Human neuroblastomas with unfavorable biologies express high levels of brain-derived neurotrophic factor mRNA and a variety of its variants.
The expression of human brain-derived neurotrophic factor (BDNF) was investigated in 16 primary human neuroblastomas with favorable biologies, 15 with unfavorable biologies, and in human neuroblastoma cell lines. We demonstrated higher expressions of human BDNF mRNA in neuroblastomas with unfavorable biologies and with N-myc amplification than in those with favorable biologies. For the first time we revealed the composition of splice variants of human BDNF mRNA and analyzed their expression in neuroblastomas by reverse transcription polymerase chain reaction (RT-PCR). Interestingly, human BDNF mRNA consisted of at least six isoforms, four isoforms resembling those of rat BDNF mRNA, a human-specific isoform and a new isoform. The expression of four isoforms were more prominent in tumors with unfavorable biologies than in those with favorable biologies (P<0.05). As previously we had reported, over 80% of the primary tumors expressed either the full-length form of BDNF receptor, TRKB, or a truncated form of TRKB lacking the tyrosine kinase domain. The full-length TRKB was predominantly detected in tumors with unfavorable biologies, and the truncated one in those with favorable biologies. These results suggest that an autocrine and/or paracrine mechanism involving BDNF may stimulate signal transduction via TRKB receptors rich in neuroblastomas with unfavorable biologies, resulting in an aberrant survival of tumor cells.
Aoyama
M
M
Department of Pediatrics, Nagoya City University Medical School, Mizuho-ku, 467-8601, Nagoya, Japan. ao.mine@med.nagoya-cu.ac.jp
Asai
K
K
Shishikura
T
T
Kawamoto
T
T
Miyachi
T
T
Yokoi
T
T
Togari
H
H
Wada
Y
Y
Kato
T
T
Nakagawara
A
A
D000367:Age Factors; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis*; D018076:DNA, Complementary / Q000378:metabolism; D005091:Exons; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008969:Molecular Sequence Data; D009447:Neuroblastoma / Q000378:metabolism*; D020033:Protein Isoforms; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D019208:Brain-Derived Neurotrophic Factor; D018076:DNA, Complementary; D020033:Protein Isoforms; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger