Downregulation of the citrullinating enzyme Peptidyl-arginine deiminase type-2 in ovarian cancer indicates poor prognosis


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Lee Machado1,Paul Moseley2,Robert Moss2,Suha Deen2,Christopher Nolan2,Ian Spendlove Spendlove2,Judith Ramage2,Stephen Chan2,Lindy Durrant2
1University of Northampton,2University of Nottingham

Abstract

Background

Peptidyl-arginine deiminase enzymes have been implicated in several tumour types where expression regulates tumour cell growth and survival. We hypothesised that PAD2 may play an important role in ovarian cancer and may provide utility as an independent prognostic marker.

Method

Using tissue microarrays of primary ovarian cancers and compiling a comprehensive database of clinicopathological variables, the expression of PAD2 was assessed by immunohistochemistry in discovery (n=194) and validation (n=360) cohorts using a monoclonal antibody specific for PAD2.

Results

Kaplan-Meier analysis indicated that there was an association of PAD2 expression with overall survival in discovery (p=0.033) and validation cohorts (p=0.026). Upregulated expression of PAD2 was protective and in a multivariate model PAD2 expression remained an independent prognostic factor (p=0.029). PAD2 expression was associated with known regulators of autophagy (HMGB1 and BCL2) and immune surveillance (HLA and IFGR1).

Conclusion

Low PAD2 expression is an independent predictor of poor survival in ovarian cancer. PAD2 is a positive regulator of citrullination within the cell and high levels of citrullinated proteins may flag the immune system to target ovarian tumors. This work suggests that targeting citrullination pathways in ovarian cancer may represent a viable therapeutic target.