Slit2 inhibits glioma cell invasion in the brain by suppression of Cdc42 activity.
Acquisition of insidious invasiveness by malignant glioma cells involves multiple genetic alterations in signaling pathways. Slit2, a chemorepulsive factor, controls cell migration of neuronal and glial cells during development and inhibits chemotaxic migration of various types of cells in vitro. However, the role of Slit2 in vitro remains controversial, and the biological significance of Slit2 expression in cancer cell invasion in vivo has not yet been determined. In the present study, we characterized the effects of Slit2 expression on the migration and invasion of invasive glioma cells in vitro and in vivo. By reverse transcriptase polymerase chain reaction (PCR) analyses, Slit2 was found to be expressed at lower levels in primary glioma specimens and invasive glioma cells compared with normal human brain cells and astrocytes. Ectopic expression of Slit2 or treatment with recombinant Slit2 on glioma cells attenuates cell migration and invasion through inhibition of Cdc42 activity in vitro. Cellular depletion of Robo1, a cognate receptor for Slit2, prevented Slit2 inhibition of Cdc42 activity and glioma cell migration. In vivo, expression of Slit2 by invasive SNB19 glioma cells markedly inhibited glioma cell infiltration into the brain of mice. Moreover, impediment of glioma cell invasion by Slit2 did not affect the expression of N-cadherin and beta-catenin in glioma cells. These results provide the first evidence demonstrating that Slit2-Robo1 inhibits glioma invasion through attenuating Cdc42 activity in vitro and in the brain. Understanding the mechanisms of Slit2-Robo1 inhibition of glioma cell invasion will foster new treatments for malignant gliomas.
Yiin
Jia-Jean
JJ
Department of Pathology, University of Pittsburgh Cancer Institute, Research Pavilion at the Hillman Cancer Center, Pittsburgh, PA 15213, USA.
Hu
Bo
B
Jarzynka
Michael J
MJ
Feng
Haizhong
H
Liu
Kui-Wei
KW
Wu
Jane Y
JY
Ma
Hsin-I
HI
Cheng
Shi-Yuan
SY
D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D005910:Glioma / Q000235:genetics / Q000473:pathology*; D006801:Humans; D015151:Immunoblotting; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009419:Nerve Tissue Proteins / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014945:Wound Healing; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D000098552:Slit Homolog 2 Protein
D015820:Cadherins; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051176:beta Catenin; D020764:cdc42 GTP-Binding Protein; D000098552:Slit Homolog 2 Protein