RRC ID 49267
著者 Chiba R, Akiya M, Hashimura M, Oguri Y, Inukai M, Hara A, Saegusa M.
タイトル ALK signaling cascade confers multiple advantages to glioblastoma cells through neovascularization and cell proliferation.
ジャーナル PLoS One
Abstract Anaplastic lymphoma kinase (ALK), which is a receptor tyrosine kinase, is essentially and transiently expressed in the developing nervous system. Here we examined the functional role of the ALK gene in glioblastomas (GBMs). In clinical samples of GBMs, high ALK expression without gene rearrangements or mutations was frequently observed in perivascular lesions, in contrast to the relatively low expression in the perinecrotic areas, which was positively correlated with N-myc and phosphorylated (p) Stat3 scores and Ki-67 labeling indices. ALK immunoreactivity was also found to be associated with neovascular features including vascular co-option and vascular mimicry. In astrocytoma cell lines, cells stably overexpressing full-length ALK showed an increase in expression of pStat3 and pAkt proteins, as well as hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor-A (VEGF-A) mRNAs, in contrast to cells with knockdown of endogenous ALK which showed decreased expression of these molecules. Transfection of the constitutively active form of Stat3 induced an increase in HIF-1α promoter activity, and the overexpression of HIF-1α in turn resulted in enhancement of VEGF-A promoter activity. In addition, cells with overexpression or knockdown of ALK also showed a tendency toward increased and decreased proliferation, respectively, through changes in expression of pAkt and pStat3. Finally, ALK promoter was significantly activated by transfection of Sox4 and N-myc, which are known to contribute to neuronal properties. These findings therefore suggest that N-myc/Sox4-mediated ALK signaling cascades containing Stat3, Akt, HIF-1α, and VEGF-A confer multiple advantages to tumor growth through alterations in neovascularization and cell proliferation in GBMs.
巻・号 12(8)
ページ e0183516
公開日 2017-8-24
DOI 10.1371/journal.pone.0183516
PII PONE-D-17-15441
PMID 28837676
PMC PMC5570309
MeSH Anaplastic Lymphoma Kinase Brain Neoplasms / blood supply Brain Neoplasms / metabolism Brain Neoplasms / pathology* Cell Line, Tumor Cell Proliferation* Glioblastoma / blood supply Glioblastoma / metabolism Glioblastoma / pathology* Humans Immunohistochemistry Neovascularization, Pathologic* Prognosis Receptor Protein-Tyrosine Kinases / metabolism* Signal Transduction*
IF 2.74
引用数 7
リソース情報
遺伝子材料 pGL4-phHIF1A (RDB07693)