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      Characterization of kallikrein-related peptidase 4 (KLK4) mRNA expression in tumor tissue of advanced high-grade serous ovarian cancer patients

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          Abstract

          Overexpression of several members of the kallikrein-related peptidase (KLK) family, including KLK4, has been reported in ovarian cancer tissue, consistent with the fact that elevated levels of KLK protein are often also found in serum and in effusion fluids of ovarian cancer patients. In the present study, we quantitatively analyzed KLK4 tumor tissue mRNA expression levels in a homogeneous cohort including 138 patients of advanced high-grade serous ovarian cancer (FIGO stage III/IV). Age as well as ascites fluid volume were found to be significantly associated with KLK4 mRNA expression levels. In univariate Cox regression analysis, the clinical factors residual tumor mass and ascites fluid volume represented univariate predictors for both overall survival (OS) and progression-free survival (PFS). Furthermore, elevated KLK4 mRNA expression levels were significantly linked with reduced OS (p = 0.001), but not with PFS. The results concerning the association of KLK4 mRNA expression with OS were validated in a publicly available Affymetrix-based mRNA data set from The Cancer Genome Atlas (n = 252) applying the Kaplan-Meier Plotter tool (p = 0.047). In multivariable analyses, elevated KLK4 mRNA values turned out as an additional, independent predictive marker for shortened OS (p = 0.006), whereas residual tumor mass, but not ascites fluid volume, remained an independent indicator for both OS and PFS (p < 0.001 and p = 0.002, respectively). The results of the present study, obtained in a well-defined, homogenous cohort of patients afflicted with advanced high-grade serous ovarian cancer, are in line with previous reports describing high KLK4 levels as an unfavorable marker in ovarian cancer patients.

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          The emerging roles of human tissue kallikreins in cancer.

          Human tissue kallikreins (hKs), which are encoded by the largest contiguous cluster of protease genes in the human genome, are secreted serine proteases with diverse expression patterns and physiological roles. Although primarily known for their clinical applicability as cancer biomarkers, recent evidence implicates hKs in many cancer-related processes, including cell-growth regulation, angiogenesis, invasion and metastasis. They have been shown to promote or inhibit neoplastic progression, acting individually and/or in cascades with other hKs and proteases, and might represent attractive targets for therapeutic intervention.
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            Kallikreins on steroids: structure, function, and hormonal regulation of prostate-specific antigen and the extended kallikrein locus.

            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 kallikrein locus will continue to be an important model in the era of genome-wide analyses.
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              Differential gene expression in ovarian carcinoma: identification of potential biomarkers.

              Ovarian cancer remains the fifth leading cause of cancer death for women in the United States. In this study, the gene expression of 20 ovarian carcinomas, 17 ovarian carcinomas metastatic to the omentum, and 50 normal ovaries was determined by Gene Logic Inc. using Affymetrix GeneChip HU_95 arrays containing approximately 12,000 known genes. Differences in gene expression were quantified as fold changes in gene expression in ovarian carcinomas compared to normal ovaries and ovarian carcinoma metastases. Genes up-regulated in ovarian carcinoma tissue samples compared to more than 300 other normal and diseased tissue samples were identified. Seven genes were selected for further screening by immunohistochemistry to determine the presence and localization of the proteins. These seven genes were: the beta8 integrin subunit, bone morphogenetic protein-7, claudin-4, collagen type IX alpha2, cellular retinoic acid binding protein-1, forkhead box J1, and S100 calcium-binding protein A1. Statistical analyses showed that the beta8 integrin subunit, claudin-4, and S100A1 provided the best distinction between ovarian carcinoma and normal ovary tissues, and may serve as the best candidate tumor markers among the seven genes studied. These results suggest that further exploration into other up-regulated genes may identify novel diagnostic, therapeutic, and/or prognostic biomarkers in ovarian carcinoma.
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                Author and article information

                Contributors
                Role: Formal analysisRole: InvestigationRole: MethodologyRole: VisualizationRole: Writing – original draft
                Role: Formal analysisRole: InvestigationRole: MethodologyRole: VisualizationRole: Writing – original draft
                Role: Project administrationRole: SupervisionRole: Writing – original draft
                Role: Writing – original draft
                Role: Data curationRole: ResourcesRole: Writing – review & editing
                Role: Formal analysisRole: MethodologyRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: Project administrationRole: SupervisionRole: VisualizationRole: Writing – original draft
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                27 February 2019
                2019
                : 14
                : 2
                : e0212968
                Affiliations
                [1 ] Clinical Research Unit, Department of Obstetrics and Gynecology, Technical University of Munich, Munich, Germany
                [2 ] Institute of Pathology, Technical University of Munich, Munich, Germany
                [3 ] Medizinisches Labor Ostsachsen, Dresden, Germany
                Universidade de Sao Paulo Instituto de Quimica, BRAZIL
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0003-0167-793X
                Article
                PONE-D-18-32108
                10.1371/journal.pone.0212968
                6392272
                30811511
                1184517d-5dbd-445b-8f4b-051f7db7671a
                © 2019 Gong et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 7 November 2018
                : 12 February 2019
                Page count
                Figures: 3, Tables: 3, Pages: 13
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100008672, Wilhelm Sander-Stiftung;
                Award ID: 2016-024.1
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: DO 1772/1–1
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: BR 4733/3-1
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: AV 109/74-1
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: MA 1236/10-1
                Award Recipient :
                The present study was supported in part by grants from the the Wilhelm Sander-Stiftung, http://wilhelm-sander-stiftung.de, grant 2016-024.1 (VM) and the Deutsche Forschungsgemeinschaft, http://www.dfg.de, grants DO 1772/1–1 (JD), BR 4733/3-1 (HB), AV 109/74-1 (ED), and MA 1236/10-1 (VM), respectively. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Gynecological Tumors
                Ovarian Cancer
                Biology and Life Sciences
                Genetics
                Gene Expression
                Medicine and Health Sciences
                Gastroenterology and Hepatology
                Ascites
                Research and Analysis Methods
                Mathematical and Statistical Techniques
                Statistical Methods
                Regression Analysis
                Physical Sciences
                Mathematics
                Statistics
                Statistical Methods
                Regression Analysis
                Medicine and Health Sciences
                Diagnostic Medicine
                Prognosis
                Biology and Life Sciences
                Biochemistry
                Biomarkers
                Biology and Life Sciences
                Anatomy
                Body Fluids
                Interstitial Fluid
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Interstitial Fluid
                Biology and Life Sciences
                Physiology
                Body Fluids
                Interstitial Fluid
                Medicine and Health Sciences
                Physiology
                Body Fluids
                Interstitial Fluid
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Custom metadata
                Data are available via the Ethics Committee of the Medical Faculty of the Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany, for researchers who meet the criteria for access to confidential data. According to the Bavarian Data Protection Authority (BayLDA) and the General Data Protection Regulation (GDPR), patient-related data will only be made available to third parties after double-pseudonymization, undertaken by the Dept. of Medical Statistics and Epidemiology, Technical University of Munich. The Ethics Committee of the Medical Faculty of the Technical University of Munich can be contacted at ethikkommission@ 123456mri.tum.de .

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