Nidogen-1/NID1 Function and Regulation during Progression and Metastasis of Colorectal Cancer.
Matjaz RokavecStephanie JaeckelHeiko HermekingPublished in: Cancers (2023)
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.
Keyphrases
- epithelial mesenchymal transition
- poor prognosis
- induced apoptosis
- cell cycle arrest
- signaling pathway
- long non coding rna
- binding protein
- extracellular matrix
- endoplasmic reticulum stress
- small cell lung cancer
- type diabetes
- cell death
- gene expression
- metabolic syndrome
- dna methylation
- single cell
- single molecule
- genome wide
- patient reported outcomes
- diabetic rats
- high glucose