ARNTL2 and SERPINE1: potential biomarkers for tumor aggressiveness in colorectal cancer.

Purpose: Cathepsin and plasmin may favor cancer cell invasion degrading extracellular matrix. Plasmin formation from plasminogen is regulated by plasminogen activator inhibitor type-1 (PAI-1). ARNTL2 activates the promoters of the PAI-1 gene, officially called SERPINE1, driving the circadian variation in circulating PAI-1 levels. Methods: We evaluated ARNTL2 and SERPINE1 expression in 50 colorectal cancer specimens and adjacent normal tissue and in colon cancer cell lines. Results: We found up-regulation of ARNTL2 ( P = 0.004) and SERPINE1 ( P = 0.002) in tumor tissue. A statistically significant association was found between high ARNTL2 mRNA levels and vascular invasion ( P < 0.0001), and between high SERPINE1 mRNA levels and microsatellite instability (MSI-H and MSI-L, P = 0.025). Sorting the subjects into quartile groups, a statistically significant association was found between high ARNTL2 expression and lymph node involvement ( P < 0.001), between high SERPINE1 expression and grading ( P < 0.001) and between high SERPINE1 expression and MSI H-L ( P < 0.0001). In SW480 cells, a more proliferative model compared to CaCo2 cells, there were higher mRNA levels of ARNTL2 ( P < 0.001) and SERPINE1 ( P = 0.001). Conclusion: ARNTL2 and SERPINE1 expression is increased in colorectal cancer and in a highly proliferative colon cancer cell line and is related to tumor invasiveness and aggressiveness. [ABSTRACT FROM AUTHOR]