1. 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
- Author
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Chuan‑Lu Jiang, Ping Zhang, Xing Liu, Hongjun Wang, Dan Zhao, Hui‑Bin Liu, Zhi‑Ren Zhang, Qiu-Shi Wang, Chen‑Long Li, Liang Chang, and Wen‑Zhong Du
- Subjects
Cancer Research ,Cyclopamine ,Cell ,Biology ,Matrix metalloproteinase ,Biochemistry ,chemistry.chemical_compound ,Phosphatidylinositol 3-Kinases ,Cell Movement ,Cell Line, Tumor ,Genetics ,medicine ,Cell Adhesion ,Humans ,LY294002 ,Hedgehog Proteins ,Neoplasm Invasiveness ,Sonic hedgehog ,Molecular Biology ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Brain Neoplasms ,Brain ,Cell migration ,Cell cycle ,Hedgehog signaling pathway ,Cell biology ,medicine.anatomical_structure ,chemistry ,Oncology ,Matrix Metalloproteinase 9 ,Apoptosis ,Immunology ,biology.protein ,Molecular Medicine ,Matrix Metalloproteinase 2 ,Signal transduction ,Corrigendum ,Glioblastoma ,Proto-Oncogene Proteins c-akt ,Signal Transduction - 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.
- Published
- 2015