Human kallikrein gene 5 (KLK5) expression is an indicator of poor prognosis in ovarian cancer

Abstract

Summary Kallikrein gene 5 (KLK5, also known as KLK-L2), located on chromosome 19q13.4, is one of the newly identified members of the kallikrein gene family, which is a subgroup of the serine protease enzyme family. In normal human tissues, KLK5 is highly expressed in skin, mammary gland and testis. Preliminary RT-PCR analysis has indicated that KLK5 is expressed in a subset of ovarian tumours. We have thus hypothesized that KLK5 may be a new prognostic indicator in ovarian cancer. We have examined the mRNA expression of KLK5 in 142 malignant ovarian tissues. Tumours were pulverized, total RNA was extracted, and cDNA was prepared by reverse transcription. KLK5 was amplified by PCR using gene specific primers, and the identity of the PCR product was verified by sequencing. Ovarian tissues were then classified as KLK5 positive or negative, based on ethidium bromide staining of the PCR product on agarose gels. KLK5 was found to be highly expressed in 58/142 (41%) of ovarian cancer samples while its level of expression was very low in normal ovarian tissues. We found a strong positive relation between KLK5 expression and tumour grade (P = 0.006) and disease stage (P = 0.027). Univariate survival analysis revealed that patients with ovarian tumours positive for KLK5 expression had an increased risk for relapse and death (P = 0.018 and 0.022, respectively). In multivariate analysis, KLK5 expression showed independent prognostic value only in the subset of tumours with lower grade disease (grades I and II). We conclude that KLK5 expression is associated with more aggressive forms of epithelial ovarian carcinoma and has indepdent prognostic value in low grade tumours. 643-650 © 2001 Cancer Research Campaign doi: 10.1054/ bjoc.2000.1649, available online at http://www.idealibrary.com on http://www.bjcancer.comIn the present study, we have evaluated KLK5 mRNA expression in relation to patient survival and other clinicopathologic variables in epithelial ovarian carcinoma. Our results demonstrate that KLK5 is an independent prognostic marker of poor prognosis in a subset of patients with grade I/II tumours. MATERIALS AND METHODS Ovarian cancer specimens and patients142 consecutive patients with epithelial ovarian carcinoma were included in this study, with ages ranging from 25 to 80 with a median of 59 years. Patients underwent surgery and treatment for primary ovarian carcinoma at the Department of Obstetrics and Gynecology, Gynecologic Oncology Unit, University of Turin, Turin, Italy between July, 1991 and April, 1999. Follow-up information (median follow-up period 48 months) was available for 138 patients, among whom 83 (60%) have relapsed and 55 (40%) died. Of the 142 ovarian adenocarcinomas, for which histological diagnosis was available, 64 (45%) were serous papillary, 26 (18%) endometrioid, 22 (16%) undifferentiated, 12 (8%) clear cell, 11 (8%) mucinous, 6 (4%) Mullerian and 1 (1%) was unclassified. Due to the relatively small sample size, the clear cell, mucinous and Mullerian types were combined into one category...

Quantitative analysis of human kallikrein gene 14 expression in breast tumours indicates association with poor prognosis

“…Interestingly, the results obtained for KLK14 in this study are comparable to those obtained for KLK3, KLK6 and KLK15 in breast cancer (Yu et al, 1995;Anisowicz et al, 1996) and KLK4, KLK5 and KLK10 in ovarian cancer (Kim et al, 2001;Luo et al, 2001b;Obiezu et al, 2001), in that high expression of these kallikrein genes also correlated with patient prognosis. Similar to KLK14, these genes are also under steroid hormone regulation ).…”

“…The kallikrein genes, denoted KLK1 -KLK15, are located on chromosome 19q13.4 and encode for corresponding kallikrein enzymes, hK1 -hK15 Yousef et al, 2000b). Accumulating evidence indicates that many members of this family are differentially expressed in certain malignancies, including prostate (Rittenhouse et al, 1998;Magklara et al, 1999;Barry, 2001;Yousef et al, 2001c;Diamandis et al, 2002), testicular (Luo et al, 2001c), breast (Yousef et al, 2000a,c) and ovarian (Anisowicz et al, 1996;Diamandis et al, 2000c;Kim et al, 2001;Luo et al, 2001b;Magklara et al, 2001;Obiezu et al, 2001;Yousef et al, 2001a) cancers. Also, many kallikrein genes examined thus far are under steroid hormone regulation, further suggesting a role for these enzymes in endocrine-related tissues (Yousef and Diamandis, 2002).…”

Characterisation of human kallikrein 6/protease M expression in ovarian cancer

“…It will be of interest to determine the functions and the potential of serum biomarker development for the other members of the kallikrein family. Indeed, recent studies have shown that the expression of many kallikreins including hK4, hK5, hK6, hK7, and hK8 has emerged as being related to breast, ovarian, and other human cancers (Underwood et al, 1999;Diamandis et al, 2000;Kim et al, 2001;Yousef et al, 2003). Further studies of these kallikreins in ovarian cancer and the development of detection tools may facilitate better understanding of this family of proteases in ovarian cancer and improve the prognosis of ovarian cancer patients.…”

Immunofluorometric quantitation and histochemical localisation of kallikrein 6 protein in ovarian cancer tissue: a new independent unfavourable prognostic biomarker

“…Investigations are proceeding as sensitive and specific assays measuring the gene expression or protein mass of each newly identified member of the kallikrein family become available. Tissue expression of the kallikreins examined to date appears to be down-regulated in aggressive forms of breast cancer (hK3 (PSA) (Levesque et al, 1998), hK10 (Liu et al, 1996;Goyal et al, 1998), hK13 (Yousef et al, 2000) and hK6 (Anisowicz et al, 1996)) and up-regulated in ovarian cancer (hK4 (Obiezu et al, 2002), hK10 (Luo et al, 2001), hK5 (Kim et al, 2001), hK8 (Magklara et al, 2001) and hK6 (Tanimoto et al, 2001)). …”