 2015
Volume 12 Issue 5

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Chang, L., Zhao, D., Liu, H., Wang, Q., Zhang, P., Li, C. ... Jiang, C. (2015). Activation of sonic hedgehog signaling enhances cell migration and invasion by induction of matrix metalloproteinase-2 and -9 via the phosphoinositide-3 kinase/AKT signaling pathway in glioblastoma Corrigendum in /mmr/12/5/7815. Molecular Medicine Reports, 12, 6702-6710. https://doi.org/10.3892/mmr.2015.4229
MLA
Chang, L., Zhao, D., Liu, H., Wang, Q., Zhang, P., Li, C., Du, W., Wang, H., Liu, X., Zhang, Z., Jiang, C."Activation of sonic hedgehog signaling enhances cell migration and invasion by induction of matrix metalloproteinase-2 and -9 via the phosphoinositide-3 kinase/AKT signaling pathway in glioblastoma Corrigendum in /mmr/12/5/7815". Molecular Medicine Reports 12.5 (2015): 6702-6710.
Chicago
Chang, L., Zhao, D., Liu, H., Wang, Q., Zhang, P., Li, C., Du, W., Wang, H., Liu, X., Zhang, Z., Jiang, C."Activation of sonic hedgehog signaling enhances cell migration and invasion by induction of matrix metalloproteinase-2 and -9 via the phosphoinositide-3 kinase/AKT signaling pathway in glioblastoma Corrigendum in /mmr/12/5/7815". Molecular Medicine Reports 12, no. 5 (2015): 6702-6710. https://doi.org/10.3892/mmr.2015.4229