High expression of a novel splicing variant of VEGF, L-VEGF144 in glioblastoma multiforme is associated with a poorer prognosis in bevacizumab treatment
A previous study confirmed that a novel splicing variant of large vascular endothelial growth factor (L-VEGF) termed L-VEGF144, a nucleolus protein, is found in glioblastoma cells and specimens, but the actual biological function and clinical significance of L-VEGF144 remain unclear.
In this study, we analyzed the expression of L-VEGF144 in 68 glioblastoma multiforme specimens using reverse transcriptase-polymerase chain reaction analysis.
The results showed that the high expression of L-VEGF144 was associated with a poor prognosis in the bevacizumab plus concurrent chemoradiotherapy with temozolomide treatment. In addition, we constructed a series truncated and mutant form of L-VEGF144 to confirm that exon 6a of L-VEGF144 is able to engage in the nuclear importation and found that 8 lysines within exon 6a play a critical role in the nucleolus aggregation of L-VEGF144. Also, the transfection of the L-VEGF144 increased the number of nucleoli. Furthermore, the recombinant protein Flag-L-VEGF144 and commercial VEGF protein have similar growth stimulatory activities in terms of inducing glioblastoma cell proliferation in vitro.
Taken together, these results indicated that the expression of L-VEGF144 could potentially serve as an independent indicator of poor prognosis in bevacizumab treatment.
KeywordsBevacizumab Nucleolus protein Novel VEGF isoform GBM Prognosis Mitogen
Vascular endothelial growth factor A
Reverse transcriptase-polymerase chain reaction
Heparin sulfate proteoglycans
U-87 MG cells
We appreciated Prof Dr. Shih-Lan Hsu (Department of Medical Research, Taichung Veterans General Hospital) for providing valuable suggestions. This study was supported by grants from Taichung Veterans General Hospital; Grant Numbers: TCVGH-CTUST 10577011, TCVGH-1054904C, TCVGH-1064904C, TCVGH-YM1060206, TCVGH-10549038, Taiwan.
Compliance with ethical standards
Conflict of interest
No potential conflicts of interest were disclosed.
- 4.Zhang HT, Scott PA, Morbidelli L, Peak S, Moore J, Turley H, Harris AL, Ziche M, Bicknell R (2000) The 121 amino acid isoform of vascular endothelial growth factor is more strongly tumorigenic than other splice variants in vivo. Br J Cancer 83:63–68. https://doi.org/10.1054/bjoc.2000.1279 CrossRefPubMedPubMedCentralGoogle Scholar