Expression of vascular endothelial growth factor-A and mRNA stability factor HuR in human astrocytic tumors.
High-grade astrocytic tumors, such as glioblastoma, possess rich vascular components, which are necessary for their growth. VEGF-A is considered to be the major mediator of angiogenesis in malignant neoplasms including high-grade astrocytic tumors. The upregulation of VEGF-A expression in tumor cells is induced by two mechanisms: the transcriptional activation and the post-transcriptional stabilization of VEGF-A mRNA. While the former mechanism mediated by hypoxia inducible factor-1 alpha (HIF-1alpha) has been revealed, the latter mediated by mRNA stability factor HuR remains unclear in astrocytic tumors. In the present study, we investigated the expression of VEGF-A and mRNA stability factor HuR in supratentorial astrocytic tumors of 27 adults using RT-PCR, ELISA, and immunohistochemistry. Furthermore, we studied the involvement of HuR in the upregulation of VEGF-A expression using malignant astrocytoma cell lines. In higher-grade astrocytic tumors, the level of VEGF-A and microvascular density were elevated, cytoplasmic expression of HuR, which potentially means the protection of VEGF-A mRNA from degradation by ribonucleases, appeared, and they were correlated positively. In in vitro experiments, the inhibition of the cytoplasmic translocation of HuR protein by leptomycin B (LMB) reduced the upregulation of VEGF-A expression in malignant astrocytic tumor cells under hypoxic conditions. These findings suggest that the expression of VEGF-A and cytoplasmic translocation of HuR relates to the histological grade, and that HuR is involved in the upregulation of VEGF-A expression, in human astrocytic tumors.
Ido
Kazunori
K
Department of Neurosurgery, Faculty of Medical Sciences, University of Fukui, Yoshida-gun, Fukui, Japan.
Nakagawa
Takao
T
Sakuma
Takahiro
T
Takeuchi
Hiroaki
H
Sato
Kazufumi
K
Kubota
Toshihiko
T
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D043925:Angiogenesis Inducing Agents; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism*; D001254:Astrocytoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003593:Cytoplasm / Q000378:metabolism; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D004797:Enzyme-Linked Immunosorbent Assay; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005260:Female; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D012323:RNA Processing, Post-Transcriptional; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015173:Supratentorial Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
D043925:Angiogenesis Inducing Agents; D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D005231:Fatty Acids, Unsaturated; D016601:RNA-Binding Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C038753:leptomycin B