The Core-Clock Gene NR1D1 Impacts Cell Motility In Vitro and Invasiveness in a Zebrafish Xenograft Colon Cancer Model

Abstract

Malfunctions of circadian clock trigger abnormal cellular processes and influence tumorigenesis. Using an <i>in vitro</i> and <i>in vivo</i> xenograft model, we show that circadian clock disruption via the downregulation of the core-clock genes <i>BMAL1</i>, <i>PER2</i>, and <i>NR1D1</i> impacts the circadian phenotype of <i>MYC</i>, <i>WEE1</i>, and <i>TP53</i>, and affects proliferation, apoptosis, and cell migration. In particular, both our <i>in vitro</i> and <i>in vivo</i> results suggest an impairment of cell motility and a reduction in micrometastasis formation upon knockdown of <i>NR1D1</i>, accompanied by altered expression levels of <i>SNAI1</i> and <i>CD44</i>. Interestingly we show that differential proliferation and reduced tumour growth <i>in vivo</i> may be due to the additional influence of the host-clock and/or to the 3D tumour architecture. Our results raise new questions concerning host-tumour interaction and show that core-clock genes are involved in key cancer properties, including the regulation of cell migration and invasion by <i>NR1D1</i> in zebrafish xenografts.