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Mol Oncol. 2015 Feb;9(2):437-49. doi: 10.1016/j.molonc.2014.09.001. Epub 2014 Oct 6.

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

Author information

1
Department of Cancer and Inflammation Research, Institute for Molecular Medicine, University of Southern Denmark, DK-5000 Odense, Denmark.
2
Department of Cancer and Inflammation Research, Institute for Molecular Medicine, University of Southern Denmark, DK-5000 Odense, Denmark; The Lundbeckfonden Center of Excellence NanoCAN, University of Southern Denmark, DK-5000 Odense, Denmark.
3
Department of Cancer and Inflammation Research, Institute for Molecular Medicine, University of Southern Denmark, DK-5000 Odense, Denmark; The Lundbeckfonden Center of Excellence NanoCAN, University of Southern Denmark, DK-5000 Odense, Denmark; Department of Oncology, Odense University Hospital, DK-5230 Odense, Denmark. Electronic address: hditzel@health.sdu.dk.
4
Department of Cancer and Inflammation Research, Institute for Molecular Medicine, University of Southern Denmark, DK-5000 Odense, Denmark. Electronic address: mgjerstorff@health.sdu.dk.

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 β-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.

KEYWORDS:

Cancer/testis antigen; Genomic instability; Oncogene; SSX2; Senescence

PMID:
25363656
PMCID:
PMC5528659
DOI:
10.1016/j.molonc.2014.09.001
[Indexed for MEDLINE]
Free PMC Article

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