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Ectopic expression of cancer/testis antigen SSX2 induces DNA damage and promotes genomic instability.

ABSTRACT: SSX cancer/testis antigens are frequently expressed in melanoma tumors and represent attractive targets for immunotherapy, but their role in melanoma tumorigenesis has remained elusive. Here, we investigated the cellular effects of SSX2 expression. In A375 melanoma cells, SSX2 expression resulted in an increased DNA content and enlargement of cell nuclei, suggestive of replication aberrations. The cells further displayed signs of DNA damage and genomic instability, associated with p53-mediated G1 cell cycle arrest and a late apoptotic response. These results suggest a model wherein SSX2-mediated replication stress translates into mitotic defects and genomic instability. Arrest of cell growth and induction of DNA double-strand breaks was also observed in MCF7 breast cancer cells in response to SSX2 expression. Additionally, MCF7 cells with ectopic SSX2 expression demonstrated typical signs of senescence (i.e. an irregular and enlarged cell shape, enhanced ?-galactosidase activity and DNA double-strand breaks). Since replication defects, DNA damage and senescence are interconnected and well-documented effects of oncogene expression, we tested the oncogenic potential of SSX2. Importantly, knockdown of SSX2 expression in melanoma cell lines demonstrated that SSX2 supports the growth of melanoma cells. Our results reveal two important phenotypes of ectopic SSX2 expression that may drive/support tumorigenesis: First, immediate induction of genomic instability, and second, long-term support of tumor cell growth.

SUBMITTER: Greve KB

PROVIDER: S-EPMC5528659 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Ectopic expression of cancer/testis antigen SSX2 induces DNA damage and promotes genomic instability.

Greve Katrine B V KB Lindgreen Jonas N JN Terp Mikkel G MG Pedersen Christina B CB Schmidt Steffen S Mollenhauer Jan J Kristensen Stine B SB Andersen Rikke S RS Relster Mette M MM Ditzel Henrik J HJ Gjerstorff Morten F MF

Molecular oncology 20141006 2

SSX cancer/testis antigens are frequently expressed in melanoma tumors and represent attractive targets for immunotherapy, but their role in melanoma tumorigenesis has remained elusive. Here, we investigated the cellular effects of SSX2 expression. In A375 melanoma cells, SSX2 expression resulted in an increased DNA content and enlargement of cell nuclei, suggestive of replication aberrations. The cells further displayed signs of DNA damage and genomic instability, associated with p53-mediated G ...[more]

PMID: 25363656

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Project description:BackgroundThe Epstein-Barr virus (EBV) is closely associated with several types of malignancies. EBV is normally present in the latent state in the peripheral blood B cell compartment. The EBV latent-to-lytic switch is required for virus spread and virus-induced carinogenesis. Immunosuppression or DNA damage can induce the reactivation of EBV replication. EBV alone is rarely sufficient to cause cancer. In this study, we investigated the roles of host microRNAs and environmental factors, such as DNA-damage agents, in EBV reactivation and its association with lymphomagenesis.MethodsWe first analyzed the publicly available microRNA array data containing 45 diffuse large B-cell lymphoma patients and 10 control lymph nodes or B cells with or without EBV infection. In situ hybridization for miR-18a and immunohistochemitry were performed to evaluate the correlation between the expression of miR-18a and nuclear EBV protein EBNA1 in lymphoid neoplasm. The proliferative effects of miR-18a were investigated in EBV-positive or -negative lymphoid neoplasm cell lines. EBV viral load was measured by a quantitative real-time EBV PCR and FISH assay. The genomic instability was evaluated by CGH-array.ResultsIn this study, we analyzed the publicly available microRNA array data and observed that the expression of the miR-17-92 cluster was associated with EBV status. In situ hybridization for miR-18a, which is a member of the miR-17-92 cluster, showed a significant upregulation in lymphoma samples. miR-18a, which shares the homolog sequence with EBV-encoded BART-5, promoted the proliferation of lymphoma cells in an EBV status-dependent manner. The DNA-damaging agent UV or hypoxia stress induced EBV activation, and miR-18a contributed to DNA damaging-induced EBV reactivation. In contrast to the promoting effect of ATM on the lytic EBV reactivation in normoxia, ATM inhibited lytic EBV gene expression and decreased the EBV viral load in the prescence of hypoxia-induced DNA damage. miR-18a reactivated EBV through inhibiting the ATM-mediated DNA damage response (DDR) and caused genomic instability.ConclusionsTaken together, these results indicate that DNA-damaging agents and host microRNAs play roles in EBV reactivation. Our study supported the interplay between host cell DDR, environmental genotoxic stress and EBV.

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Ectopic expression of cancer/testis antigen SSX2 induces DNA damage and promotes genomic instability.

Publications

Ectopic expression of cancer/testis antigen SSX2 induces DNA damage and promotes genomic instability.

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