Investigating Mechanisms that Mediate Cyclooxygenase‐2 Signaling in Colon Cancer Development

Abstract

During early development of colon cancer, cyclooxygenase 2 (COX‐2) is constitutively induced. Constitutive expression of COX‐2 promotes colon carcinogenesis, however the underlying mechanisms are not totally understood. Western blot analysis showed reduced protein levels of an adhesion molecule α‐catenin in HCA‐7 colon cancer cells that endogenously express COX‐2 and HCT‐15 colon cancer cells that stably express recombinant COX‐2 (HCT‐15‐COX‐2). High levels of phosphorylated active ERKs were also detected in HCA‐7 and HCT‐15‐COX‐2 cells. Inhibition of COX‐2 stimulated α‐catenin levels and prevented activation of ERKs. Scratch wound gap assays were used to monitor cell motility and proliferation. HCT‐15‐COX‐2 cells closed the gap faster than parental HCT‐15 cells. Inhibition of COX‐2 or ERKs in HCA‐7 and HCT‐15‐COX‐2 cells decreased the gap closing. The Human Cancer RT2‐miRNA PCR array screening showed that 39 microRNAs (miRNAs) are modulated by COX‐2 signaling. Quantitative RT‐PCR confirmed that expression levels of 6 miRNAs were significantly lower in HCA‐7 or HCT‐15‐COX‐2 than in HCA‐7 cells that were treated with the COX‐2‐selecetive inhibitor NS‐398 or HCT‐15 parental cells. Those 6 miRNAs were selected due to their relevance to cancer cell migration. In summary, we have identified that activation of ERKs and modulation of miRNAs mediate COX‐2 signaling to promote colon carcinogenesis.