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The Immediate Early Gene Ier2 Promotes Tumor Cell Motility and Metastasis, and Predicts Poor Survival of Colorectal Cancer Patients

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The Immediate Early Gene Ier2 Promotes Tumor Cell Motility and Metastasis, and Predicts Poor Survival of Colorectal Cancer Patients Oncogene (2012) 31, 3796–3806 & 2012 Macmillan Publishers Limited All rights reserved 0950-9232/12 www.nature.com/onc ORIGINAL ARTICLE The immediate early gene Ier2 promotes tumor cell motility and metastasis, and predicts poor survival of colorectal cancer patients A Neeb1,5, S Wallbaum1,5, N Novac1,5, S Dukovic-Schulze1,2, I Scholl1, C Schreiber1,2, P Schlag3, J Moll1, U Stein4 and JP Sleeman1,2 1Karlsruhe Institute of Technology, Institut fu¨r Toxikologie und Genetik, Karlsruhe, Germany; 2Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; 3Charite´ Comprehensive Cancer Center, Invalidenstrae 80, Berlin, Germany and 4Experimental and Clinical Research Center, Charite´ University Medicine Berlin at the Max-Delbru¨ck-Center for Molecular Medicine, Berlin, Germany Here, we report unbiased screens for genes expressed in penetrate vessels of the circulatory system and are metastatic tumor cells that are associated with cell transported to distant sites where they need additional motility. These screens identified Ier2, an immediate early properties to form metastatic lesions. Much remains to gene of unknown function, as potentially having a role in be discovered about the changes in gene expression tumor cell motility and metastasis. Knockdown of Ier2 in required for metastasis. The identification of genes 3T3 fibroblasts inhibited their motility upon relief of specifically expressed or suppressed in metastatic tumor contact inhibition in monolayer wounding assays. Further- cells compared with their non-metastatic counterparts more, ectopic Ier2 expression promoted the motility and will not only aid in the understanding of the molecular invasiveness of poorly metastatic 1AS pancreatic tumor regulation of metastasis but will also have potential cells in vitro. Relief of contact inhibition was associated applications in the development of novel diagnostic and with translocation of the Ier2 protein from the cytoplasm therapeutic tools for use in the care of cancer patients. to the nucleus in both 3T3 fibroblasts and 1AS tumor cells. We have previously used suppression subtractive Importantly, ectopic Ier2 expression in 1AS cells stimu- hybridization to identify a library of genes the expres- lated metastasis formation when cells were implanted into sion of which correlates with the metastatic potential of experimental animals. Furthermore, we found elevated tumor cells (Nestl et al., 2001). Here, we describe the Ier2 expression in a wide variety of human tumor types. further screening of this library to identify genes that This correlated with poor metastasis-free and overall might have a role in the migration of metastasizing cells. survival in patients with colorectal adenocarcinomas. This was achieved by looking for the differential Together, these data reveal Ier2 as a new player in the expression of the library genes in activated and non- regulation of tumor progression and metastasis, and activated T lymphocytes. Antigen-activated T cells share suggest that Ier2 may be useful prognostically and many properties with metastatic tumor cells (Herrlich therapeutically in the management of cancer. et al., 1993). We reasoned that genes commonly Oncogene (2012) 31, 3796–3806; doi:10.1038/onc.2011.535; expressed by both activated T cells and metastatic published online 28 November 2011 tumor cells may be functionally relevant for tumor metastasis. One gene identified by the secondary screen- Keywords: Ier2; Pip92; ETR101; metastasis; motility; ing of the subtractive library was Ier2, the expression of invasion which was found to be elevated in both activated lymphocytes and in various metastatic tumor cells. Ier2 (also called ETR101, Pip92, 3CH92 and CHX1, hereafter referred to as Ier2, regardless of species) is an Introduction immediate early gene ( Rollins and Stiles, 1989) that was originally found to be upregulated in fibroblasts upon Tumor metastasis is a highly complex molecular and their activation (Lau and Nathans, 1985). Immediate cellular process (reviewed in Sleeman et al. (2011)). early genes are a group of genes that are rapidly induced Local invasion of tumor cells involves changes in in quiescent cells by proliferation- and migration- adhesive properties, activation of proteolysis and inducing stimuli. Mutation or inappropriate expression acquisition of cell motility. Thereafter, tumor cells of several of these genes (for example, members of the fos, jun and nuclear factor-kB gene families) has been Correspondence: Professor JP Sleeman, Universita¨tsmedizin shown to cause them to function as oncogenes and/or to Mannheim, University of Heidelberg, Centre for Biomedicine and contribute to tumor progression (reviewed in Aggarwal Medical Technology Mannheim (CBTM), TRIDOMUS-Geba¨ude (2004) and Milde-Langosch (2005). Haus C, Ludolf-Krehl-Str. 13–17, Mannheim D-68167, Germany. Here, we show that expression of Ier2 correlates with E-mail: [email protected] 5These authors contributed equally to this work. the metastatic phenotype in a wide range of rodent and Received 28 July 2011; revised 7 October 2011; accepted 17 October human tumor types. Ectopic expression of Ier2 in poorly 2011; published online 28 November 2011 metastatic pancreatic tumor cells promotes their metas- Ier2 and metastasis A Neeb et al 3797 tasis in vivo and enhances their motility and invasiveness non-metastatic cells in a broad panel of tumor cell lines. in culture. Furthermore, high expression of Ier2 in To this end, we performed northern blots using RNA human colorectal carcinoma patients was found to be derived from rat pancreatic, mammary and prostate significantly associated with short metastasis-free survi- tumor cell lines with verified metastatic potential in vivo. val and poor overall survival. Therefore, these data Only one of these nine clones was consistently upregu- identify Ier2 as a metastasis-relevant immediate early lated in a metastasis-relevant manner in all cell lines gene the expression of which represents a prognostic tested (Figure 1a). Sequence analysis of this clone marker and a potential target for cancer therapy. revealed a 128-bp insert with complete homology to the 50 coding sequence of Ier2. To confirm the RNA expression data at the protein Results level, we generated and affinity purified polyclonal anti- Ier2 antibodies that cross-reacted with the rat, mouse Ier2 is expressed in both activated T cells and metastatic and human Ier2 protein. Western blots of lysates from tumor cells tumor cell lines with defined metastatic potential in vivo 1AS pancreatic carcinoma cells form primary tumors were probed with these antibodies. These data con- but rarely metastasize in vivo, whereas ASML cells firmed that constitutive Ier2 protein expression in tumor derived from the same primary tumor as 1AS cells are cells correlates with metastatic potential (Figure 1b). highly metastatic and disseminate from subcutaneous sites through the lymphatics to colonize the lungs (Nestl Ier2 expression can promote cell motility et al., 2001). We have previously described a subtractive Activation of resting lymphocytes and stimulation of library that was created through suppression subtractive quiescent fibroblasts increase their migratory activity hybridization comparison of these two cell lines (Nestl (Herrlich et al., 1993; Bradley, 2003; Li et al., 2004). As et al., 2001). To identify genes in this library that may previously reported, we found that concanavilin A- have a role in invasive migration, we screened the library activated splenocytes and serum-stimulated quiescent to identify transcripts that are upregulated in activated murine 3T3 fibroblasts exhibit immediate early expres- T cells in comparison with non-activated T cells. For sion of Ier2 (Figure 1, Supplementary Figure 1a). this purpose, inserts of the cDNA library were PCR Therefore, we investigated whether Ier2 expression amplified and differentially hybridized with radiolabeled might influence cell motility, as enhanced motility is probes derived from concanavilin A-activated and non- associated with metastasis. activated splenocytes. Nine clones from the library were Using the well-established 3T3 fibroblast model system found to be upregulated in concanavilin A-treated cells for investigating cell motility, we first knocked down Ier2 compared with non-treated cells (data not shown). expression (Supplementary Figure 1b) and examined the We further screened the nine clones to identify those effect on motility after relief of contact inhibition in dense that are upregulated in metastatic cells compared with monolayers. To this end, we included a silicon insert in cell cultures during establishment of the monolayer that was subsequently removed to create a cell-free area, thereby relieving contact inhibition. Serum-starved fibroblasts filled the cell-free area more slowly than did serum- stimulated cells. In both cases, knockdown of Ier2 retarded closure of the cell-free area. This retardation was most pronounced in serum-stimulated cells (Figure 2). Knock- down of Ier2 had no effect on cell proliferation or apoptosis (Supplementary Figure 2), supporting the notion that Ier2 supports the motility of fibroblasts. To examine the consequences of constitutively aug- mented Ier2 expression in non-transformed cells, we used the ecdysone-based Rheoswitch-inducible expres- sion system to ectopically express Ier2 conditionally in 3T3 fibroblasts (Wallbaum et al., 2009). In these cells, Ier2 expression is upregulated after 3 h of treatment with the Rheoswitch ligand RSL1, and
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