Therapeutic targeting of Id2 reduces growth of human colorectal carcinoma in the murine liver.
Therapeutic targeting of Id2 reduces growth of human colorectal carcinoma in the murine liver.
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DOI：
10.1038/onc.2008.356
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发表时间：
2008-12-04
期刊：
影响因子：
8
通讯作者：
Ellis, L. M.
中科院分区：
文献类型：
--
作者：
Gray, M. J.;Dallas, N. A.;Van Buren, G.;Xia, L.;Yang, A. D.;Somcio, R. J.;Gaur, P.;Mangala, L. S.;Vivas-Mejia, P. E.;Fan, F.;Sanguino, A. M.;Gallick, G. E.;Lopez-Berestein, G.;Sood, A. K.;Ellis, L. M.
在发育过程中，DNA结合抑制剂2（Id 2）调节增殖和分化。Id 2表达已在癌细胞中检测到，但其作为治疗靶点的细胞功能和有效性在很大程度上仍然未知。结直肠癌（CRC）标本的免疫组化分析显示，Id 2在正常结肠粘膜中检测不到，但在40%的原发性肿瘤和大多数CRC肝转移中出现（P < 0.0001）。此外，Id 2在测定的所有CRC细胞系中表达。Id 2表达降低的CRC细胞表现出增殖降低。CRC细胞周期调节蛋白的分析表明，降低Id 2水平降低细胞周期蛋白D1水平和增加p21水平。Id 2表达的减少也增强了肿瘤细胞凋亡，增加了促凋亡蛋白Bim/Bod的水平，以及caspase-7和聚（ADP-核糖）聚合酶的裂解。体内研究表明，与正常水平的肿瘤相比，Id 2水平降低的细胞衍生的肿瘤形成更小的肿瘤，转移更少（P < 0.05）。此外，与对照治疗相比，腹膜内施用与中性脂质体1，2-二油酰-sn-甘油-3-磷脂酰胆碱缀合的Id 2小干扰RNA（siRNA）降低小鼠中的肿瘤负荷（P = 0.006）。我们得出结论，Id 2在CRC中上调，并且在促进细胞存活中是重要的。通过siRNA体内靶向Id 2确立了它是其表达发生的有效治疗靶标。Oncogene（2008）27，7192-7200; doi：10.1038/onc.2008.356; 2008年9月22日在线发表
During development inhibitor of DNA-bind-2 (Id2) regulates proliferation and differentiation. Id2 expression has been detected in cancer cells, yet its cellular function and validity as a therapeutic target remains largely unknown. Immunohistochemical analysis of colorectal cancer (CRC) specimens revealed that Id2 was undetectable in normal colonic mucosa, but occurs in 40% of primary tumors and in most CRC liver metastases (P < 0.0001). Additionally, Id2 was expressed in all CRC cell lines assayed. CRC cells with reduced Id2 expression demonstrated reduced proliferation. Analysis of CRC cell cycle regulatory proteins showed that reducing Id2 levels reduces cyclin D1 levels and increased p21 levels. Reduction of Id2 expression also enhanced tumor cell apoptosis, increasing levels of the pro-apoptotic protein Bim/Bod, and cleavage of caspase-7 and poly (ADP-ribose) polymerase. In vivo studies show tumors derived from cells with decreased Id2 levels formed smaller tumors with fewer metastases compared with tumors with normal levels (P < 0.05). Furthermore, intraperitoneal administration of Id2 small interfering RNA (siRNA) conjugated with the neutral liposome 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine decreased tumor burden in mice compared with control treatment (P = 0.006). We conclude that Id2 is upregulated in CRC, and is important in promoting cell survival. In vivo targeting of Id2 by siRNA establishes that it is a valid therapeutic target where its expression occurs. Oncogene (2008) 27, 7192–7200; doi:10.1038/onc.2008.356; published online 22 September 2008
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