Genetic Factors Involved in Human Colorectal Cancer Metastasis
Experimental and clinical studies have shown that one of the most accurate clinical markers of metastasis in epithelial cancers is the increasing level of carcinoembryonic antigen (CEA, CEACAM-5, CD66e) in the patient’s serum. However, the signaling mechanism determining the ability of cells to produce CEA and to stimulate metastasis has been insufficiently studied. We first cloned a gene of the receptor protein on the surface of liver macrophages - Kupffer cells, which interacts with CEA. This receptor protein has been named CEAR. The CEA/CEAR interaction on the surface of Kupffer cells enhances survival of metastatic cancer cells in the liver through stimulation of cytokine production and influences cell adhesion molecules in the liver. To elucidate CEAR function, its expression was inhibited by short interfering RNAs (siRNA) in MIP-101, a colorectal cancer cell line. Comparative analysis of cell lines with different levels of CEAR and CEA production showed that the inhibition of CEAR expression decreases the expression level of CEA, Ecadherin and integrin alpha 3, and also affects the ability of colorectal cancer cells to adhesion and invasiveness. In vivo experiments showed the catalytic role of CEAR in the formation of tumors in immunodeficient mice. These data revealed the CEAR as a potential new target molecule to prevent the development of CEA-dependent malignancies in humans. The comparative analysis of transcriptomes of four genetically-related colorectal cancer cell lines with different expression levels of CEA and CEAR was carried out using RNA sequencing technology. We discovered 3 genes that are down-regulated in colorectal cancer cells as a result of the CEA production. These genes are major protein-coding cell regulators, including transcription factors that are involved in the response to the DNA-damage, stress, cell cycle and apoptosis. Also we discovered 5 genes that are up-regulated in response to CEA production. These genes are all protein coding genes for the cell surface complexes and signaling proteins that interact with the cytoskeleton and regulate intracellular junctions, cell proliferation and signaling pathways. The analysis of RNAseq data, obtained by Trinity and Tophat pipelines, was performed using the KEGG pathway and GO enrichment analysis.
Bajenova, Olga and Stephen J. O'Brien. 2014. "Genetic Factors Involved in Human Colorectal Cancer Metastasis." Anticancer Research 34, (10): 5824-5825. http://nsuworks.nova.edu/cnso_bio_facarticles/419