Nidogen-1/NID1 Function and Regulation during Progression and Metastasis of Colorectal Cancer

SIMPLE SUMMARY: Nidogen1 (NID1) is a component of the extracellular matrix and basement membranes. NID1 represents a linker between laminins, collagens, proteoglycans and cell surface receptors to control cell polarization, migration, and invasion. In this article, we show that elevated expression of NID1 mRNA and of the genes ITGA3, ITGB1, and ITGAV, which encode NID1 receptors, is associated with poor prognosis and advanced tumor stage of colorectal cancer (CRC) patients. Furthermore, we demonstrate the direct induction of the NID1 gene by the transcription factor SNAIL/SNAI-1. In addition, we determined that NID1 promotes metastasis in a xenograft mouse model of CRC. Finally, we show that the NID1 receptor ITGAV represents a potential therapeutic target for CRC. ABSTRACT: We have previously shown that the extracellular matrix and basement membrane protein Nidogen1 (NID1) is secreted by more malignant, mesenchymal-like CRC cells and induces the epithelial–mesenchymal transition (EMT) and promotes the migration and invasion of less malignant, epithelial-like CRC cells. Here, we performed a comprehensive bioinformatics analysis of multiple datasets derived from CRC patients and showed that elevated expression of NID1 and the genes ITGA3, ITGB1, and ITGAV, which encode NID1 receptors, is associated with poor prognosis and advanced tumor stage. Accordingly, the expression of NID1, ITGA3, ITGB1, and ITGAV was associated with an EMT signature, which included SNAIL/SNAI1, an EMT-inducing transcription factor. In CRC cells, ectopic SNAIL expression induced NID1 and SNAIL occupancy was detected at an E-box upstream of the NID1 transcription start site. Therefore, NID1 represents a direct target of SNAIL. Ectopic expression of NID1 or treatment with NID1-containing medium endowed non-metastatic CRC cells with the capacity to form lung metastases after xenotransplantation into mice. Suppression of the NID1 receptor ITGAV decreased cell viability, particularly in CMS/consensus molecular subtype 4 CRC cells. Taken together, our results show that NID1 is a direct target of EMT-TF SNAIL and is associated with and promotes CRC progression and metastasis. Furthermore, the NID1 receptor ITGAV represents a candidate therapeutic target in CMS4 colorectal tumors.