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Higher Human Kallikrein Gene 4 (KLK4) Expression Indicates Poor Prognosis of Ovarian Cancer Patients

Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, M5G 1X5 Canada, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, M5G 1L5 Canada [C. V. O., A. S., G. M. Y., E. P. D.]; Department of Obstetrics and Gynecology, Gynecologic Oncology Unit, University of Turin, Turin, Italy 10126 [D. K., M. M., S. F., I. A. R.d. l. L.]; and Department of Pathology, St. Anna Hospital, Turin, Italy 10126 [R. A.]

Purpose: Kallikrein gene 4 (KLK4, also known as prostase/KLK-L1), located on chromosome 19q13.4, is one of the newly discovered members of the human KLK-like gene family. This gene is up-regulated by androgens in the LNCaP prostatic carcinoma cell line and by androgens and progestins in the BT-474 breast cancer cell line. On the basis of its apparent association with hormonally regulated tissues, we have undertaken to examine the prognostic value of KLK4 expression in 147 malignant ovarian tissues.

Experimental Design: Tumors were pulverized, total RNA was extracted, and cDNA was prepared by reverse transcription. KLK4 was amplified by PCR using gene-specific primers, and its identity was verified by sequencing. Ovarian tissues were then classified as KLK4-positive or -negative, based on ethidium bromide visualization of the PCR product on agarose gels.

Results: KLK4 was found to be expressed in 69 (55%) of 147 of ovarian cancer samples. We found a strong positive association between KLK4 expression and tumor grade (P = 0.02) and clinical stage (P < 0.001). Univariate survival analysis revealed that patients with ovarian tumors positive for KLK4 expression had an increased risk for relapse and death (P = 0.003 and 0.001, respectively). Whereas knowledge of KLK4 status did not significantly increase the prognostic power of the multivariate models, additional analyses did determine that KLK4 was an independent unfavorable prognostic factor in patients with grade 1 and 2 tumors.

Conclusions: Our findings indicate that KLK4 expression is associated with more aggressive forms of ovarian cancer.

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