鸟氨酸脱羧酶抗酶抑制因子-1高表达抑制黑素瘤细胞在小鼠体内的生长

Overexpression of Ornithine Decarboxylase Antienzyme Inhibitor-1 Inhibits Growth of Melanoma Cells in Mice

鸟氨酸脱羧酶抗酶抑制因子-1(ornithine decarboxylase antienzyme inhibitor-1,OAZI-1)是细胞内调节多胺代谢的重要蛋白质因子。已有研究发现,OAZI-1高表达的黑素瘤细胞在体外能更有效地被抗原提呈细胞识别和吞噬,提示OAZI-1在肿瘤免疫治疗中具有潜在的应用价值。为进一步分析OAZI-1高表达对黑素瘤细胞在小鼠体内生长的影响,高表达OAZI-1的黑素瘤细胞(B16/OAZI-1)被接种到实验小鼠体内,结果发现,接种瘤出现先成瘤随后逐渐消退的现象,至第24 d时,接种瘤的平均体积为36±25 mm3~,而对照细胞接种瘤的平均体积为326±309 mm^3。为探索上述现象的机制,随后分析了B16/OAZI-1在小鼠体内诱导的抗肿瘤免疫效应,结果发现:1)B16/OAZI-1接种显著增加了小鼠脾脏细胞对B16-F1瘤细胞的杀伤活性;2)源于B16-F1的细胞抗原能更有效地促进B16/OAZI-1接种小鼠脾脏细胞的增殖;3)B16/OAZI-1接种小鼠的脾脏细胞具有更强的分泌IFN-γ的能力;4)当在预接种B16/OAZI-1 30 d后的小鼠体内再次接种B16-F1活细胞时,新接种瘤细胞的生长受到显著抑制,小鼠的存活率增加。上述研究结果提示,高表达OAZI-1的黑素瘤细胞在实验动物体内的生长受到显著抑制,其机制可能与OAZI-1能促进肿瘤抗原提呈和诱导抗肿瘤免疫效应相关。

Ornithine decarboxylase antienzyme inhibitor-1 （OAZI-1） is an important protein factor involved in the regulation of polyamine metabolism. Studies had found that melanoma cells with OAZI-1 overexpression could be effectively identified and engulfed in vitro by antigen-presenting cells, and this suggested a potential value of OAZI-1 in tumor immunotherapy. In order to explore the effect of overexpression of OAZI-1 on growth of B16-F1 melanoma cells in mice, the B16-F1 cells with OAZI-1-overexpression （B16/OAZI-1） were inoculated into the mice. The results showed that the resulted tumor mass increased normally within first 12 days and then began to shrink gradually. At the day 24, mean tumor volume in the mice inoculated with control tumor cells was 326±309 mm3 but only 36±25 mm3 in the mice inoculated with B16/OAZI-1 cells. To explore the underlying mechanism for this phenomenon, OAZI-1-mediated immune effects were determined. The results showed： 1） the spleen cells of mice inoculated with B16/OAZI-1 had enhanced cytotoxic activity against B16-F1 tumor cells; 2） proliferation of the splenocytes from B16/OAZl-l-inoculated micewas more efficiently stimulated by the lysate from B16-F1 cells; 3） the splenocytes from the B16/OAZI-1- inoculated mice exhibited elevated interferon--γ （INF--γ） secretion; 4） when the mice were inoculated with B 16/ OAZI-1 followed by re-challenge with live B16-F1 cells 30 days later, a decreased tumor growth and prolonged mouse survival time were observed. These results suggest that overexpression of OAZI-1 can inhibit the growth of B16-F1 melanoma cells in mice. The underlying mechanism may be related to the ability of OAZI-1 in promoting tumor antigen presentation and inducing anti-tumor immune response.