Inflammation-associated carcinogenesis involves interaction between the iNOS/NO and Wnt/β-catenin signaling pathways

Abstract

Wnt/β-catenin/TCF signaling is associated with carcinogenesis, and chronic inflammation activated NF-κB plays an essential role in the initiation of a cancer. Recent evidence shows that NF-κB constitutive activation synergizes with Wnt signaling. iNOS/NO signaling causes APC loss of heterozygosity and activates the Wnt/β-catenin signaling pathway, which contributes to oncogenic initiation and cancer development. In this chapter, we focus on the molecular interactions between iNOS and Wnt/β-catenin signaling for carcinogenesis. iNOS is induced in chronic inflammation by cytokines mainly through the NF-?B and STAT transcription pathways. The iNOS/NO signaling exerts key roles in driving carcinogenesis mediated by Wnt/β-catenin. iNOS/NO induces reactive oxygen and nitrogen species (RONS) and can cause APC or β-catenin mutation, resulting in β-catenin accumulation. However, chemical or genetic inhibition of iNOS can decrease Wnt/β-catenin signaling and carcinogenesis. At least three pathways are established for the interaction between iNOS and Wnt signaling: (1) a positive feedback loop established by iNOS causing APC or β-catenin mutation via reactive species, and by Wnt targeting iNOS gene expression; (2) a negative feedback mechanism between Wnt and Dickkofp-1 (DKK1) where iNOS inhibits DKK1 gene expression; and (3) crossregulation between NF-κB and Wnt/β-catenin pathways mainly through iNOS/NO generating reactive species which induce β-catenin activation. We conclude that the iNOS/NO signaling plays a central role in the interaction between NF-κB and Wnt/β-catenin pathways that regulate inflammation-associated carcinogenesis.