Antitumor activity of type III interferon alone or in combination with type I interferon against human non-small cell lung cancer
Antitumor activity of type III interferon alone or in combination with type I interferon against human non-small cell lung cancer
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DOI：
10.1111/j.1349-7006.2011.02079.x
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发表时间：
2011-11-01
期刊：
影响因子：
5.7
通讯作者：
Numasaki, Muneo
中科院分区：
文献类型：
--
作者：
Fujie, Hitomi;Tanaka, Toshiaki;Numasaki, Muneo
以人非小细胞肺癌(NSCLC)为模型，评价了III型干扰素(IL-28和IL-29)及其与I型干扰素联合应用的抗肿瘤活性。在NSCLC细胞系中检测到III型和I型受体复合体的表达。IL-29对多种非小细胞肺癌细胞株的体外生长有明显的抑制作用，且呈剂量依赖关系。IL-28A在一定程度上也具有生长抑制活性。III型干扰素的抗肿瘤活性与细胞周期停滞于G1期和细胞凋亡有关。IL-29上调细胞周期蛋白依赖性激酶抑制因子p21Waf1/Cip1对抗增殖活性敏感但不敏感，用小干扰RNA敲除p21可显著减弱其抗增殖作用。在严重联合免疫缺陷小鼠中，瘤内和全身应用IL-29可抑制OBA-LK1和LK-1的生长，但不能抑制A549的生长。免疫组织化学分析显示，经IL-29治疗的肿瘤中p21表达显著上调，Ki-67表达显著下调。干扰素联合IL-29和干扰素-α在体外显示出比单独使用更有效的抗增殖作用和更强的p21表达。此外，干扰素联合治疗比单一干扰素治疗更有效地抑制体内NSCLC的生长。这些结果表明，III型干扰素可以通过增加p21的表达和诱导细胞凋亡来介导直接的抗肿瘤活性，并与I型干扰素协同产生更有效的直接抗肿瘤活性，提示III型干扰素有可能提高I型干扰素的疗效，减少毒副作用。(《癌症科学》2011；102：1977-1990)
The antitumor activities of type III interferon (IFN) (interleukin [IL]-28 and IL-29) and the combination of type III IFN and type I IFN (IFN-alpha) were evaluated using human non-small cell lung cancer (NSCLC). The expression of type III and type I receptor complexes was detected in NSCLC lines. IL-29 significantly inhibited the in vitro growth of a wide range of NSCLC lines in a dose-dependent fashion. To a lesser degree, IL-28A also displayed growth inhibitory activity. Antitumor activity of type III IFN is associated with cell cycle arrest at the G1 phase and apoptosis. IL-29 upregulated cyclin-dependent kinase inhibitor p21Waf1/Cip1 in cells sensitive, but not insensitive, to antiproliferative activity, and knockdown of p21 with small interfering RNA largely attenuated the antiproliferative effect. Intratumoral and systemic administration of IL-29 inhibited OBA-LK1 and LK-1, but not A549, tumor growth in severe combined immunodeficiency mice. Immunohistochemical analyses demonstrated marked upregulated p21 and downregulated Ki-67 expression in tumors treated with IL-29. The interferon combination of IL-29 and IFN-alpha displayed a more effective antiproliferative effect and a more intense p21 expression than each reagent alone in vitro. Furthermore, interferon combination therapy suppressed in vivo NSCLC growth more effectively than interferon monotherapy. These findings demonstrate that type III IFN can mediate direct antitumor activities via increased p21 expression and induction of apoptosis and cooperate with type I IFN to elicit more efficient direct antitumor activities, and suggest the possibility that type III IFN might improve the efficacy and reduce the side-effects of type I IFN cancer therapy. (Cancer Sci 2011; 102: 1977-1990)