CCAAT/Enhancer-binding Protein δ Mediates Tumor Necrosis Factor α-induced Aurora Kinase C Transcription and Promotes Genomic Instability

Abstract

Epidemiologic and clinical research indicates that chronic inflammation increases the risk of certain cancers, possibly through chromosomal instability. However, the mechanism of inflammation-dependent chromosomal instability associated with tumorigenesis is not well characterized. The transcription factor CCAAT/enhancer-binding protein ␦ (C/EBP␦, CEBPD) is induced by tumor necrosis factor ␣ (TNF␣) and expressed in chronically inflamed tissue. In this study, we show that TNF␣ promotes aneuploidy. Loss of CEBPD attenuated TNF␣-induced aneuploidy, and CEBPD caused centromere abnormality. Additionally, TNF␣-induced CEBPD expression augmented anchorage-independent growth. We found that TNF␣ induced expression of aurora kinase C (AURKC) through CEBPD, and that AURKC also causes aneuploidy. Furthermore, high CEBPD expression correlated with AURKC expression in inflamed cervical tissue specimens. These data provide insight into a novel function for CEBPD in inducing genomic instability through the activation of AURKC expression in response to inflammatory signals.

Aurora kinase A (AURKA) and never in mitosis gene A-related kinase 6 (NEK6) genes are upregulated in erosive esophagitis and esophageal adenocarcinoma

“…These genes were not expressed in EAC. Wu et al stated that AURKC was overexpressed in inflamed cervical tissue specimens and HDAC inhibitors are therapeutic for several inflammatory conditions (38,39). Do these genes have a role in addition to defect of the defense mechanism of the esophagus in patients with EE in gastroesophageal disease?…”

Tumor Necrosis Factor-Induced Cerebral Insulin Resistance in Alzheimer's Disease Links Numerous Treatment Rationales

“…Cerebral ischemia has also been reported (Wen et al, 2004a) to induce aberrant neuronal cell cycle re-entry that can be reduced by 17␤-estradiol, an inhibitor of TNF (Hsu et al, 2000), a cytokine with a long history of interfering with mitosis (Darzynkiewicz et al, 1984) and more recently demonstrated to cause aneuploidy (Wu et al, 2011), the phenomenon that sets the scene for aberrant cell cycling and thus apoptosis. As recently reviewed by Clark et al (2010), trauma triggers release of inflammatory cytokines through the action of mitochondrial DNA set free from disrupted cells .…”

“…Another approach, based on synthesizing GLP-1 analogs, has led to other subcutaneous agents, such as liraglutide (Buse et al, 2009). Both of these types of GLP-1 mimetics pass through the blood-brain barrier and have proved to be strikingly active against AD models (Perry et al, 2003;Liu et al, 2009;Porter et al, 2010;Li et al, 2011;McClean et al, 2011) as well as against a model of the cognitive defects in T2DM . Recent basic studies give impressively detailed reinforcement to this approach (Bomfim et al, 2012;Talbot et al, 2012).…”

Inhibition of the EGFR/STAT3/CEBPD Axis Reverses Cisplatin Cross-resistance with Paclitaxel in the Urothelial Carcinoma of the Urinary Bladder

“…However, unlike the inflammatory effectors NF-kB and STAT3 that are consistently activated in cancer cells, CEBPD inactivation has been observed in several types of cancer, including cervical and hepatocellular carcinoma (10,14), breast (15), prostate cancer (9), and leukemia (16). In addition to acting as a tumor suppressor, several recent reports have suggested that CEBPD plays an oncogenic role under certain conditions (17,18). Furthermore, CEBPD attenuation can sensitize CDDPinduced cell death in CDDP-resistant UCUB cells (19).…”