Role of SCC-S2 in experimental metastasis and modulation of VEGFR-2, MMP-1, and MMP-9 expression.
SCC-S2/GG2-1/NDED (approved gene symbol TNFAIP8) is a transcription factor NF-kappaB-inducible, antiapoptotic, and oncogenic molecule. In this study, we examined the role of SCC-S2 in invasion and experimental metastasis. We demonstrate that expression of SCC-S2 cDNA in MDA-MB 435 human breast cancer cells is associated with enhanced invasion in vitro and increased frequency of pulmonary colonization of tumor cells in athymic mice. Systemic treatment of athymic mice with a cationic liposomal formulation of SCC-S2 antisense oligo led to decreased incidence of pulmonary metastasis and inhibition of SCC-S2 expression in vivo. Antisense inhibition of endogenous SCC-S2 expression correlated with decreased expression of VEGF receptor-2 in tumor cells and human lung microvascular endothelial cells and loss of endothelial cell viability. In addition, downregulation of SCC-S2 expression in tumor cells was associated with decreased expression of known metastasis-related molecules MMP-1 and MMP-9. These results demonstrate a novel role for SCC-S2 in tumor progression, involving multiple effectors, and provide a basis for SCC-S2-targeted cancer gene therapy.
Zhang
Chuanbo
C
Department of Radiation Medicine, Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA.
Chakravarty
Debyani
D
Sakabe
Isamu
I
Mewani
Rajshree R
RR
Boudreau
Howard E
HE
Kumar
Deepak
D
Ahmad
Imran
I
Kasid
Usha N
UN
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008081:Liposomes; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D045726:Metalloproteases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000188:drug therapy; D009368:Neoplasm Transplantation; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D008081:Liposomes; D016376:Oligonucleotides, Antisense; D011506:Proteins; C404190:TNFAIP8 protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D045726:Metalloproteases; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1