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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Review KLK11 (Kallikrein-related peptidase 11) Liu-Ying Luo, Eleftherios P Diamandis R&D Systems, Inc. 614 McKinley Place, N. E. Minneapolis, MN 55413, USA (LYL), Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, 600 University Ave. Toronto, ON M5G 1X5, Canada (EPD) Published in Atlas Database: March 2008 Online updated version: http://AtlasGeneticsOncology.org/Genes/KLK11ID41077ch19q13.html DOI: 10.4267/2042/44378 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2009 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity the cells. Upon activation, the propetide is removed to generate the mature active protein. Other names: Hippostasin; hK11; PRSS20; TLSP HGNC (Hugo): KLK11 Location: 19q13.41 Local order: Telomere to centromere. Expression The KLK11 gene is about 5.8 Kb in length, consisting of 6 exons and 5 introns. KLK11 is mainly expressed in epithelial tissues, such as stomach, trachea, and skin, with high levels in the brain and the prostate. KLK11 has also been identified in many biological fluids. Seminal plas-ma, containing an average of 15 µg/mL of KLK11, is the biological fluid reported to have the most abundant KLK11 so far. Other specimens, includ-ing serum, lactating milk, cerebrospinal fluid, and amniotic fluid, all have detectable amounts of KLK11. Transcription Localisation Three alternatively spliced variants have been described in the literature: including isoform 1, isoform 2, and isoform 3. Isoform 1 is preferentially expressed in the brain and it encodes a protein of 250 amino acids. Isoform 2 and isoform 3 are mainly expressed in the prostate. Compared to isoform 1, isoform 2 has additional 32 amino acids at the N-terminus and isoform 3 contains extra 25 amino acids inserted in the catalytic triad. Tissue-specific expression of these isoforms is regulated by multiple promoters that locate in the first exon of each isoform. Secreted. DNA/RNA Description Function The physiology functions of KLK11 and the mechanisms of its involvement in cancer have yet to be determined. Using positional scanning combinatorial tetrapeptide substrate library, it has revealed that KLK11 preferentially cleaves peptide bonds after methionine, arginine, and lysine. However, its physiology substrates remain unidenti-fied. One hypothesis is that KLK11 may be part of a proteolytic cascade consisting of multiple kalli-kreins (KLKs). Since KLK11 is unable to auto-activate, in the cascade, it is likely that KLK11 is activated by upstream KLKs, then subsequently activate/inactaivate other downstream KLKs or other proteins. Accumulating experimental evi-dence is in accord with this hypothesis. It has been shown in in vitro experiments that, both KLK12 and KLK14 are able to activate KLK11. Another hypothesis is that KLK11 may be involved in the homeostasis of insulin growth factor. This hypo-thesis comes from the observation that KLK11 is able to degrade insulin growth factor binding Pseudogene Not identified so far Protein Description Full-length KLK11 is composed of a signal peptide (aa 1-50), a propeptide (aa 51-53), and a mature chain (aa 54-282). KLK11 is synthesized as a full-length protein intracellularly. In the secretary pathway, the signal peptide is cleaved and the zymogen is released outside Atlas Genet Cytogenet Oncol Haematol. 2009; 13(1) 15 KLK11 (Kallikrein-related peptidase 11) Luo LY, Diamandis EP from noncancer individuals whose total PSA levels are in the range of 2.5 to 10 ng/mL. Prognosis Tissue expression levels of KLK11 may be used as a prognostic indicator for prostate cancer. Lower KLK11 mRNA levels have been found to be associated with higher tumor grade, tumor stage, and Gleason score, suggesting that KLK11 might be able to indicate the aggressiveness of prostate tumors. Cytogenetics No cytogenetic abnormalities are identified so far. Hybrid/Mutated gene Not identified so far. protein 3 (IGFBP3) to facilitate the release of insulin growth factor. KLK11 enzymatic activity is mainly regulated by internal cleavage. In seminal plasma, about half the KLK11 is in the cleaved inactive form. Some abundant serine protease inhibitors present in the circulation or in seminal plasma, such as α1-antitrypsin, protein C inhibitor, α2-antiplasmin, and C1 inhibitor, fail to show rapid inhibition of KLK11. Homology Human KLK11 protein sequence shares 98% and 82% identity with that of chimpanzee and dog/bovine/mouse/rat, respectively. Mutations Ovarian cancer Note No germinal or somatic mutations are identified to be associated with cancer so far. Disease KLK11 has shown promise as a diagnostic biomarker for ovarian cancer. Earlier studies have revealed that serum KLK11 concentrations are elevated in the majority of ovarian cancer patients. Subsequent investigations further demonstrate that KLK11 is able to distinguish ovarian cancer cases from healthy controls. More importantly, it is less sensitive to benign ovarian diseases than is CA125, the most widely used diagnostic marker for ovarian cancer. Moreover, it has high temporal stability, which implies that it could be used in a longitudinal screening program for early detection. Prognosis Many investigations have clearly demonstrated that KLK11 has elevated protein levels in primary ovarian tumors than in normal tissue, benign or nonovarian metastatic tumors. In general, higher levels of KLK11 in ovarian tumor extracts are predictive of favorable outcome. They are more likely to be associated with early stage, responsive to chemotherapy, and longer progression free survival. Cytogenetics No cytogenetic abnormalities are identified so far. Hybrid/Mutated gene Not identified so far. Implicated in Prostate cancer Disease A number of investigations have been reported concerning the role of KLK11 as a potential diagnostic biomarker for prostate cancer (CaP). Prostate specific antigen (PSA) is currently the most widely used diagnostic marker for CaP. However, measuring PSA alone is lack of specificity, since some benign prostatic diseases, such as benign prostatic hyperplasia (BPH) and prostatitis, can also have increased serum PSA levels, whereas some CaP patients may have only mild elevation of PSA (4-10 ng/mL). To improve the specificity, a number of additional analyses, such as measuring the molecular forms of PSA, have been proposed. Patients with low free to total PSA ratios are considered to have higher risk of developing CaP. In spite of these efforts, false positive and false negative still occur and doctors frequently need to rely on prostate biopsy to make the final diagnosis. Some investigations have shown that measuring serum KLK11 concentrations may help discriminate CaP from BPH and reduce the number of unnecessary biopsies. Similar to PSA, serum KLK11 concentrations are elevated in the majority of CaP patients. However, compared to the BPH patients, the CaP patients tend to have lower serum KLK11 concentrations and lower KLK11 to total PSA ratios. In those patients that have less than 20% free PSA, measuring KLK11 to total PSA ratio identified 54% to have BPH. As such, it seems that KLK11 to total PSA ratio might be a complementary marker for free PSA percentage and combination of these two markers results in better specificity for CaP. KLK11 might not be superior to PSA in population screening. In a retrospective study, serum KLK11 or KLK11 to PSA ratio showed no advantage over PSA alone to differentiate CaP patients Atlas Genet Cytogenet Oncol Haematol. 2009; 13(1) Lung cancer Prognosis The prognostic role of KLK11 has also been explored in lung cancer both at the mRNA and protein levels. With quantitative PCR, it has shown that KLK11 mRNA levels are lower in tumor tissues in comparison with adjacent normal counter-parts. No significant correlation is identified with clinical stages, tumor status, and lymph node status. However, those patients with low KLK11 mRNA expression seem to have a significantly worse prognosis than those with high levels. At the protein level, serum KLK11 concentrations in non-small cell lung cancer patients are higher than in healthy controls and they are positively correlated with tumor stages. 16 KLK11 (Kallikrein-related peptidase 11) Luo LY, Diamandis EP candidate prostate and ovarian cancer biomarker, from seminal plasma. Clin Cancer Res. 2006 Feb 1;12(3 Pt 1):74250 Cytogenetics No cytogenetic abnormalities are identified so far. Hybrid/Mutated gene Not identified so far. Mitsui S, Nakamura T, Okui A, Kominami K, Uemura H, Yamaguchi N. Multiple promoters regulate tissue-specific alternative splicing of the human kallikrein gene, KLK11/hippostasin. FEBS J. 2006 Aug;273(16):3678-86 Breakpoints Planque C, Aïnciburu M, Heuzé-Vourc'h N, Régina S, de Monte M, Courty Y. Expression of the human kallikrein genes 10 (KLK10) and 11 (KLK11) in cancerous and non-cancerous lung tissues. Biol Chem. 2006 Jun;387(6):783-8 Note Not described so far. References Sasaki H, Kawano O, Endo K, Suzuki E, Haneda H, Yukiue H, Kobayashi Y, Yano M, Fujii Y. Decreased kallikrein 11 messenger RNA expression in lung cancer. Clin Lung Cancer. 2006 Jul;8(1):45-8 Mitsui S, Yamada T, Okui A, Kominami K, Uemura H, Yamaguchi N. A novel isoform of a kallikrein-like protease, TLSP/hippostasin, (PRSS20), is expressed in the human brain and prostate. Biochem Biophys Res Commun. 2000 May 27;272(1):205-11 Scorilas A, Gregorakis AK. mRNA expression analysis of human kallikrein 11 (KLK11) may be useful in the discrimination of benign prostatic hyperplasia from prostate cancer after needle prostate biopsy. Biol Chem. 2006 Jun;387(6):789-93 Nakamura T, Mitsui S, Okui A, Kominami K, Nomoto T, Ukimura O, Kawauchi A, Miki T, Yamaguchi N. Alternative splicing isoforms of hippostasin (PRSS20/KLK11) in prostate cancer cell lines. Prostate. 2001 Sep 15;49(1):72-8 Stephan C, Meyer HA, Cammann H, Nakamura T, Diamandis EP, Jung K. Improved prostate cancer detection with a human kallikrein 11 and percentage free PSA-based artificial neural network. Biol Chem. 2006 Jun;387(6):801-5 Diamandis EP, Okui A, Mitsui S, Luo LY, Soosaipillai A, Grass L, Nakamura T, Howarth DJ, Yamaguchi N. Human kallikrein 11: a new biomarker of prostate and ovarian carcinoma. Cancer Res. 2002 Jan 1;62(1):295-300 Dorn J, Schmitt M, Kates R, Schmalfeldt B, Kiechle M, Scorilas A, Diamandis EP, Harbeck N. Primary tumor levels of human tissue kallikreins affect surgical success and survival in ovarian cancer patients. Clin Cancer Res. 2007 Mar 15;13(6):1742-8 Borgoño CA, Fracchioli S, Yousef GM, Rigault de la Longrais IA, Luo LY, Soosaipillai A, Puopolo M, Grass L, Scorilas A, Diamandis EP, Katsaros D. Favorable prognostic value of tissue human kallikrein 11 (hK11) in patients with ovarian carcinoma. Int J Cancer. 2003 Sep 10;106(4):605-10 McIntosh MW, Liu Y, Drescher C, Urban N, Diamandis EP. Validation and characterization of human kallikrein 11 as a serum marker for diagnosis of ovarian carcinoma. Clin Cancer Res. 2007 Aug 1;13(15 Pt 1):4422-8 Nakamura T, Mitsui S, Okui A, Miki T, Yamaguchi N. Molecular cloning and expression of a variant form of hippostasin/KLK11 in prostate. Prostate. 2003 Mar 1;54(4):299-305 Memari N, Jiang W, Diamandis EP, Luo LY. Enzymatic properties of human kallikrein-related peptidase 12 (KLK12). Biol Chem. 2007 Apr;388(4):427-35 Nakamura T, Scorilas A, Stephan C, Jung K, Soosaipillai AR, Diamandis EP. The usefulness of serum human kallikrein 11 for discriminating between prostate cancer and benign prostatic hyperplasia. Cancer Res. 2003 Oct 1;63(19):6543-6 Ochiai A, Shukla A, Davis JW, Fritsche HA, Bhadkamkar V, Babaian RJ. Is there a role for serum human tissue kallikrein in detection of prostate cancer? Urology. 2007 Sep;70(3):519-22 Nakamura T, Stephan C, Scorilas A, Yousef GM, Jung K, Diamandis EP. Quantitative analysis of hippostasin/KLK11 gene expression in cancerous and noncancerous prostatic tissues. Urology. 2003 May;61(5):1042-6 Sano A, Sangai T, Maeda H, Nakamura M, Hasebe T, Ochiai A. Kallikrein 11 expressed in human breast cancer cells releases insulin-like growth factor through degradation of IGFBP-3. Int J Oncol. 2007 Jun;30(6):1493-8 Yousef GM, Polymeris ME, Yacoub GM, Scorilas A, Soosaipillai A, Popalis C, Fracchioli S, Katsaros D, Diamandis EP. Parallel overexpression of seven kallikrein genes in ovarian cancer. Cancer Res. 2003 May 1;63(9):2223-7 Zheng Y, Katsaros D, Shan SJ, de la Longrais IR, Porpiglia M, Scorilas A, Kim NW, Wolfert RL, Simon I, Li L, Feng Z, Diamandis EP. A multiparametric panel for ovarian cancer diagnosis, prognosis, and response to chemotherapy. Clin Cancer Res. 2007 Dec 1;13(23):6984-92 Shigemasa K, Gu L, Tanimoto H, O'Brien TJ, Ohama K. Human kallikrein gene 11 (KLK11) mRNA overexpression is associated with poor prognosis in patients with epithelial ovarian cancer. Clin Cancer Res. 2004 Apr 15;10(8):2766-70 Emami N, Diamandis EP. Human kallikrein-related peptidase 14 (KLK14) is a new activator component of the KLK proteolytic cascade. Possible function in seminal plasma and skin. J Biol Chem. 2008 Feb 8;283(6):3031-41 Stavropoulou P, Gregorakis AK, Plebani M, Scorilas A. Expression analysis and prognostic significance of human kallikrein 11 in prostate cancer. Clin Chim Acta. 2005 Jul 24;357(2):190-5 Planque C, Li L, Zheng Y, Soosaipillai A, Reckamp K, Chia D, Diamandis EP, Goodglick L. A multiparametric serum kallikrein panel for diagnosis of non-small cell lung carcinoma. Clin Cancer Res. 2008 Mar 1;14(5):1355-62 Debela M, Magdolen V, Schechter N, Valachova M, Lottspeich F, Craik CS, Choe Y, Bode W, Goettig P. Specificity profiling of seven human tissue kallikreins reveals individual subsite preferences. J Biol Chem. 2006 Sep 1;281(35):25678-88 This article should be referenced as such: Luo LY, Diamandis EP. KLK11 (Kallikrein-related peptidase 11). Atlas Genet Cytogenet Oncol Haematol. 2009; 13(1):1517. Luo LY, Jiang W. Inhibition profiles of human tissue kallikreins by serine protease inhibitors. Biol Chem. 2006 Jun;387(6):8136 Luo LY, Shan SJ, Elliott MB, Soosaipillai A, Diamandis EP. Purification and characterization of human kallikrein 11, a Atlas Genet Cytogenet Oncol Haematol. 2009; 13(1) 17