The immediate early gene Ier2 promotes tumor cell motility and metastasis, and predicts poor survival of colorectal cancer patients

Abstract

Here, we report unbiased screens for genes expressed in metastatic tumor cells that are associated with cell motility. These screens identified Ier2, an immediate early gene of unknown function, as potentially having a role in tumor cell motility and metastasis. Knockdown of Ier2 in 3T3 fibroblasts inhibited their motility upon relief of contact inhibition in monolayer wounding assays. Furthermore, ectopic Ier2 expression promoted the motility and invasiveness of poorly metastatic 1AS pancreatic tumor cells in vitro. Relief of contact inhibition was associated with translocation of the Ier2 protein from the cytoplasm to the nucleus in both 3T3 fibroblasts and 1AS tumor cells. Importantly, ectopic Ier2 expression in 1AS cells stimulated metastasis formation when cells were implanted into experimental animals. Furthermore, we found elevated Ier2 expression in a wide variety of human tumor types. This correlated with poor metastasis-free and overall survival in patients with colorectal adenocarcinomas. Together, these data reveal Ier2 as a new player in the regulation of tumor progression and metastasis, and suggest that Ier2 may be useful prognostically and therapeutically in the management of cancer.

Identification of immediate early response protein 2 as a regulator of angiogenesis through the modulation of endothelial cell motility and adhesion

“…Knockdown of the endogenous IER2 by LV-shR infection significantly decreased the HUVECs migration and invasion. This result was in accordance with another study showing that IER2 promoted cell motility and tumor metastasis (13). These findings suggested that knockdown and overexpression of IER2 modulated the general capacity of endothelial cell motility, and the endogenous IER2 expression may be required for endothelial cell migration and invasion.…”

“…Currently, IER2 has been characterized as a putative nuclear protein that served function as a fibroblast growth factor intracellular binding protein 1-interacting partner (12), and as a transcription factor or transcriptional co-activator for the human myo-inositol 1-phosphate synthase gene involved in the regulation of cellular responses (9,12). Furthermore, data from a previous study indicated that IER2 is involved in the regulation of tumor progression and metastasis (13), although the precise role and signaling mechanism involved remain elusive. In our previous study, microarray was performed to analyze the gene expression profile in response to basic fibroblast growth factor (bFGF), which is a proangiogenic factor (14), at selective time points during different phases of human dermal microvascular endothelial cells morphogenesis (15) in fibrin matrices by bFGF led to a significant upregulation of IER2 within 24 h and a subsequently significant downregulation between 24 and 72 h (data not shown), which prompted the evaluation of whether IER2 participates in the regulation of the endothelial cell morphogenesis and angiogenesis.…”

T‐Cell Immunopeptidomes Reveal Cell Subtype Surface Markers Derived From Intracellular Proteins

“…4C). IER2 is a DNA-binding protein expressed in activated tumor cells and metastatic tumor cells that can promote cell motility and been reported to correlate with poor metastasis-free and overall survival [52]. Its post-translational modification has not previously been reported.…”

Potential role of differentially expressed lncRNAs in the pathogenesis of oral squamous cell carcinoma

“…It is well established that tumors are known as wounds that do not heal, in other words, chronic wounds predispose to tumor formation. Mechanistically, many genes that are involved in response to wounding, such as RHBDF2 and Ier2, have been shown to be prominent factors in the progression and metastasis of cancer (Blaydon et al, 2012;Neeb et al, 2012). Interestingly, product of PLAU gene (uPA) and its receptor have been proved to be key regulators in cancer adhesion, migration and invasion (Han, Nakamura, Mori, Nakamura, & Kakudo, 2005;Laufs, Schumacher, & Allgayer, 2006).…”