Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine (CRSA), 75571 Paris, France.
Institut National de la Santé et de la Recherche Médicale (INSERM) U938, 75012 Paris, France.
Cells. 2022 May 31;11(11):1808. doi: 10.3390/cells11111808.
In colorectal cancer (CRC), disease-related death is closely linked to tumor aggressiveness and metastasis. Gene expression profiling of patient tumors has suggested that a more mesenchymal phenotype, present in about one-fourth of all patients, is associated with increased aggressiveness. Accordingly, the mesenchymal transcription factor Slug/ has been associated with decreased disease-free survival. To decipher the basis for the Slug-mediated phenotype, we conducted RNAseq experiments with a panel of HT-29 CRC cells expressing different levels of Slug, both in vitro and in tumor models. The results show that osteopontin, a secreted pleotropic protein involved in multiple steps of colorectal cancer progression, was highly upregulated by Slug in vitro, as well as in vivo. We further show that Slug is a direct regulator of osteopontin at the promoter level. The levels of secreted osteopontin were correlated with Slug expression, thereby linking the tumor phenotype to a biomarker available by liquid biopsies. The results also suggest that osteopontin neutralization may attenuate at least some of the Slug-mediated functions.
在结直肠癌（CRC）中，与疾病相关的死亡与肿瘤侵袭性和转移密切相关。对患者肿瘤的基因表达谱分析表明，大约四分之一的患者存在更具间质表型的特征，与侵袭性增加有关。因此，间质转录因子 Slug/与无病生存期缩短有关。为了解 Slug 介导的表型的基础，我们使用一组表达不同水平 Slug 的 HT-29 CRC 细胞进行了 RNAseq 实验，无论是在体外还是在肿瘤模型中。结果表明，骨桥蛋白是一种参与结直肠癌进展多个步骤的分泌性多功能蛋白，在体外以及体内均由 Slug 高度上调。我们进一步表明，Slug 是启动子水平上骨桥蛋白的直接调节因子。分泌型骨桥蛋白的水平与 Slug 表达相关，从而将肿瘤表型与液体活检中可用的生物标志物联系起来。结果还表明，骨桥蛋白中和可能至少减轻 Slug 介导的部分功能。
