Squitti Rosanna, Tondolo Vincenzo, Pal Amit, Rizzo Gianluca, Arijit Samanta, Mehboob Hoque, di Veroli Laura, Catalano Piera, Ventura Marco Della, Mastromoro Gioia, Rossi Luisa, Rongioletti Mauro, De Luca Anastasia
Department of Laboratory Science, Research and Development Division, Ospedale Isola Tiberina-Gemelli Isola, 00186, Rome, Italy.
Department of Theoretical and Applied Sciences, eCampus University, Viale Massenzio Masia, 26, 22100, Como, Novedrate, Italy.
Biol Trace Elem Res. 2024 Nov 19. doi: 10.1007/s12011-024-04440-w.
Colorectal cancer (CRC) is among the most diagnosed cancers worldwide, whose risk of mortality is associated with the development of metastases to the liver, lungs, and peritoneum. Of note, CRC is highly dependent on copper to sustain its proliferation and aggressiveness. Copper acts not only as a pivotal cofactor for several cuproproteins but also as an allosteric modulator of kinases essential to fulfill the epithelial-to-mesenchymal-transition (EMT), the main mechanism driving cancer cell spreading. System biology identified the APP and SOD1 genes among the top 10 genes shared between CRC and copper metabolism, as confirmed by the upregulation of the protein/mRNA levels of APP observed in CRC tissues. The significant increase of copper found in the sera of CRC patients was paralleled by a strong reduction of copper in the CRC tissues, in agreement with the decreased level of the high-affinity copper transporter CTR1 mRNA (SLC31A1) and LOXL2. As expected, in CRC tissues the mesenchymal marker fibronectin was significantly increased, whereas vimentin and vinculin protein levels were decreased compared to adjacent healthy mucosa. Interestingly, correlation analysis showed an interconnection between vinculin and both CCS and APP. A positive correlation was also observed between APP mRNA and both CDH1 and SOD1 mRNAs. Overall, we demonstrate a correlation between cell copper imbalance and CRC progression via EMT. The results obtained lay the scientific basis for further investigation to describe the kinetics of copper dysregulation during CRC progression and to identify the main cuproproteins involved in the modulation of EMT.
结直肠癌（CRC）是全球诊断率最高的癌症之一，其死亡风险与肝、肺和腹膜转移的发生有关。值得注意的是，CRC高度依赖铜来维持其增殖和侵袭性。铜不仅是几种铜蛋白的关键辅因子，也是实现上皮-间质转化（EMT）所必需的激酶的变构调节剂，EMT是驱动癌细胞扩散的主要机制。系统生物学确定APP和SOD1基因是CRC和铜代谢共有的前10个基因之一，CRC组织中观察到的APP蛋白/mRNA水平上调证实了这一点。CRC患者血清中铜的显著增加与CRC组织中铜的强烈减少同时出现，这与高亲和力铜转运蛋白CTR1 mRNA（SLC31A1）和LOXL2水平的降低一致。正如预期的那样，在CRC组织中，间充质标志物纤连蛋白显著增加，而与相邻健康黏膜相比，波形蛋白和纽蛋白的蛋白水平降低。有趣的是，相关性分析显示纽蛋白与CCS和APP之间存在相互联系。APP mRNA与CDH1和SOD1 mRNA之间也观察到正相关。总体而言，我们证明了细胞铜失衡与通过EMT的CRC进展之间的相关性。所获得的结果为进一步研究描述CRC进展过程中铜失调的动力学以及确定参与EMT调节的主要铜蛋白奠定了科学基础。
