Metastasis is the chief cause of mortality from cancer, but the mechanisms leading to metastasis are poorly understood. We used a proteomics approach to screen for metastasis-associated proteins and found that collapsin response mediator protein-4 (CRMP4) expression was inversely associated with the lymph node metastasis of prostate cancer (PCa). Subsequent in vitro and in vivo studies revealed that overexpression of CRMP4 not only suppressed the invasion ability of PCa cells, but also strongly inhibited tumor metastasis in an animal model. Furthermore, methylation of a CpG island within the promoter region of the CRMP4 gene is responsible for downregulation of CRMP4 expression. Thus, in this study, we show new function of CRMP4 as a metastasissuppressor in PCa. The findings provide new mechanistic insights into metastasis and therapeutic potential for this most common male cancer.
Induction of liver allograft immunological tolerance was performed in rats by intramuscular injection of recombinant adeno-associated virus-human cytotoxic T-lymphocyte-associated antigen-4 immunoglobulin (rAAV-hCTLA4Ig). Dark Agouti and Lewis rats were liver allograft donors and recipients, respectively, in four groups: (A) syngeneic control, (B) blank control, (C) rAAV-enhanced green fluorescent protein negative control, (D) rAAV-hCTLA4Ig. Gene transfers occurred 6 weeks before transplantation. Group D had a significantly longer liver graft survival time (> 100 days) than groups B (11.9 +/- 1.3 days) and C (11.6 +/- 1.1 days). Groups B and C showed severe rejection responses and large amounts of CD4(+) and CD8(+) T-lymphocyte infiltration, while only a mild response and few T-lymphocytes were observed in group D. There were no significant differences in interleukin-2 and interferon-gamma levels in liver grafts between groups D and C, but there were significant decreases in granzyme B and lymphotoxin beta levels in group D compared with group C. It is concluded that immunological tolerance to liver allograft could be achieved by gene transfer of rAAV-hCTLA4Ig through intramuscular injection.
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