GAGE Cancer-Germline Antigens Are Recruited to the Nuclear Envelope by Germ Cell-Less (GCL)

Gjerstorff, Morten F.; Rösner, Heike I.; Pedersen, Christina Gundgaard; Greve, Katrine Buch Vidén; Schmidt, Steffen; Wilson, Katherine L.; Mollenhauer, Jan; Besir, Hüseyin; Poulsen, Flemming M.; Møllegaard, Niels Erik; Ditzel, Henrik J.

doi:10.1371/journal.pone.0045819

Cited by 17 publications

(15 citation statements)

References 52 publications

(89 reference statements)

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“…The tumorigenic effect of cancer/testis antigen on the X chromosome (CT-X) was also shown in SSX4 (34) and MAGE (35,36). For XAGE-related GAGE genes, the proteins bind to the metazoan transcriptional regulator, germ cellless (GCL), at the nuclear envelope and cause tumorigenesis (37). These findings suggest that the tumorigenic effect is a common characteristic of CT-X antigens.…”

Section: Discussionmentioning

confidence: 98%

Prolongation of Overall Survival in Advanced Lung Adenocarcinoma Patients with the XAGE1 (GAGED2a) Antibody

Ohue

Koyama

Mizote

et al. 2014

Clinical Cancer Research

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Purpose: The cancer/testis antigen XAGE1 (GAGED2a) is expressed in approximately 40% of advanced lung adenocarcinomas. We investigated the clinical relevance of the XAGE1 (GAGED2a) immune responses in patients with advanced lung adenocarcinoma.Experimental Design: The XAGE1 (GAGED2a) antigen expression and EGFR mutation were determined with tumor tissues. The XAGE1 (GAGED2a) antibody and T-cell immune responses, as well as immune cell phenotypes, were analyzed with blood samples. Patients with EGFR wild-type (EGFRwt) tumors were treated with conventional platinum-based doublet chemotherapy and patients with EGFR-mutated (EGFRmt) tumors were treated with EGFR-TKI and conventional chemotherapy. The overall survival (OS) rates of the antibody-positive and -negative patients were investigated.Results: The results showed that the OS of antibody-positive patients was prolonged significantly compared with that of antibody-negative patients with either XAGE1 (GAGED2a) antigen-positive EGFRwt (31.5 vs. 15.6 months, P ¼ 0.05) or EGFRmt (34.7 vs. 11.1 months, P ¼ 0.001) tumors. Multivariate analysis showed that the presence of the XAGE1 (GAGED2a) antibody was a strong predictor for prolonged OS in patients with XAGE1 (GAGED2a) antigen-positive tumors and in patients with either EGFRwt or EGFRmt tumors. On the other hand, XAGE1 (GAGED2a) antigen expression was a worse predictor in patients with EGFRmt tumors. Phenotypic and functional analyses of T cells indicated immune activation in the antibodypositive patients.Conclusions: The findings suggest that production of the XAGE1 (GAGED2a) antibody predicts good prognosis for patients with lung adenocarcinoma as an immune biomarker and the protective effect of this naturally occurring immune response supports the concept of immunotherapy.

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Section: Discussionmentioning

confidence: 98%

Prolongation of Overall Survival in Advanced Lung Adenocarcinoma Patients with the XAGE1 (GAGED2a) Antibody

Ohue

Koyama

Mizote

et al. 2014

Clinical Cancer Research

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“…The transcripts encoded by these genes are normally not found in somatic tissues, but are frequently expressed in embryonic tissues and various cancers (reviewed in Simpson et al [38]). The GAGE antigens are not well described, but they have been shown to confer resistance to apoptosis [39], and they might be involved in reorganization of chromatin [40]. The MAGE antigens have been more studied, and MAGE2C, which was increased 15-fold in IMSC#3, has been demonstrated to promote both cell proliferation and viability of mast cells [41].…”

Section: Discussionmentioning

confidence: 99%

Generation and Characterization of an Immortalized Human Mesenchymal Stromal Cell Line

Skårn

Noordhuis

Wang

et al. 2014

Stem Cells and Development

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Human mesenchymal stromal cells (hMSCs) show great potential for clinical and experimental use due to their capacity to self-renew and differentiate into multiple mesenchymal lineages. However, disadvantages of primary cultures of hMSCs are the limited in vitro lifespan, and the variable properties of cells from different donors and over time in culture. In this article, we describe the generation of a telomerase-immortalized nontumorigenic human bone marrow-derived stromal mesenchymal cell line, and its detailed characterization after long-term culturing (up to 155 population doublings). The resulting cell line, iMSC#3, maintained a fibroblast-like phenotype comparable to early passages of primary hMSCs, and showed no major differences from hMSCs regarding surface marker expression. Furthermore, iMSC#3 had a normal karyotype, and highresolution array comparative genomic hybridization confirmed normal copy numbers. The gene expression profiles of immortalized and primary hMSCs were also similar, whereas the corresponding DNA methylation profiles were more diverse. The cells also had proliferation characteristics comparable to primary hMSCs and maintained the capacity to differentiate into osteoblasts and adipocytes. A detailed characterization of the mRNA and microRNA transcriptomes during adipocyte differentiation also showed that the iMSC#3 recapitulates this process at the molecular level. In summary, the immortalized mesenchymal cells represent a valuable model system that can be used for studies of candidate genes and their role in differentiation or oncogenic transformation, and basic studies of mesenchymal biology.

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“…For example, GAGE functions as a regulator of chromatin reorganization in both germ and cancer cells (41). To date, 156 families of CT genes have been collected in the CT database (http://www.cta.lncc.br).…”

Section: Discussionmentioning

confidence: 99%

Proteomic analysis reveals that MAEL, a component of nuage, interacts with stress granule proteins in cancer cells

et al. 2013

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The Maelstrom (MAEL) gene is a cancer-testis (or cancer-germline) gene, which is predominantly expressed in germline cells under normal conditions, but is aberrantly expressed in a range of human cancer cells. In germline cells, MAEL is found predominantly in the nuage, where it plays an essential role in piRNA biogenesis and piRNA-mediated silencing of transposons. However, the role of MAEL in cancer has not been elucidated. We performed immunoprecipitation and Nano-LC-MS/MS analysis to investigate the interactome of MAEL, and identified 14 components of stress granules (SGs) as potential binding partners of MAEL in MDA-MB-231 human breast cancer and SW480 colorectal cancer cells. The interactions between MAEL and 8 of these SG components (PABPC1, YBX1, KHSRP, SYNCRIP, DDX39, ELAV1, EIF4A1 and EIF3F) were confirmed by anti-tag immunoprecipitation. Immunofluorescence analysis showed that MAEL co-localizes with the SG marker PABPC1 in SGs during oxidative stress. Nuages and SGs are the cytoplasmic RNA granules of germline cells and stressed somatic cells, respectively, and both serve as a platform for small RNA-mediated gene silencing. It is, therefore, suggested that MAEL may be involved in miRNA-mediated gene silencing in SGs, as it does in the nuage. This finding should be valuable toward understanding the function of MAEL in carcinogenesis.

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GAGE Cancer-Germline Antigens Are Recruited to the Nuclear Envelope by Germ Cell-Less (GCL)

Cited by 17 publications

References 52 publications

Prolongation of Overall Survival in Advanced Lung Adenocarcinoma Patients with the XAGE1 (GAGED2a) Antibody

Prolongation of Overall Survival in Advanced Lung Adenocarcinoma Patients with the XAGE1 (GAGED2a) Antibody

Generation and Characterization of an Immortalized Human Mesenchymal Stromal Cell Line

Proteomic analysis reveals that MAEL, a component of nuage, interacts with stress granule proteins in cancer cells

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