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Andreas Scorilas - One of the best experts on this subject based on the ideXlab platform.

  • discovery of novel transcripts of the human tissue kallikrein klk1 and kallikrein related peptidase 2 KLK2 in human cancer cells exploiting next generation sequencing technology
    Genomics, 2019
    Co-Authors: Panagiotis G Adamopoulos, Christos K Kontos, Andreas Scorilas
    Abstract:

    Abstract Tissue kallikrein, kallikrein-related peptidases (KLKs), and plasma kallikrein form the largest group of serine proteases in the human genome, sharing many structural and functional properties. Several KLK transcripts have been found aberrantly expressed in numerous human malignancies, confirming their prognostic or/and diagnostic values. However, the process of alternative splicing can now be studied in-depth due to the development of Next-Generation Sequencing (NGS). In the present study, we used NGS to discover novel transcripts of the KLK1 and KLK2 genes, after nested touchdown PCR. Bioinformatics analysis and PCR experiments revealed a total of eleven novel KLK transcripts (two KLK1 and nine KLK2 transcripts). In addition, the expression profiles of each novel transcript were investigated with nested PCR experiments using variant-specific primers. Since KLKs are implicated in human malignancies, qualifying as potential biomarkers, the quantification of the presented novel transcripts in human samples may have clinical applications in different types of cancer.

  • loss of mir 378 in prostate cancer a common regulator of KLK2 and klk4 correlates with aggressive disease phenotype and predicts the short term relapse of the patients
    Biological Chemistry, 2014
    Co-Authors: Margaritis Avgeris, Konstantinos Stravodimos, Andreas Scorilas
    Abstract:

    Abstract A large number of prostate cancer (PCa) patients receive treatment without significant benefits, strengthening the need for accurate prognosis, which can be supported by the study of miRNAs. In silico specificity analysis was performed for the identification of miRNAs able to regulate KLK2 and KLK4 expression. Total RNA was extracted from prostate tissues obtained from PCa and benign prostate hyperplasia patients. Thereafter, RNA was polyadenylated and reverse transcribed to cDNA, which was used for qPCR analysis. miR-378 was predicted to target both KLK2 and KLK4 and downregulated levels detected in PCa patients (p=0.050). The reduction of miR-378 was correlated with higher Gleason score (p=0.018), larger diameter tumors (p=0.034), and elevated serum PSA (p=0.006). Regarding prognosis, miR-378 was able to improve risk stratification according to Gleason score or tumor stage, while higher risk to recur highlighted for the patients expressing lower miR-378 levels. Finally, the loss of miR-378 was able to predict the short-term relapse of 'high'- and 'very high'-recurrence-risk patients, independent of Gleason score, tumor stage, PSA, and age as indicated by Kaplan-Meier survival curves (p=0.030) and multivariate Cox regression analysis (p=0.018). In conclusion, loss of miR-378 expression increases the risk for PCa progression and relapse, despite active treatment.

  • 1 downregulation of the KLK2 klk4 targeting mir 378a predicts the short term relapse of prostate cancer patients
    5th International Symposium on Kallikreins and Kallikrein-Related Peptidases: Biochemistry Molecular Biology and Association to Disease September 28 –, 2013
    Co-Authors: Margaritis Avgeris, Konstantinos Stravodimos, Konstantinos Mavridis, Andreas Scorilas
    Abstract:

    Submitted by Sarafidou Maria (msaraf@ekt.gr) on 2016-05-05T16:20:02Z No. of bitstreams: 1 ISK 2013.pdf: 437247 bytes, checksum: 6594fcbf44761b82adcd2c2cb2d60262 (MD5)

  • Down-regulation of kallikrein-related peptidase 5 (KLK5) expression in breast cancer patients: a biomarker for the differential diagnosis of breast lesions
    Clinical Proteomics, 2011
    Co-Authors: Margaritis Avgeris, Georgia Papachristopoulou, Athanasios Polychronis, Andreas Scorilas
    Abstract:

    Background Kallikrein-related peptidase 5 (KLK5) is a secreted trypsin-like protease of the KLK family, encoded by the KLK5 gene. KLK5 has been found to cleave various extracellular matrix components, as well as to activate several other KLK proteases, triggering the stimulation of tissue microenvironment proteolytic cascades. Material and Methods KLK5 expression levels were quantified in 102 cancerous and benign breast tissue specimens, obtained by randomly chosen patients, using RT-qPCR assay. Subsequently, advanced biostatistics were applied in order to analyze the KLK5 expression profile in the two patients' cohorts and also to evaluate its clinical significance for the discrimination of breast tumors. Results A statistically significant (p < 0.001) down-regulation of the KLK5 expression levels were observed in the malignant specimens compared to the benign ones. Logistic regression and ROC curve analysis revealed the significant (p < 0.001) and the independent (p < 0.001) value of the KLK5 expression quantification, for the discrimination of the malignant from the benign mammary gland biopsies. Moreover, KLK5 expression levels correlate with the pre-menopausal status (p < 0.005) as well as the ER-negative staining (p = 0.028) of women with breast cancer. Conclusions The quantification of KLK5 expression in breast tissue biopsies may be considered as a novel and independent biomarker for the differential diagnosis between malignant and benign tumors of the mammary gland.

  • Kallikrein-related peptidase 4 gene (KLK4) in prostate tumors: Quantitative expression analysis and evaluation of its clinical significance
    Prostate, 2011
    Co-Authors: Margaritis Avgeris, Konstantinos Stravodimos, Andreas Scorilas
    Abstract:

    BACKGROUND: Recently accumulating evidences underline the central role of the kallikrein-related peptidases family (KLKs) in prostate cancer (PCa) development and progression. The KLK4 is a prostate highly expressed gene under the transcriptional control of androgens, encoding for the KLK4 extracellular serine protease. The aim of this study is to investigate the expression status of KLK4 in PCa patients in order to reveal its utility in PCa establishment and clinical management. METHODS: Prostatic tissue specimens were obtained from 60 PCa and 59 benign prostate hyperplasia (BPH) randomly chosen patients. Using a developed quantitative real-time RT-PCR method, KLK4 expression levels were determined in the specimens of the two patients' cohorts. Advance biostatistical analysis was completed to explore the clinical value of KLK4 expression in PCa and BPH patients. RESULTS: PCa patients presented a statistically significant (P = 0.002) elevation, more than threefold, of the KLK4 transcripts compared to BPH ones. The KLK4 expression levels were also positive correlated with PCa patients' stage (P = 0.031) and preoperative prostate-specific antigen (PSA) serum concentrations (P < 0.001). ROC curve and logistic regression analysis revealed the significant (P = 0.002) and the independent (P = 0.044) clinical value of the KLK4 expression for the discrimination of PCa from BPH patients. CONCLUSIONS: The KLK4 expression analysis reveals its up-regulation in PCa cells, which is significantly associated with the advanced stages of the disease and the patients' preoperative PSA serum levels. KLK4 quantification serves as an independent biomarker for the discrimination between the malignant and the benign nature of prostate tumors.

Eleftherios P. Diamandis - One of the best experts on this subject based on the ideXlab platform.

  • Human tissue Kallikreins: Blood levels and response to radiotherapy in intermediate risk prostate cancer
    Radiotherapy and Oncology, 2017
    Co-Authors: Nicola J. Nasser, Eleftherios P. Diamandis, John Thoms, Antoninus Soosaipillai, Melania Pintilie, Ri Wang, Robert G. Bristow
    Abstract:

    Abstract Objectives Kallikreins are serine proteases over expressed in many malignancies. In this study, we measure changes in serum kallikrein (KLKs) levels during intensity-modulated radiotherapy (IMRT) in prostate cancer patients, and find potential correlations between serum kallikrein level and normal tissues toxicity during radiation. Methods Forty-nine patients with prostate cancer were recruited as follows: group 1, definitive standard fractionation IMRT (78Gy in 39 fractions, n =15); group 2, definitive hypofractionated IMRT (60Gy in 20 fractions, n =15); and group 3, IMRT postprostatectomy (66Gy in 33 fractions, n =19). Patients treated with definitive radiation therapy were intermediate risk. Blood samples were collected at baseline and quarterly during IMRT and at each follow-up visit. Acute toxicity was graded weekly during radiotherapy using CTC-AE v4.0 criteria. Multiplexed immunoassays were used to quantify total, free, and intact Prostate Specific Antigen (PSA), as well as Kallikreins 2, 4, 6, and 11. Results The serum kallikreins, PSA (total, free and intact), KLK2, 6, and 11 change significantly after definitive radiotherapy. KLK2 and intact PSA decrease as fast as two weeks after initiation of radiation, while the first significant decrease in total and free PSA is noted only at the completion of radiation. KLK6 and KLK11 surge temporarily during radiation therapy and decrease below baseline levels at 8weeks and 12months, respectively after completion of radiation. KLK4 levels did not change with radiation. There was no correlation between GU or GI toxicities and serum kallikreins. Conclusions PSA, KLK2, 6, and 11, change significantly after definitive prostate radiotherapy, though KLK2 and PSA decrease by the end of the radiation course while KLK6 and KLK11 decrease significantly starting at 2 and 12months, respectively, after radiation. There was no correlation between GU or GI toxicities and serum kallikreins.

  • unleashing the therapeutic potential of human kallikrein related serine proteases
    Nature Reviews Drug Discovery, 2015
    Co-Authors: Eleftherios P. Diamandis, Ioannis Prassas, Azza Eissa, Gennadiy Poda
    Abstract:

    Members of the family of kallikrein (KLK)-related proteases are found in various tissues — including the airway, prostate and brain — and have a wide range of functions. The authors describe the roles of KLKs in health and disease, and highlight the small-molecule, peptide-based, protein-based, antibody-based and immunotherapeutic strategies that are being used to target KLKs in certain diseases.

  • Human tissue kallikreins: The cancer biomarker family
    Cancer Letters, 2007
    Co-Authors: Miltiadis Paliouras, Carla Borgono, Eleftherios P. Diamandis
    Abstract:

    Human tissue kallikreins (KLKs) are attracting increased attention due to their role as biomarkers for the screening, diagnosis, prognosis, and monitoring of various cancers including those of the prostate, ovarian, breast, testicular, and lung. Human tissue kallikrein genes represent the largest contiguous group of proteases within the human genome. Originally thought to consist of three genes, the identification of the human kallikrein locus has expanded this number to fifteen. These genes, and their encoded proteins, share a high degree of homology and are expressed in different tissues. Prostate-specific antigen (PSA), the most commonly known kallikrein, is a useful biomarker for prostate cancer. Several other kallikreins, including kallikreins 2 (KLK2) and 11 (KLK11) are emerging as complementary prostate cancer biomarkers. Along with these kallikreins, several others have been implicated in the other cancers. For example, KLK5, 6, 7, 10, 11, and 14 are emerging biomarkers for ovarian cancer. The identification of kallikrein substrates and the development of proteolytic cascade models implicate kallikrein proteins in cancer progression. This review describes the current status of kallikreins as cancer biomarkers. © 2006 Elsevier Ireland Ltd. All rights reserved.

  • a potential role for multiple tissue kallikrein serine proteases in epidermal desquamation
    Journal of Biological Chemistry, 2006
    Co-Authors: Carla Borgono, Iacovos P Michael, Nahoko Komatsu, Arumugam Jayakumar, Ravi M Kapadia, Gary L Clayman, Georgia Sotiropoulou, Eleftherios P. Diamandis
    Abstract:

    Abstract Desquamation of the stratum corneum is a serine protease-dependent process. Two members of the human tissue kallikrein (KLK) family of (chymo)tryptic-like serine proteases, KLK5 and KLK7, are implicated in desquamation by digestion of (corneo)desmosomes and inhibition by desquamation-related serine protease inhibitors (SPIs). However, the epidermal localization and specificity of additional KLKs also supports a role for these enzymes in desquamation. This study aims to delineate the probable contribution of KLK1, KLK5, KLK6, KLK13, and KLK14 to desquamation by examining their interactions, in vitro, with: 1) colocalized SPI, lympho-epithelial Kazal-type-related inhibitor (LEKTI, four recombinant fragments containing inhibitory domains 1–6 (rLEKTI(1–6)), domains 6–8 and partial domain 9 (rLEKTI(6–9′)), domains 9–12 (rLEKTI(9–12)), and domains 12–15 (rLEKTI(12–15)), secretory leukocyte protease inhibitor, and elafin and 2) their ability to digest the (corneo)desmosomal cadherin, desmoglein 1. KLK1 was not inhibited by any SPI tested. KLK5, KLK6, KLK13, and KLK14 were potently inhibited by rLEKTI(1–6), rLEKTI(6–9′), and rLEKTI(9–12) with Ki values in the range of 2.3–28.4 nm, 6.1–221 nm, and 2.7–416 nm for each respective fragment. Only KLK5 was inhibited by rLEKTI(12–15) (Ki = 21.8 nm). No KLK was inhibited by secretory leukocyte protease inhibitor or elafin. Apart from KLK13, all KLKs digested the ectodomain of desmoglein 1 within cadherin repeats, Ca2+ binding sites, or in the juxtamembrane region. Our study indicates that multiple KLKs may participate in desquamation through cleavage of desmoglein 1 and regulation by LEKTI. These findings may have clinical implications for the treatment of skin disorders in which KLK activity is elevated.

  • In silico identification and Bayesian phylogenetic analysis of multiple new mammalian kallikrein gene families
    Genomics, 2006
    Co-Authors: Marc B. Elliott, David M. Irwin, Eleftherios P. Diamandis
    Abstract:

    Kallikrein gene families have been identified previously in genomes of the human, the mouse, and the rat, and individual kallikrein-like genes have been found in many more species. This study presents the in silico identification of kallikrein gene families in the recently sequenced genomes of four additional mammalian species, the chimpanzee, the dog, the pig, and the opossum. Phylogenies were constructed with gene sequences from all seven mammalian families, using Bayesian analysis, which clarified the evolutionary relationships between these genes. Individual gene sequences, as well as concatenated constructs of multiple sequences, were used. Fifteen kallikrein genes were located in the chimpanzee (Pan troglodytes) genome, while only 14 were identified in the canine (Canis familiaris) genome as no orthologue to human KLK3 was found. Thirteen genes were identified from the pig (Sus scrofa) genome, which lacked homologues to KLK2 and KLK3, and 11 genes, orthologous to human KLK5 through KLK15, were found in the opossum (Monodelphis domestica) genome. No kallikrein genes were identified from the available genome sequences of the chicken (Gallus gallus) or African clawed frog (Xenopus tropicalis). Within the family of kallikreins several subfamilies were suggested by phylogenetic analysis. One consisted of KLK4, KLK5, and KLK14; another of KLK9, KLK11, and KLK15; a third of KLK10 and KLK12; a fourth of KLK6 and KLK13; and finally one of KLK8 and the classical kallikreins (KLK1, KLK2, and KLK3).

Hans Lilja - One of the best experts on this subject based on the ideXlab platform.

  • Prostate-specific kallikrein-related peptidases and their relation to prostate cancer biology and detection
    Thrombosis and Haemostasis, 2020
    Co-Authors: Daniel L.j. Thorek, Michael J. Evans, David Ulmert, Sigrid V. Carlsson, Hans Lilja
    Abstract:

    summaryKallikreins are a family of serine proteases with a range of tissue-specific and essential proteolytic functions. Among the best studied are the prostate tissue-specific KLK2 and KLK3 genes and their secreted protease products, human kallikrein 2, hk2, and prostate-specific antigen (PSA). Members of the so-called classic kallikreins, these highly active trypsin-like serine proteases play established roles in human reproduction. Both hK2 and PSA expression is regulated by the androgen receptor which has a fundamental role in prostate tissue development and progression of disease. This feature, combined with the ability to sensitively detect different forms of these proteins in blood and biopsies, result in a crucially important biomarker for the presence and recurrence of cancer. Emerging evidence has begun to suggest a role for these kallikreins in critical vascular events. This review discusses the established and developing biological roles of hK2 and PSA, as well as the historical and advanced use of their detection to accurately and non-invasively detect and guide treatment of prostatic disease.

  • genetic variation in KLK2 and klk3 is associated with concentrations of hk2 and psa in serum and seminal plasma in young men
    Clinical Chemistry, 2014
    Co-Authors: Charlotta Savblom, Christer Halldén, Robert J. Klein, Angel M Cronin, Torbjorn Sall, Caroline Savage, Emily Vertosick, Aleksander Giwercman, Hans Lilja
    Abstract:

    BACKGROUND: Genetic variants in KLK2 and KLK3 have been associated with increased serum concentrations of their encoded proteins, human kallikrein-related peptidase 2 (hK2) and prostate-specific antigen (PSA), and with prostate cancer in older men. Low PSA concentrations in seminal plasma (SP) have been associated with low sperm motility. To evaluate whether KLK2 and KLK3 genetic variants affect physiological prostatic secretion, we studied the association of SNPs with hK2 and PSA concentrations in SP and serum of young, healthy men. METHODS: Leukocyte DNA was extracted from 303 male military conscripts (median age 18.1 years). Nine SNPs across KLK2–KLK3 were genotyped. We measured PSA and hK2 in SP and serum using immunofluorometric assays. The association of genotype frequencies with hK2 and PSA concentrations was tested with the Kruskal–Wallis test. RESULTS: Four KLK2 SNPs (rs198972, rs198977, rs198978, and rs80050017) were strongly associated with hK2 concentrations in SP and serum, with individuals homozygous for the major alleles having 3- to 7-fold higher concentrations than the intermediate concentrations found in other homozygotes and heterozygotes (all P < 0.001). Three of these SNPs were significantly associated with percentage of free PSA (%fPSA) in serum (all P < 0.007). Three KLK3 SNPs showed associations with PSA in SP, and the rs1058205 SNP was associated with total PSA in serum ( P = 0.001) and %fPSA ( P = 0.015). CONCLUSIONS: Associations observed in young, healthy men between the SP and serum concentrations of hK2 and PSA and several genetic variants in KLK2 and KLK3 could be useful to refine models of PSA cutoff values in prostate cancer testing.

  • Prostate-specific kallikrein-related peptidases and their relation to prostate cancer biology and detection. Established relevance and emerging roles.
    Thrombosis and Haemostasis, 2013
    Co-Authors: Daniel L.j. Thorek, Michael J. Evans, Sigrid Carlsson, David Ulmert, Hans Lilja
    Abstract:

    Kallikreins are a family of serine proteases with a range of tissue-specific and essential proteolytic functions. Among the best studied are the prostate tissue-specific KLK2 and KLK3 genes and their secreted protease products, human kallikrein 2, hk2, and prostate-specific antigen (PSA). Members of the so-called classic kallikreins, these highly active trypsin-like serine proteases play established roles in human reproduction. Both hK2 and PSA expression is regulated by the androgen receptor which has a fundamental role in prostate tissue development and progression of disease. This feature, combined with the ability to sensitively detect different forms of these proteins in blood and biopsies, result in a crucially important biomarker for the presence and recurrence of cancer. Emerging evidence has begun to suggest a role for these kallikreins in critical vascular events. This review discusses the established and developing biological roles of hK2 and PSA, as well as the historical and advanced use of their detection to accurately and non-invasively detect and guide treatment of prostatic disease.

  • Association of transcript levels of 10 established or candidate-biomarker gene targets with cancerous versus non-cancerous prostate tissue from radical prostatectomy specimens
    Clinical Biochemistry, 2013
    Co-Authors: Riina-minna Väänänen, Angel M Cronin, Hans Lilja, Leni Kauko, Maria Rissanen, Otto Kauko, Henna Kekki, Siina Vidbäck, Martti Nurmi, Kalle Alanen
    Abstract:

    Objectives: The benefits of PSA (prostate specific antigen)-testing in prostate cancer remain controversial with a consequential need for validation of additional biomarkers. We used highly standardized reverse-transcription (RT)-PCR assays to compare transcript levels of 10 candidate cancer marker genes - BMP6, FGF-8b, KLK2, KLK3, KLK4, KLK15, MSMB, PCA3, PSCA and Trpm8 - in carefully ascertained non-cancerous versus cancerous prostate tissue from patients with clinically localized prostate cancer treated by radical prostatectomy. Design and methods: Total RNA was isolated from fresh frozen prostate tissue procured immediately after resection from two separate areas in each of 87 radical prostatectomy specimens. Subsequent histopathological assessment classified 86 samples as cancerous and 88 as histologically benign prostate tissue. Variation in total RNA recovery was accounted for by using external and internal standards and enabled us to measure transcript levels by RT-PCR in a highly quantitative manner. Results: Of the ten genes, there were significantly higher levels only of one of the less abundant transcripts, PCA3, in cancerous versus non-cancerous prostate tissue whereas PSCA mRNA levels were significantly lower in cancerous versus histologically benign tissue. Advanced pathologic stage was associated with significantly higher expression of KLK15 and PCA3 mRNAs. Median transcript levels of the most abundantly expressed genes (i.e. MSMB, KLK3, KLK4 and KLK2) in prostate tissue were up to 10(5)-fold higher than those of other gene targets. Conclusions: PCA3 expression was associated with advanced pathological stage but the magnitude of overexpression of PCA3 in cancerous versus non-cancerous prostate tissue was modest compared to previously reported data. (C) 2013 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. (Less)

  • Prostate-specific mRNA detection in whole blood as an analytically validated prognostic biomarker for patients with castration-resistant prostate cancer (CRPC).
    Journal of Clinical Oncology, 2013
    Co-Authors: Daniel Costin Danila, Aseem Anand, Hans Lilja, Glenn Heller, Amrita Herkal, Chintan Patel, Raya Khanin, Nikolaus Schultz, Martin Fleisher
    Abstract:

    45 Background: To estimate the association between molecular biomarkers and outcomes, robust assays are needed before qualification in prospective trials. Although tumor specific transcripts detected in blood by PCR have been associated with outcome, an analytically validated PCR platform enabling detection of CTC-associated transcripts in clinical settings remains to be identified. Here we explore detecting a panel of prostate specific transcripts in conjunction with conventional markers in CRPC. Methods: Blood was collected from 97 patients with progressive CRPC in PAXgene tubes (2.5 ml) for total RNA extraction. Five genes expressed in prostate but not in nucleated blood cells were analyzed by primer-specific RT-PCR. Fluidigm Dynamic Array platform was analytically validated for KLK3, KLK2, HOXB13, GHRL2 and FOXA1 assays. Each PCR-reaction was run in 6 replicates, detection thresholds for each gene were chosen by ROC analysis of an independent set of 56 CRPC patients versus 51 healthy volunteers, and results were reported as transcripts present or absent. CellSearch reported CTC number/7.5 ml of blood drawn into CellSave tube. Results: Prostate specific transcripts for KLK3, KLK2, HOXB13, GHRL2 and FOXA1were detected in 50 (52%), 39 (40%), 53 (55%), 28 (29%) and 47 (48%) of patients, respectively.Two or more genes were detected in 53/97 patients (55%, 95% CI 45-65%) of patients with progressive CRPC studied with a median survival time of 17 months (95% CI: 13.8, 23.5). 40/45 CRPC-patients with ≥5 CTC and 13/52 CRPC patients with <5 CTC had transcripts present in blood. CTC and the gene panel had a substantial level of agreement, kappa of 0.631 (95% CI: 0.479, 0.783). Transcript detection predicted overall survival in proportional hazards models that included LDH dichotomized at 250. The predictive accuracy (CPE) of PCR detection + LDH was 0.759 (SE 0.035), comparable to CTC-enumeration + LDH (0.771, SE 0.033). Conclusions: Detecting prostate specific mRNA in whole blood using validated RT-PCR assays, applicable to larger CRPC cohorts, provides prognostic value. The clinical utility in monitoring treatment will be prospectively explored.

Margaritis Avgeris - One of the best experts on this subject based on the ideXlab platform.

  • loss of mir 378 in prostate cancer a common regulator of KLK2 and klk4 correlates with aggressive disease phenotype and predicts the short term relapse of the patients
    Biological Chemistry, 2014
    Co-Authors: Margaritis Avgeris, Konstantinos Stravodimos, Andreas Scorilas
    Abstract:

    Abstract A large number of prostate cancer (PCa) patients receive treatment without significant benefits, strengthening the need for accurate prognosis, which can be supported by the study of miRNAs. In silico specificity analysis was performed for the identification of miRNAs able to regulate KLK2 and KLK4 expression. Total RNA was extracted from prostate tissues obtained from PCa and benign prostate hyperplasia patients. Thereafter, RNA was polyadenylated and reverse transcribed to cDNA, which was used for qPCR analysis. miR-378 was predicted to target both KLK2 and KLK4 and downregulated levels detected in PCa patients (p=0.050). The reduction of miR-378 was correlated with higher Gleason score (p=0.018), larger diameter tumors (p=0.034), and elevated serum PSA (p=0.006). Regarding prognosis, miR-378 was able to improve risk stratification according to Gleason score or tumor stage, while higher risk to recur highlighted for the patients expressing lower miR-378 levels. Finally, the loss of miR-378 was able to predict the short-term relapse of 'high'- and 'very high'-recurrence-risk patients, independent of Gleason score, tumor stage, PSA, and age as indicated by Kaplan-Meier survival curves (p=0.030) and multivariate Cox regression analysis (p=0.018). In conclusion, loss of miR-378 expression increases the risk for PCa progression and relapse, despite active treatment.

  • 1 downregulation of the KLK2 klk4 targeting mir 378a predicts the short term relapse of prostate cancer patients
    5th International Symposium on Kallikreins and Kallikrein-Related Peptidases: Biochemistry Molecular Biology and Association to Disease September 28 –, 2013
    Co-Authors: Margaritis Avgeris, Konstantinos Stravodimos, Konstantinos Mavridis, Andreas Scorilas
    Abstract:

    Submitted by Sarafidou Maria (msaraf@ekt.gr) on 2016-05-05T16:20:02Z No. of bitstreams: 1 ISK 2013.pdf: 437247 bytes, checksum: 6594fcbf44761b82adcd2c2cb2d60262 (MD5)

  • Down-regulation of kallikrein-related peptidase 5 (KLK5) expression in breast cancer patients: a biomarker for the differential diagnosis of breast lesions
    Clinical Proteomics, 2011
    Co-Authors: Margaritis Avgeris, Georgia Papachristopoulou, Athanasios Polychronis, Andreas Scorilas
    Abstract:

    Background Kallikrein-related peptidase 5 (KLK5) is a secreted trypsin-like protease of the KLK family, encoded by the KLK5 gene. KLK5 has been found to cleave various extracellular matrix components, as well as to activate several other KLK proteases, triggering the stimulation of tissue microenvironment proteolytic cascades. Material and Methods KLK5 expression levels were quantified in 102 cancerous and benign breast tissue specimens, obtained by randomly chosen patients, using RT-qPCR assay. Subsequently, advanced biostatistics were applied in order to analyze the KLK5 expression profile in the two patients' cohorts and also to evaluate its clinical significance for the discrimination of breast tumors. Results A statistically significant (p < 0.001) down-regulation of the KLK5 expression levels were observed in the malignant specimens compared to the benign ones. Logistic regression and ROC curve analysis revealed the significant (p < 0.001) and the independent (p < 0.001) value of the KLK5 expression quantification, for the discrimination of the malignant from the benign mammary gland biopsies. Moreover, KLK5 expression levels correlate with the pre-menopausal status (p < 0.005) as well as the ER-negative staining (p = 0.028) of women with breast cancer. Conclusions The quantification of KLK5 expression in breast tissue biopsies may be considered as a novel and independent biomarker for the differential diagnosis between malignant and benign tumors of the mammary gland.

  • Kallikrein-related peptidase 4 gene (KLK4) in prostate tumors: Quantitative expression analysis and evaluation of its clinical significance
    Prostate, 2011
    Co-Authors: Margaritis Avgeris, Konstantinos Stravodimos, Andreas Scorilas
    Abstract:

    BACKGROUND: Recently accumulating evidences underline the central role of the kallikrein-related peptidases family (KLKs) in prostate cancer (PCa) development and progression. The KLK4 is a prostate highly expressed gene under the transcriptional control of androgens, encoding for the KLK4 extracellular serine protease. The aim of this study is to investigate the expression status of KLK4 in PCa patients in order to reveal its utility in PCa establishment and clinical management. METHODS: Prostatic tissue specimens were obtained from 60 PCa and 59 benign prostate hyperplasia (BPH) randomly chosen patients. Using a developed quantitative real-time RT-PCR method, KLK4 expression levels were determined in the specimens of the two patients' cohorts. Advance biostatistical analysis was completed to explore the clinical value of KLK4 expression in PCa and BPH patients. RESULTS: PCa patients presented a statistically significant (P = 0.002) elevation, more than threefold, of the KLK4 transcripts compared to BPH ones. The KLK4 expression levels were also positive correlated with PCa patients' stage (P = 0.031) and preoperative prostate-specific antigen (PSA) serum concentrations (P < 0.001). ROC curve and logistic regression analysis revealed the significant (P = 0.002) and the independent (P = 0.044) clinical value of the KLK4 expression for the discrimination of PCa from BPH patients. CONCLUSIONS: The KLK4 expression analysis reveals its up-regulation in PCa cells, which is significantly associated with the advanced stages of the disease and the patients' preoperative PSA serum levels. KLK4 quantification serves as an independent biomarker for the discrimination between the malignant and the benign nature of prostate tumors.

  • Kallikrein-related peptidase genes as promising biomarkers for prognosis and monitoring of human malignancies.
    Biological Chemistry, 2010
    Co-Authors: Margaritis Avgeris, Konstantinos Mavridis, Andreas Scorilas
    Abstract:

    Tissue kallikrein (KLK1) and the kallikrein-related peptidase (KLK2-15) genes encode for a subgroup of 15 homologous secreted serine proteases possessing numerous physiological roles, such as the regulation of blood pressure, hormone processing and tissue remodeling. The expression of KLKs is detected in a broad spectrum of human tissues where it has been found to be regulated mainly by steroids hormones. The aberrant expression of KLKs, presented in many human malignancies, highlights the significance of this gene family for early diagnosis, prognosis and monitoring of cancer patients, as it is strongly emphasized by the routine use of PSA (KLK3) for prostate cancer management. Here, we review the presently known data regarding the role of KLKs as cancer biomarkers, giving emphasis on novel information about the subject.

Judith A. Clements - One of the best experts on this subject based on the ideXlab platform.

  • Kallikrein-Related Peptidases in Prostate Cancer: From Molecular Function to Clinical Application.
    EJIFCC, 2014
    Co-Authors: Ruth A. Fuhrman-luck, Daniela Loessner, Judith A. Clements
    Abstract:

    Prostate cancer is a leading contributor to male cancer-related deaths worldwide. Kallikrein-related peptidases (KLKs) are serine proteases that exhibit deregulated expression in prostate cancer, with KLK3, or prostate specific antigen (PSA), being the widely-employed clinical biomarker for prostate cancer. Other KLKs, such as KLK2, show promise as prostate cancer biomarkers and, additionally, their altered expression has been utilised for the design of KLK-targeted therapies. There is also a large body of in vitro and in vivo evidence supporting their role in cancer-related processes. Here, we review the literature on studies to date investigating the potential of other KLKs, in addition to PSA, as biomarkers and in therapeutic options, as well as their current known functional roles in cancer progression. Increased knowledge of these KLK-mediated functions, including degradation of the extracellular matrix, local invasion, cancer cell proliferation, interactions with fibroblasts, angiogenesis, migration, bone metastasis and tumour growth in vivo, may help define new roles as prognostic biomarkers and novel therapeutic targets for this cancer.

  • Analysis of androgen and anti-androgen regulation of KLK-related peptidase 2, 3, and 4 alternative transcripts in prostate cancer
    2014
    Co-Authors: Jiyuan An, Colleen C. Nelson, Melanie L. Lehman, Jyotsna Batra, Judith A. Clements
    Abstract:

    We assessed whether alternative transcripts (using KLK2, KLK3 and KLK4 as models) are differentially regulated by androgens and anti-androgens as an indicator of prostate cancers as they acquire treatment resistance. Using RNAseq of LNCaP cells treated with dihydrotestosterone, bicalutamide and enzalutamide, we show that the expression of variant KLK transcripts is markedly different to other variant transcripts at those loci. We also reveal that KLK variants are also over 2-fold more highly expressed in prostate cancers compared to their corresponding normal prostate. We propose that androgens and anti-androgens can activate specific variant transcripts of critical prostate cancer genes during treatment resistance

  • The Human Tissue Kallikrein and Kallikrein-related Peptidase Family
    Handbook of Proteolytic Enzymes, 2013
    Co-Authors: Judith A. Clements, John D. Hooper, Ying Dong
    Abstract:

    The human kallikrein-related peptidases are a subgroup of trypsin and chymotrypsin-like serine peptidases that are characterized by their homology to tissue kallikrein or kallikrein 1 (KLK1) encoded by the KLK1 gene (reviewed in[1-4]). The human KLK locus spans an approximately 320 kb region on chromosome 19q13.3-13.4 and contains fifteen genes encoding KLK1 and fourteen other kallikrein-related peptidases, KLK2-KLK15, which have been named contiguously in the locus in the order of their discovery [5-8] (Figure 606.1). It is the largest contiguous cluster of serine protease encoding genes in the human genome which has evolved from gene duplication of KLK1 and then subsequent reduplication of the newly evolved KLK genes [2]. The high conservation noted for KLK1-KLK3 (62-77%) reflects the proposed duplication of the KLK1 gene that produced the KLK2 gene which further generated the KLK3 gene. In contrast, the newer KLK4-KLK15 proteases share much less similarity, from 24-66%, although strong homology between KLK4 and KLK5, KLK9 and KLK11, and KLK10 and KLK12 suggests these genes are duplications of each other [2]...

  • Selective cleavage of human sex hormone-binding globulin by kallikrein-related peptidases and effects on androgen action in LNCaP prostate cancer cells
    Endocrinology, 2012
    Co-Authors: Washington Y. Sanchez, Geoffrey L. Hammond, Joakim E. Swedberg, Eui Ju Hong, Janet C. Reid, Terry P. Walsh, John D. Hooper, Judith A. Clements, Simon J. De Veer, Jonathan M. Harris
    Abstract:

    Stimulation of the androgen receptor via bioavailable androgens, including testosterone and testosterone metabolites, is a key driver of prostate development and the early stages of prostate cancer. Androgens are hydrophobic and as such require carrier proteins, including sex hormone-binding globulin (SHBG), to enable efficient distribution from sites of biosynthesis to target tissues. The similarly hydrophobic corticosteroids also require a carrier protein whose affinity for steroid is modulated by proteolysis. However, proteolytic mechanisms regulating the SHBG/androgen complex have not been reported. Here, we show that the cancer-associated serine proteases, kallikrein-related peptidase (KLK)4 and KLK14, bind strongly to SHBG in glutathione S-transferase interaction analyses. Further, we demonstrate that active KLK4 and KLK14 cleave human SHBG at unique sites and in an androgen-dependent manner. KLK4 separated androgen-free SHBG into its two laminin G-like (LG) domains that were subsequently proteolytically stable even after prolonged digestion, whereas a catalytically equivalent amount of KLK14 reduced SHBG to small peptide fragments over the same period. Conversely, proteolysis of 5α-dihydrotestosterone (DHT)-bound SHBG was similar for both KLKs and left the steroid binding LG4 domain intact. Characterization of this proteolysis fragment by [(3)H]-labeled DHT binding assays revealed that it retained identical affinity for androgen compared with full-length SHBG (dissociation constant = 1.92 nM). Consistent with this, both full-length SHBG and SHBG-LG4 significantly increased DHT-mediated transcriptional activity of the androgen receptor compared with DHT delivered without carrier protein. Collectively, these data provide the first evidence that SHBG is a target for proteolysis and demonstrate that a stable fragment derived from proteolysis of steroid-bound SHBG retains binding function in vitro.

  • Kallikreins on Steroids: Structure, Function, and Hormonal Regulation of Prostate-Specific Antigen and the Extended Kallikrein Locus
    Endocrine Reviews, 2010
    Co-Authors: Mitchell G. Lawrence, Judith A. Clements
    Abstract:

    The 15 members of the kallikrein-related serine peptidase (KLK) family have diverse tissue-specific expression profiles and putative proteolytic functions. The kallikrein family is also emerging as a rich source of disease biomarkers with KLK3, commonly known as prostate-specific antigen, being the current serum biomarker for prostate cancer. The kallikrein locus is also notable because it is extraordinarily responsive to steroids and other hormones. Indeed, at least 14 functional hormone response elements have been identified in the kallikrein locus. A more comprehensive understanding of the transcriptional regulation of kallikreins may help the field make more informed hypotheses about the physiological functions of kallikreins and their effectiveness as biomarkers. In this review, we describe the organization of the kallikrein locus and the structure of kallikrein genes and proteins. We also focus on the transcriptional regulation of kallikreins by androgens, progestins, glucocorticoids, mineralocorticoids, estrogens, and other hormones in animal models and human prostate, breast, and reproductive tract tissues. The interaction of the androgen receptor with androgen response elements in the promoter and enhancer of KLK2 and KLK3 is also summarized in detail. There is evidence that all kallikreins are regulated by multiple nuclear receptors. Yet, apart from KLK2 and KLK3, it is not clear whether all kallikreins are direct transcriptional targets. Therefore, we argue that gaining more detailed information about the mechanisms that regulate kallikrein expression should be a priority of future studies and that the kallikreinlocuswillcontinuetobeanimportantmodelintheeraofgenome-wideanalyses.(EndocrineReviews 31: 407–446, 2010)