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Human Kallikrein 6: A New Potential Serum Biomarker for Uterine Serous Papillary Cancer

Authors' Affiliations: ¹ Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas; ² Department of Pathology and Laboratory Medicine, Mount Sinai Hospital and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; and ³ Division of Gynecologic Oncology, University of Brescia, Brescia, Italy

Requests for reprints: Alessandro D. Santin, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Arkansas for Medical Sciences, 4301 West Markham, Little Rock, AR 72205-7199. Phone: 501-686-7162; Fax: 501-686-8091; E-mail: santinalessandrod{at}uams.edu.

Purpose: The discovery of novel biomarkers might greatly contribute to improve clinical management and outcomes in uterine serous papillary carcinoma (USPC), a highly aggressive variant of endometrial cancer.

Experimental Design: Human kallikrein 6 (hK6) gene expression levels were evaluated in 29 snap-frozen endometrial biopsies, including 13 USPC, 13 endometrioid carcinomas, and 3 normal endometrial cells by real-time PCR. Secretion of hK6 protein by 14 tumor cultures, including 3 USPC, 3 endometrioid carcinoma, 5 ovarian serous papillary carcinoma, and 3 cervical cancers, was measured using a sensitive ELISA. Finally, hK6 concentration in 79 serum and plasma samples from 22 healthy women, 20 women with benign diseases, 20 women with endometrioid carcinoma, and 17 USPC patients was studied.

Results: hK6 gene expression levels were significantly higher in USPC when compared with endometrioid carcinoma (mean copy number by real-time PCR, 1,927 versus 239, USPC versus endometrioid carcinoma; P < 0.01). In vitro hK6 secretion was detected in all primary USPC cell lines tested (mean, 11.5 µg/L) and the secretion levels were similar to those found in primary ovarian serous papillary carcinoma cultures (mean, 9.6 µg/L). In contrast, no hK6 secretion was detectable in primary endometrioid carcinoma and cervical cancer cultures. hK6 serum and plasma concentrations (mean ± SE) among normal healthy females (2.7 ± 0.2 µg/L), patients with benign diseases (2.4 ± 0.2 µg/L), and patients with endometrioid carcinoma (2.6 ± 0.2 µg/L) were not significantly different. In contrast, serum and plasma hK6 values in USPC patients (6.1 ± 1.1) were significantly higher than those in the noncancer group (P = 0.006), benign group (P = 0.003), and endometrioid carcinoma patients (P = 0.005).

Conclusions: hK6 is highly expressed in USPC and is released in the plasma and serum of USPC patients. hK6 may represent a novel biomarker for USPC for monitoring early disease recurrence and response to therapy.

Key Words: Uterine serous papillary cancer • kallikrein 6 • Biomarkers • Serine proteases • Tumor markers