Interruption of β-catenin suppresses the EGFR pathway by blocking multiple oncogenic targets in human glioma cells.
Malignant gliomas are the most common type of intrinsic central nervous system (CNS) tumors with high mortality and morbidity. β-catenin is overexpressed in human glioblastoma and knockdown of β-catenin inhibits glioblastoma cell proliferation and invasive ability, and induces apoptotic cell death. Furthermore, treating the nude mice carrying established subcutaneous LN229 gliomas with siRNA targeting β-catenin intratumorally also delayed the tumor growth. However, the mechanisms of down-regulation of β-catenin that represses glioblastoma malignancy behavior remain to be elucidated. We utilized text-mining of MEDLINE abstracts with natural language processing to establish the β-catenin biologic association network, and identified several interactions of this network with the EGFR pathway. In both in vitro and in vivo studies, our results confirmed down-regulation of β-catenin induced reduced expression of EGFR, STAT3 and AKT1 mRNA and protein, besides, the level of phosphorylated Akt also decreased. A similar reduction in expression of CyclinD1, MMP2 and MMP9, downstream genes of the EGFR pathway, was observed. These results suggest that the Wnt/β-catenin pathway regulates glioma cell proliferation and invasion, in part via the EGFR pathway.
Laboratory of Neuro-Oncology, Tianjin Neurological Institute, PR China.
Xiao
X
Yue
FengMing
F
Lan
WeiDong
W
Yang
Yang
Y
Yang
Lei
L
Han
AnLing
A
Zhang
JiLong
J
Liu
HuaZong
H
Zeng
Tao
T
Jiang
PeiYu
P
Pu
ChunSheng
C
Kang
D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry / Q000379:methods; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism*
D002273:Carcinogens; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051176:beta Catenin; C512478:EGFR protein, human; D066246:ErbB Receptors; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D020778:Matrix Metalloproteinase 2