Differential expression of hedgehog signaling components and Snail/E-cadherin in human brain tumors.
The hedgehog (Hh) transcription factor Gli induces transformation of epithelial cells via induction of Snail, a repressor of E-cadherin. Epithelial-mesenchymal transition is also a determinant of the progression of tumorigenesis, following down-regulation of E-cadherin. However, the role of Hh signaling components and Snail/E-cadherin in brain tumors is not yet fully understood. We analyzed the expression of Hh signaling components and Snail/E-cadherin in 69 brain tumors by reverse transcription-polymerase chain reaction (RT-PCR). The data showed that overexpression of Smo (35/69), Ptch (50/69), Gli1 (56/69), Gli2 (29/69) and N-myc (39/69) might contribute to brain tumorigenesis. Our results also indicated that Snail and E-cadherin showed opposing expression in malignant tumors (high grade astrocytoma and metastasis). Snail and E-cadherin showed less correlation in benign brain tumors. We further investigated mutations of Gli2 and Snail by RT-PCR and direct sequencing. No mutation was observed on Gli2 but several sporadic mutations on Snail were found, including S96G, S111L, S111L/S119Y and one nonsense mutation at codon 158 (Y158*). An in vitro E-cadherin promoter assay showed that S96G, S111L, S111L/S119Y Snail mutants were decreased by 15, 25 and 50%, respectively, whereas Y158* was increased by 40% compared to wild-type. Furthermore, our data showed that wild-type Snail and S96G, S111L, S111L/S119Y translocated to the nucleus, while the Y158* mutant failed to translocate to the nucleus. Taken together, our results demonstrate that Hh signaling components, the expression and mutations of Snail and the expression of E-cadherin may play an important role in human brain tumorigenesis.
Chou
Chia-Hua
CH
Department of Biochemistry, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC.
Lieu
Ann-Shung
AS
Wu
Chia-Hung
CH
Chang
Li-Kwan
LK
Loh
Joon-Khim
JK
Lin
Run-Chin
RC
Chen
Wei-Jay
WJ
Liao
Huei-De
HD
Fu
Wen-Shane
WS
Chang
Chung-Shing
CS
Lin
Ching-Chih
CC
Hsu
Ching-Mei
CM
Chio
Chung-Ching
CC
Howng
Shen-Long
SL
Hong
Yi-Ren
YR
D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D013347:Subcellular Fractions / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism
D015820:Cadherins; D053823:Hedgehog Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors