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Overexpression and Mislocalization of the Chromosomal Segregation Protein Separase in Multiple Human Cancers
Ist Teil von
Clinical cancer research, 2009-04, Vol.15 (8), p.2703-2710
Ort / Verlag
Philadelphia, PA: American Association for Cancer Research
Erscheinungsjahr
2009
Link zum Volltext
Quelle
MEDLINE
Beschreibungen/Notizen
Purpose: Separase, an endopeptidase, plays a pivotal role in chromosomal segregation by separating sister chromatids during the metaphase
to anaphase transition. Using a mouse mammary tumor model we have recently shown that overexpression of Separase induces aneuploidy
and tumorigenesis (Zhang et al., Proc Natl Acad Sci 2008;105:13033). In the present study, we have investigated the expression
level of Separase across a wide range of human tumors.
Experimental Design: To examine the expression levels and localization of Separase in human tumors, we have performed immunofluorescence microscopy
using human Separase antibody and tumor tissue arrays from osteosarcoma, colorectal, breast, and prostate cancers with appropriate
normal controls.
Results: We show that Separase is significantly overexpressed in osteosarcoma, breast, and prostate tumor specimens. There is a strong
correlation of tumor status with the localization of Separase into the nucleus throughout all stages of the cell cycle. Unlike
the normal control tissues, where Separase localization is exclusively cytoplasmic in nondividing cells, human tumor samples
show significantly higher number of resting cells with a strong nuclear Separase staining. Additionally, overexpression of
Separase transcript strongly correlates with high incidence of relapse, metastasis, and lower 5-year overall survival rate
in breast and prostate cancer patients.
Conclusion: These results further strengthen our hypothesis that Separase might be an oncogene, whose overexpression induces tumorigenesis,
and indicates that Separase overexpression and aberrant nuclear localization are common in many tumor types and may predict
outcome in some human cancers.