title: 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.
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.
authors: Department of Neurosurgery, The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
authors: Liang
authors: L
authors: Chang
authors: Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
authors: Dan
authors: D
authors: Zhao
authors: Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
authors: Hui-Bin
authors: HB
authors: Liu
authors: Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
authors: Qiu-Shi
authors: QS
authors: Wang
authors: Department of Neurosurgery, The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
authors: Ping
authors: P
authors: Zhang
authors: Department of Neurosurgery, The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
authors: Chen-Long
authors: CL
authors: Li
authors: Department of Neurosurgery, The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
authors: Wen-Zhong
authors: WZ
authors: Du
authors: Department of Neurosurgery, The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
authors: Hong-Jun
authors: HJ
authors: Wang
authors: Department of Neurosurgery, The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
authors: Xing
authors: X
authors: Liu
authors: Department of Clinical Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
authors: Zhi-Ren
authors: ZR
authors: Zhang
authors: Department of Neurosurgery, The Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
authors: Chuan-Lu
authors: CL
authors: Jiang
mesh_terms: D001921:Brain / Q000378:metabolism / Q000473:pathology*; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D053823:Hedgehog Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9