Neuropilin-2 mediated β-catenin signaling and survival in human gastro-intestinal cancer cell lines.
NRP-2 is a high-affinity kinase-deficient receptor for ligands belonging to the class 3 semaphorin and vascular endothelial growth factor families. NRP-2 has been detected on the surface of several types of human cancer cells, but its expression and function in gastrointestinal (GI) cancer cells remains to be determined. We sought to determine the function of NRP-2 in mediating downstream signals regulating the growth and survival of human gastrointestinal cancer cells. In human gastric cancer specimens, NRP-2 expression was detected in tumor tissues but not in adjacent normal mucosa. In CNDT 2.5 cells, shRNA mediated knockdown NRP-2 expression led to decreased migration and invasion in vitro (p<0.01). Focused gene-array analysis demonstrated that loss of NRP-2 reduced the expression of a critical metastasis mediator gene, S100A4. Steady-state levels and function of β-catenin, a known regulator of S100A4, were also decreased in the shNRP-2 clones. Furthermore, knockdown of NRP-2 sensitized CNDT 2.5 cells in vitro to 5FU toxicity. This effect was associated with activation of caspases 3 and 7, cleavage of PARP, and downregulation of Bcl-2. In vivo growth of CNDT 2.5 cells in the livers of nude mice was significantly decreased in the shNRP-2 group (p<0.05). Intraperitoneal administration of NRP-2 siRNA-DOPC decreased the tumor burden in mice (p = 0.01). Collectively, our results demonstrate that tumor cell-derived NRP-2 mediates critical survival signaling in gastrointestinal cancer cells.
Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
Shaija
S
Samuel
Puja
P
Gaur
Fan
F
Fan
Ling
L
Xia
Michael J
MJ
Gray
Nikolaos A
NA
Dallas
Debashish
D
Bose
Cristian
C
Rodriguez-Aguayo
Gabriel
G
Lopez-Berestein
Greg
G
Plowman
Anil
A
Bagri
Anil K
AK
Sood
Lee M
LM
Ellis
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D039943:Neuropilin-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D021381:Protein Transport; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000235:genetics; D015398:Signal Transduction; D051176:beta Catenin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D039943:Neuropilin-2; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; D051176:beta Catenin; C077591:S100A4 protein, human