Copper Dysmetabolism is Connected to Epithelial-Mesenchymal Transition: A Pilot Study in Colorectal Cancer Patients.

Abstract

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.