Cellular and Molecular Gastroenterology and Hepatology | 2019
FOXO3 Loss Drives Inflammation-Associated CRC: The Consequences of Being (Knock)Out-FOX’d
Abstract
olorectal cancer (CRC) is the third most common Ccancer diagnosed worldwide and the third leading cause of all cancer deaths. Although surgical resection of the primary tumor often is possible with early detection and can be associated with greater than 90% 5-year survival, overall 5-year survival is only 65%. The etiology of CRC is multifaceted with genetic, environmental, and inflammatory factors driving the transformation of normal epithelium of the colon or rectum to benign adenoma and ultimately adenocarcinoma. Local chronic injury and inflammation, such as that observed in ulcerative colitis (UC) patients, is associatedwith a heightened risk of CRC. In the tumor microenvironment, inflammation promotes tumorigenesis on several levels, influencing cellular proliferation, survival, angiogenesis, metastasis, and reduced responsiveness to chemotherapeutic agents. The range of molecular pathways linking inflammation and CRC are only beginning to be unravelled. Forkhead box O3 (FOXO3), a member of the FOXO family, has been implicated in several key pathways involved in tumorigenesis and CRC, including proliferation, apoptosis, and cell metabolism. FOXO3 is a transcriptional activator that triggers apoptosis in the absence of survival factors and plays a key role in protein turnover. Similar to other FOXO proteins, FOXO3 is phosphorylated to induce nuclear export, where it is targeted for ubiquitination and proteosomal degradation. More recently, FOXO3 activity has been implicated in the maintenance of immune progenitor cell homeostasis, and FOXO3 deficiency enhances lymphocyte activity during infection. Loss of FOXO3 has been identified in CRC cancer tissues and inflammatory diseases including inflammatory bowel disease, and is associated with deficiencies in apoptosis and cell-cycle progression. Although previous studies have identified that FOXO3 loss drives inflammation and increases cellular proliferation in CRC , the underlying mechanisms driving these pathologies are largely undefined. In the current issue of Cellular and Molecular Gastroenterology and Hepatology, Penrose et al reported their use of transcriptomic profiling to examine the consequences of Foxo3 gene deletion in a mouse model of inflammation-associated CRC. They identified novel Foxo3-dependent changes in immune cell recruitment and downstream inflammatory and proliferative pathways associated with tumorigenesis. Foxo3 knockout mice subjected to the Azoxymethane (AOM)/Dextran sodium sulfate (DSS) model of inflammation-associated CRC showed enhanced intestinal tumorigenesis, with significant increases in tumor number and volume. Transcriptomic analysis showed similar gene expression profiles to transcripts from UC patients with