Guijarro Maria V, Leal Juan F M, Blanco-Aparicio Carmen, Alonso Soledad, Fominaya Jesús, Lleonart Matilde, Castellvi Josep, Ramon y Cajal Santiago, Carnero Amancio
Experimental Therapeutics Program, Centro Nacional de Investigaciones Oncológicas, Melchor Fernandez Almagro, 3, 28029 Madrid, Spain.
Carcinogenesis. 2007 Oct;28(10):2096-104. doi: 10.1093/carcin/bgm124. Epub 2007 Jun 4.
Tumorigenesis occurs when the mechanisms involved in the control of tissue homeostasis are disrupted and cells stop responding to physiological signals. Therefore, genes capable of desensitizing tumoral cells from physiological signals may provide a selective advantage within the tumoral mass and influence the outcome of the disease. We undertook a large-scale genetic screen to identify genes able to alter the cellular response to physiological signals and provide selective advantage once tumorigenesis has begun. We identified MAP17, a small 17 kDa non-glycosylated membrane protein previously identified by differential display being over-expressed in carcinomas. Tumor cells that over-express MAP17 show an increased tumoral phenotype with enhanced proliferative capabilities both in presence or absence of contact inhibition, decreased apoptotic sensitivity and increased migration. MAP17-expressing clones also grow better in nude mice. The increased malignant cell behavior induced by MAP17 are associated with an increase in reactive oxygen species (ROS) production, and the treatment of MAP17-expressing cells with antioxidants results in a reduction in the tumorigenic properties of these cells. Treatment of melanoma cells with inhibitors of Na+-coupled co-transporters lead to an inhibition of ROS increase and a decrease in the malignant cell behavior in MAP17-expressing clones. Finally, we show that MAP17-dependent ROS increase and tumorigenesis are dependent on its PDZ-binding domain, since disruption of its sequence by point mutations abolishes its ability to enhance ROS production and tumorigenesis. Our work shows the tumorigenic capability of MAP17 through a connection between Na+-coupled co-transporters and ROS.
当参与组织稳态控制的机制被破坏且细胞停止对生理信号作出反应时，肿瘤发生就会出现。因此，能够使肿瘤细胞对生理信号脱敏的基因可能在肿瘤块内提供选择性优势并影响疾病的转归。我们进行了一项大规模基因筛选，以鉴定能够改变细胞对生理信号的反应并在肿瘤发生开始后提供选择性优势的基因。我们鉴定出了MAP17，一种先前通过差异显示鉴定出的17 kDa小的非糖基化膜蛋白，在癌组织中过度表达。过度表达MAP17的肿瘤细胞表现出增强的肿瘤表型，在有或无接触抑制的情况下增殖能力均增强，凋亡敏感性降低且迁移增加。表达MAP17的克隆在裸鼠中也生长得更好。MAP17诱导的恶性细胞行为增加与活性氧（ROS）产生增加有关，用抗氧化剂处理表达MAP17的细胞会导致这些细胞的致瘤特性降低。用Na +偶联共转运体抑制剂处理黑色素瘤细胞会导致ROS增加受到抑制，并且表达MAP17的克隆中的恶性细胞行为减少。最后，我们表明MAP17依赖性ROS增加和肿瘤发生依赖于其PDZ结合结构域，因为点突变破坏其序列会消除其增强ROS产生和肿瘤发生的能力。我们的工作通过Na +偶联共转运体与ROS之间的联系展示了MAP17的致瘤能力。
