INSERM U682, Section of Kidney Cancer and Renal Physiopathology, University of Strasbourg, School of Medicine, Strasbourg, France.
Oncogene. 2011 Apr 14;30(15):1753-63. doi: 10.1038/onc.2010.557. Epub 2010 Dec 6.
Human clear cell renal cell carcinoma (CCC) remains resistant to therapies. The transcription factor LIM-class homeobox gene Lim1 is required for normal organogenesis, including nephrogenesis, by regulating cell movements, differentiation and growth. Its expression is controlled partly by the sonic hedgehog-Gli signaling pathway, which we have recently shown to be reactivated in human CCC. So far, no study has assessed whether Lim1 may be associated with tumorigenesis. Using a panel of human CCC cell lines expressing or not the von Hippel-Lindau tumor suppressor gene and 44 tumor/normal tissues pairs, we found that Lim1 is constitutively and exclusively reexpressed in tumors. Through Lim1 silencing or overexpressing, we show that Lim1 is a growth and survival factor in human CCC, at least through the activation of oncogenic pathways including the phosphoinositide kinase-3/Akt and nuclear factor-kappaB pathways. More importantly, in nude mice bearing human CCC tumors, Lim1 silencing abolished tumor growth through the same mechanism as in vitro. In Lim1-depleted cells and tumors, cell movements were substantially impaired because of the inhibition of expression of various proteins involved in metastatic spread, such as paxillin or tenascin-C. These findings establish that the developmental marker Lim1 acts as an oncogene in cancer cells and targeting Lim1 may constitute an innovative therapeutic intervention in human CCC.
人肾透明细胞癌（CCC）仍然对治疗有抵抗力。转录因子 LIM 类同源盒基因 Lim1 通过调节细胞运动、分化和生长，对于正常器官发生，包括肾发生是必需的。其表达部分受 sonic hedgehog-Gli 信号通路的控制，我们最近已经证明该信号通路在人 CCC 中被重新激活。到目前为止，尚无研究评估 Lim1 是否与肿瘤发生有关。使用一组表达或不表达 von Hippel-Lindau 肿瘤抑制基因的人 CCC 细胞系和 44 对肿瘤/正常组织对，我们发现 Lim1 在肿瘤中持续且特异性地重新表达。通过 Lim1 沉默或过表达，我们表明 Lim1 是人 CCC 的生长和存活因子，至少通过激活包括磷酸肌醇激酶-3/Akt 和核因子-κB 途径在内的致癌途径。更重要的是，在携带人 CCC 肿瘤的裸鼠中，Lim1 沉默通过与体外相同的机制消除了肿瘤生长。在 Lim1 耗尽的细胞和肿瘤中，由于参与转移扩散的各种蛋白质（如 paxillin 或 tenascin-C）的表达受到抑制，细胞运动受到严重损害。这些发现确立了发育标记物 Lim1 在癌细胞中作为癌基因的作用，并且靶向 Lim1 可能构成人 CCC 的创新性治疗干预。
