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Human Kallikrein Gene 11 (KLK11) Mrna Overexpression Is Associated with Poor Prognosis in Patients with Epithelial Ovarian Cancer

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Human Kallikrein Gene 11 (KLK11) Mrna Overexpression Is Associated with Poor Prognosis in Patients with Epithelial Ovarian Cancer 2766 Vol. 10, 2766–2770, April 15, 2004 Clinical Cancer Research Human Kallikrein Gene 11 (KLK11) mRNA Overexpression Is Associated with Poor Prognosis in Patients with Epithelial Ovarian Cancer 0.0225 ؍ Kazushi Shigemasa,1 Lijun Gu,1 significantly associated with overall survival (P ؍ Hirotoshi Tanimoto,2 Timothy J. O’Brien,3 and and P 0.0202, respectively) after multivariate analysis. Conclusions: KLK11 expression may play an important Koso Ohama1 role in ovarian cancer development and act as an independ- 1 Department of Obstetrics and Gynecology, Hiroshima University ent prognostic marker in ovarian cancer patients. Graduate School of Biomedical Sciences, Hiroshima, Japan; 2Department of Gynecology, National Hiroshima Hospital, Higashi Hiroshima, Japan; and 3Departments of Biochemistry and Molecular INTRODUCTION Biology and Obstetrics and Gynecology, University of Arkansas for Serine proteases comprise a family of protein-degrading Medical Sciences, Little Rock, Arkansas enzymes that serve a variety of biological functions, including induction of blood coagulation, activation of growth and angio- ABSTRACT genic factors, and degradation of extracellular matrix compo- nents (1–4). Purpose: The purpose of this study was to examine The human kallikrein gene family, a subfamily of serine expression levels of the human tissue kallikrein 11 gene proteases, is located at the chromosomal locus 19q13.3-q13.4. (KLK11) in epithelial ovarian tumors and to identify the Until recently, this family was thought to include only three relationship between KLK11 expression and patient sur- genes, the pancreatic renal kallikrein gene (KLK1), the human vival. glandular kallikrein gene (KLK2), and KLK3, which encodes Experimental Design: KLK11 mRNA expression was prostate-specific antigen (hK3). However, in the past few years examined by semiquantitative PCR in 64 epithelial ovarian several groups have reported the cloning of new serine proteases tumors (7 adenomas, 6 low malignant potential tumors, and that colocalized with and were homologous to the three known 51 adenocarcinomas) and in 10 normal ovaries. Semiquan- kallikreins, such that 15 members of human kallikrein gene titative PCR results were correlated with clinicopathologic family are now recognized (5, 6). KLKs share many common variables and overall survival. cDNA from human normal structural features, and a universal nomenclature for KLK struc- tissues and tumor tissues was also analyzed. ture has been established (7). There is now growing evidence Results: KLK11 mRNA expression was detected in var- that KLKs are involved in human malignancies. Prostate- ious human cancer tissues including breast, lung, colon, specific antigen (hK3) has been used successfully as a tumor prostate, pancreas, and ovarian carcinoma. The mean value marker for the early detection of prostate cancer due to its of relative KLK11 expression ratio was significantly higher abnormal prevalence in the peripheral blood of affected patients in ovarian tumor samples than in normal ovary samples (8). Prostate-specific antigen (hK3) is also recognized as a low favorable prognostic factor for breast cancer (9, 10). Recent ;0.0006 ؍ compared with normal samples: adenoma, P) -and carcinoma, P < reports have suggested that hK2 could be another useful diag ;0.0049 ؍ malignant potential tumor, P 0.0001). No statistically significant associations between nostic marker for prostate cancer (11, 12). We reported previ- KLK11 mRNA expression level and clinical stage, histologi- ously that protease M (KLK6) is highly overexpressed in ovarian cal type, or histological grade were observed. The log-rank tumors (13) and that the stratum corneum chymotryptic enzyme test showed that high KLK11 mRNA expression and ad- (KLK7) is expressed at abnormally high levels in ovarian cancer vanced clinical stage significantly correlated with poor pa- (14). We also reported the cloning of tumor-associated differ- respectively). entially expressed gene-14 (TADG-14; KLK8), a novel serine ,0.0043 ؍ and P 0.0185 ؍ tient survival (P High KLK11 mRNA expression and clinical stage remained protease overexpressed in ovarian cancer (15). In addition, hK6, hK10, and hK11 have been shown to be potential serum bi- omarkers in ovarian cancer (16–19). The KLK11 gene was originally cloned from human hip- pocampus cDNA, using PCR with primers targeted to conserved Received 9/23/03; revised 11/25/03; accepted 12/01/03. serine protease regions, and was originally named trypsin-like Grant support: Tsuchiya Medical Research Foundation, Japan. serine protease (20). With the newly established kallikrein gene The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked nomenclature, this gene was renamed as KLK11 (7). KLK11 advertisement in accordance with 18 U.S.C. Section 1734 solely to mRNA expression has been demonstrated in many tissues, in- indicate this fact. cluding brain, skin, salivary gland, stomach, prostate, and intes- Requests for reprints: Kazushi Shigemasa, Department of Obstet- tine (21). Diamandis et al. (19) have developed an immunoflu- rics and Gynecology, Hiroshima University Graduate School of Biomedical Sciences, 1-2-3, Kasumi, Minami-ku, Hiroshima 734- orometric procedure for measuring hK11 in biological fluids 8551, Japan. Phone: 81-82-257-5262; Fax: 81-82-257-5264; E-mail: and tissue extracts. They reported that elevated serum levels of [email protected]. hK11 were found in 70% of women with ovarian cancer and in Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2004 American Association for Cancer Research. Clinical Cancer Research 2767 60% of men with prostate cancer, which suggested that hK11 Semiquantitative PCR. Extraction of mRNA from ovar- may be of potential value as an ovarian and prostate cancer ian tissue specimens and cDNA synthesis were carried out biomarker (19). In addition, a recently published article by according to methods described previously (25–28). mRNA was Borgon˜o et al. (22) reported that higher hK11 concentration in isolated using a RiboSep mRNA isolation kit (Becton Dickinson ovarian tumor cytosolic extract is a marker of favorable prog- Labware, Bedford, MA) and the amount of mRNA recovered nosis in patients with ovarian cancer. measured using a UV spectrophotometer. cDNA was synthe- The aim of the present study was to determine the potential sized from 2.0 ␮g mRNA by random hexamer priming using the role of KLK11 mRNA expression in ovarian cancer develop- Advantage RT-for-PCR kit (Clontech). ment and/or progression. KLK11 mRNA expression in various KLK11 mRNA expression levels were determined by semi- normal and cancer tissues was investigated by the application of quantitative PCR, which was performed according to a method semiquantitative PCR to samples of epithelial ovarian tumors described previously with some modifications (25–28). The oligo- and normal ovaries. The results were analyzed in terms of tumor nucleotide primer sequences used for PCR were KLK11 sense type, clinical stage, histological grade, and histological type. primer, 5Ј-CCG CTA CAT AGT TCA CCT GG-3Ј; and KLK11 The prognostic significance of KLK11 mRNA expression level antisense primer, 5Ј-AGG TGT GAG GCA GGC GTA ACT-3Ј. in ovarian cancer patients was also analyzed. ␤-Tubulin cDNA was coamplified with target sequence and used as an internal PCR control. The ␤-tubulin sense primer was 5Ј- TGC ATT GAC AAC GAG GC-3Ј, and the antisense primer was MATERIALS AND METHODS 5Ј-CTG TCT TGA CAT TGT TG-3Ј. The predicted sizes of the Tissue Samples and Clinical and Pathological Data. amplified genes were 284 bp for KLK11 and 454 bp for ␤-tubulin. For semiquantitative PCR analysis, fresh surgical epithelial Thirty cycles of PCR were carried out in a Thermal Cycler (Perkin- ovarian tumor tissue samples were collected from 64 patients Elmer, Foster City, CA). Each PCR cycle involved 30-s denatur- treated surgically between 1993 and 2001. Patients were diag- ation at 94°C, 60-s primer annealing at 60°C, and 60-s extension at nosed histologically and received follow-up care in the Depart- 72°C. We confirmed that amplification under these conditions ment of Obstetrics and Gynecology at Hiroshima University resulted in the linear production of each product. Tubes containing Hospital. In addition, 10 normal ovaries were obtained from all of the ingredients except templates were included in all of the patients before undergoing surgery for benign gynecological runs as a negative control. PCR products were separated on 2.0% disease. Informed consent was obtained from each subject ac- agarose gels, and the density of each PCR product determined cording to institutional guidelines. Specimens were obtained using a Printgraph-Densitograph system (ATTO Corp., Tokyo, immediately after surgery and were cut in half, with one half Japan). The expression ratio of KLK11:␤-tubulin was measured by processed for histological examination to determine the percent- densitometry to evaluate gene expression and the results expressed age of tumor cells, which was never Ͻ80%, whereas the other as the mean Ϯ SD. Differences in the mean value of the KLK11 half was used for mRNA preparation. Tissues were frozen in expression ratio between groups were assessed with respect to liquid nitrogen and stored at Ϫ80°C before mRNA isolation. tumor type, clinical stage, histological grade, and histological type. The histological subtype of each ovarian tumor sample was In addition, in ovarian
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