Koslowski Michael, Sahin Ugur, Mitnacht-Kraus Rita, Seitz Gerhard, Huber Christoph, Türeci Ozlem
Department of Internal Medicine III, Division of Experimental and Translational Oncology, Johannes Gutenberg University, Mainz, Germany.
Cancer Res. 2007 Oct 1;67(19):9528-34. doi: 10.1158/0008-5472.CAN-07-1350.
The identification and functional characterization of tumor-specific genes is a prerequisite for the development of targeted cancer therapies. Using an integrated data mining and experimental validation approach for the discovery of new targets for antibody therapy of cancer, we identified PLAC1. PLAC1 is a placenta-specific gene with no detectable expression in any other normal human tissue. However, it is frequently aberrantly activated and highly expressed in a variety of tumor types, in particular breast cancer. RNAi-mediated silencing of PLAC1 in MCF-7 and BT-549 breast cancer cells profoundly impairs motility, migration, and invasion and induces a G1-S cell cycle block with nearly complete abrogation of proliferation. Knockdown of PLAC1 is associated with decreased expression of cyclin D1 and reduced phosphorylation of AKT kinase. Moreover, PLAC1 is localized on the surface of cancer cells and is accessible for antibodies which antagonize biological functions of this molecule. These features, in summary, make PLAC1 an attractive candidate for targeted immunotherapeutic approaches.
肿瘤特异性基因的鉴定和功能表征是开发靶向癌症疗法的先决条件。我们采用综合数据挖掘和实验验证方法来发现癌症抗体治疗的新靶点,在此过程中鉴定出了PLAC1。PLAC1是一种胎盘特异性基因,在任何其他正常人体组织中均未检测到其表达。然而,它在多种肿瘤类型中经常异常激活并高表达,尤其是在乳腺癌中。RNAi介导的MCF-7和BT-549乳腺癌细胞中PLAC1的沉默会严重损害细胞的运动性、迁移和侵袭能力,并诱导G1-S期细胞周期阻滞,几乎完全消除细胞增殖。PLAC1的敲低与细胞周期蛋白D1表达降低和AKT激酶磷酸化减少有关。此外,PLAC1定位于癌细胞表面,可被拮抗该分子生物学功能的抗体所作用。总之,这些特性使PLAC1成为靶向免疫治疗方法的一个有吸引力的候选靶点。