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Tumor-Associated Alterations in Caspase-14 Expression in Epithelial Malignancies

Authors' Affiliations: ¹ The Burnham Institute, La Jolla, California; ² College of Medicine, Yonsei University, Seoul, Korea; ³ Royal Victoria Eye and Ear Hospital, Dublin, Ireland; ⁴ St. Vincent's University Hospital, Department of Surgery, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland; ⁵ The Chinese University of Hong Kong, Prince of Wales Hospital, Department of Obstetrics and Gynaecology, Hong Kong, China; ⁶ Applied Imaging Corporation, San Jose, California; ⁷ Department of Pathology, University of California-San Diego, California; and ⁸ Department of Gynecology and Obstetrics, University Hospital of Schleswig-Holstein, Kiel, Germany

Requests for reprints: Stan Krajewski, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037. Phone: 858-646-3663; Fax: 858-646-3194; E-mail: reedoffice{at}burnham.org.

Purpose: Caspase-14 is unique among caspase family proteases in that its proteolytic processing has been principally associated with epithelial cell differentiation rather than apoptosis or inflammation. We investigated caspase-14 expression in several types of human epithelial malignancy by immunohistochemistry, correlating results with stage, histologic grade, and patient survival.

Experimental Design: Tumor-associated alterations in caspase-14 expression were observed for cervical, ovarian, breast, gastric, and colon cancers.

Results: In cervical (n = 445), ovarian (n = 91), and colon (n = 106) specimens, expression of caspase-14 was significantly reduced in cancers compared with normal epithelium. Decreases in caspase-14 immunopositivity correlated with the histologic progression of cervical cancer (P < 0.0001, ANOVA). In localized gastric cancers, caspase-14 immunostaining was significantly lower in poorly differentiated tumors compared with well-differentiated tumors (P = 0.02, Pearson's ² analysis). Lower caspase-14 expression was associated with advanced clinical stage in ovarian cancer (P = 0.04, ANOVA) and with shorter overall survival among ovarian cancer patients with serous tumors (n = 62) in both univariate (P = 0.005) and multivariate (P = 0.03) analysis. Lower caspase-14 expression correlated with shorter overall survival among patients with T₃N₀M₀ stage gastric cancers (n = 94; P = 0.006, log-rank test). In contrast to cervical, ovarian, and colon cancers, caspase-14 expression was increased in ductal carcinoma in situ and invasive cancers compared with normal mammary epithelium (P = 0.001, t test).

Conclusions: The findings reveal tumor-specific alterations in caspase-14 expression and suggest that differences in its expression may define subsets of epithelial cancers with distinct clinical behaviors.

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