KLK5

Gene Summary

Gene:KLK5; kallikrein related peptidase 5
Aliases: SCTE, KLKL2, KLK-L2
Location:19q13.41
Summary:Kallikreins are a subgroup of serine proteases having diverse physiological functions. Growing evidence suggests that many kallikreins are implicated in carcinogenesis and some have potential as novel cancer and other disease biomarkers. This gene is one of the fifteen kallikrein subfamily members located in a cluster on chromosome 19. Its expression is up-regulated by estrogens and progestins. The encoded protein is secreted and may be involved in desquamation in the epidermis. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:kallikrein-5
Source:NCBIAccessed: 11 March, 2017

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: KLK5 (cancer-related)

Johnson JJ, Miller DL, Jiang R, et al.
Protease-activated Receptor-2 (PAR-2)-mediated Nf-κB Activation Suppresses Inflammation-associated Tumor Suppressor MicroRNAs in Oral Squamous Cell Carcinoma.
J Biol Chem. 2016; 291(13):6936-45 [PubMed] Article available free on PMC after 25/03/2017 Related Publications
Oral cancer is the sixth most common cause of death from cancer with an estimated 400,000 deaths worldwide and a low (50%) 5-year survival rate. The most common form of oral cancer is oral squamous cell carcinoma (OSCC). OSCC is highly inflammatory and invasive, and the degree of inflammation correlates with tumor aggressiveness. The G protein-coupled receptor protease-activated receptor-2 (PAR-2) plays a key role in inflammation. PAR-2 is activated via proteolytic cleavage by trypsin-like serine proteases, including kallikrein-5 (KLK5), or by treatment with activating peptides. PAR-2 activation induces G protein-α-mediated signaling, mobilizing intracellular calcium and Nf-κB signaling, leading to the increased expression of pro-inflammatory mRNAs. Little is known, however, about PAR-2 regulation of inflammation-related microRNAs. Here, we assess PAR-2 expression and function in OSCC cell lines and tissues. Stimulation of PAR-2 activates Nf-κB signaling, resulting in RelA nuclear translocation and enhanced expression of pro-inflammatory mRNAs. Concomitantly, suppression of the anti-inflammatory tumor suppressor microRNAs let-7d, miR-23b, and miR-200c was observed following PAR-2 stimulation. Analysis of orthotopic oral tumors generated by cells with reduced KLK5 expression showed smaller, less aggressive lesions with reduced inflammatory infiltrate relative to tumors generated by KLK5-expressing control cells. Together, these data support a model wherein KLK5-mediated PAR-2 activation regulates the expression of inflammation-associated mRNAs and microRNAs, thereby modulating progression of oral tumors.

Leusink FK, van Diest PJ, Frank MH, et al.
The Co-Expression of Kallikrein 5 and Kallikrein 7 Associates with Poor Survival in Non-HPV Oral Squamous-Cell Carcinoma.
Pathobiology. 2015; 82(2):58-67 [PubMed] Related Publications
OBJECTIVE: Oral squamous-cell carcinoma (OSCC) still has a poor prognosis. Lymph node metastasis (LNM) is a major determinant of treatment decisions and prognosis. Serine protease inhibitor Kazal-type 5 (SPINK5) is the inhibitor of kallikrein 5 (KLK5) and KLK7. SPINK5, KLK5 and KLK7 are three of the genes of a recently validated LNM-predicting gene expression profile in OSCC. This study evaluates their clinicopathological role and value as biomarkers in OSCC.
METHODS: Eighty-three patients with primary OSCC, treated surgically between 1996 and 2000, were included. Gene expression data were acquired from a previously reported study. Human papillomavirus (HPV) status was determined by an algorithm for HPV-16. Protein expression for KLK5, KLK7 and SPINK5 was semi-quantitatively determined in all 83 tumours by immunohistochemistry. All expression data were correlated with clinicopathological parameters.
RESULTS: Concurrent loss of KLK5 and KLK7 correlates with worse disease-specific and overall survival (DSS and OS). Multivariate analysis proved that co-expression is an independent prognostic factor for DSS (p = 0.029) and OS (p = 0.001).
CONCLUSION: This report demonstrates that concurrent loss of KLK5 and KLK7 associates with a poor clinical outcome in OSCC and could therefore serve as prognostic marker in this disease.

Zubor P, Hatok J, Moricova P, et al.
Gene expression abnormalities in histologically normal breast epithelium from patients with luminal type of breast cancer.
Mol Biol Rep. 2015; 42(5):977-88 [PubMed] Related Publications
The gene expression profile of breast cancer has been described as a great breakthrough on the way to comprehend differences in cancer origin, behavior and therapy. However, gene expression profile in histologically normal epithelium (HNEpi) which could harbor genetic abnormalities predisposing breast tissue to develop malignancy was minor scope for scientists in the past. Thus, we aimed to analyze gene expressions in HNEpi and breast cancer tissue (BCTis) in order to establish its value as potential diagnostic marker for cancer development. We evaluated a panel of disease-specific genes in luminal type (A/B) of breast cancer and tumor surrounding HNEpi by qRT-PCR Array in 32 microdissected samples. There was 20.2 and 2.4% deregulation rate in genes with at least 2-fold or 5-fold over-expression between luminal (A/B) type breast carcinomas and tumor surrounding HNEpi, respectively. The high-grade luminal carcinomas showed higher number of deregulated genes compared to low-grade cases (50.6 vs. 23.8% with at least 2-fold deregulation rate). The main overexpressed genes in HNEpi were KLK5, SCGB1D2, GSN, EGFR and NGFR. The significant differences in gene expression between BCTis and HNEpi samples were revealed for BAG1, C3, CCNA2, CD44, FGF1, FOSL1, ID2, IL6R, NGFB, NGFR, PAPPA, PLAU, SERPINB5, THBS1 and TP53 gene (p < 0.05) and BCL2L2, CTSB, ITGB4, JUN, KIT, KLF5, SCGB1D2, SCGB2A1, SERPINE1 (p < 0.01), and EGFR, GABRP, GSN, MAP2K7 and THBS2 (p < 0.001), and GSN, KLK5 (p < 0.0001). The ontological gene analyses revealed high deregulations in gene group directly associated with breast cancer prognosis and origin.

Zubor P, Hatok J, Moricova P, et al.
Gene expression profiling of histologically normal breast tissue in females with human epidermal growth factor receptor 2‑positive breast cancer.
Mol Med Rep. 2015; 11(2):1421-7 [PubMed] Related Publications
Gene expression profile‑based taxonomy of breast cancer (BC) has been described as a significant breakthrough in comprehending the differences in the origin and behavior of cancer to allow individually tailored therapeutic approaches. In line with this, we hypothesized that the gene expression profile of histologically normal epithelium (HNEpi) could harbor certain genetic abnormalities predisposing breast tissue cells to develop human epidermal growth factor receptor 2 (HER2)‑positive BC. Thus, the aim of the present study was to assess gene expression in normal and BC tissue (BCTis) from patients with BC in order to establish its value as a potential diagnostic marker for cancer development. An array study evaluating a panel of 84 pathway‑ and disease‑specific genes in HER2‑positive BC and tumor‑adjacent HNEpi was performed using quantitative polymerase chain reaction in 12 patients using microdissected samples from frozen tissue. Common prognostic and predictive parameters of BC were assessed by immunohistochemistry and in situ hybridization. In the BCTis and HNEpi samples of 12 HER2‑positive subjects with BC, the expression of 2,016 genes was assessed. A total of 39.3% of genes were deregulated at a minimal two‑fold deregulation rate and 10.7% at a five‑fold deregulation rate in samples of HNEpi or BCTis. Significant differences in gene expression between BCTis and HNEpi samples were revealed for BCL2L2, CD44, CTSD, EGFR, ERBB2, ITGA6, NGFB, RPL27, SCBG2A1 and SCGB1D2 genes (P<0.05), as well as GSN, KIT, KLK5, SERPINB5 and STC2 genes (P<0.01). Insignificant differences (P<0.07) were observed for CCNA1, CLU, DLC1, GABRP and IL6 genes. The ontological gene analyses revealed that the majority of the deregulated genes in the HNEpi samples were part of the functional gene group directly associated with BC origin and prognosis. Functional analysis showed that the most frequent gene deregulations occurred in genes associated with apoptosis and cell cycle regulation in BCTis samples, and with angiogenesis, regulation of the cell cycle and transcriptional activity in HNEpi samples. The molecular profiling of HNEpi breast tissue revealed gene expression abnormalities that may represent potential markers of increased risk for HER2‑positive malignant transformation of breast tissue, and may be able to be employed as predictors of prognosis.

Pampalakis G, Obasuyi O, Papadodima O, et al.
The KLK5 protease suppresses breast cancer by repressing the mevalonate pathway.
Oncotarget. 2014; 5(9):2390-403 [PubMed] Article available free on PMC after 25/03/2017 Related Publications
Kallikrein-related peptidase 5 (KLK5) displays aberrant expression in cancer. However, any functional association is missing. Here, we show that reconstitution of KLK5 expression in non-expressing MDA-MB-231 breast cancer cells suppresses malignancy in vitro and in vivo dose-dependently. Reactivation of KLK5 suppressed key EMT genes. Unexpectedly, we identified altered expression of genes encoding enzymes of the mevalonate pathway typical of those observed upon cholesterol starvation. Consistently, we found that SREBF1, the master regulator of the mevalonate pathway was induced. KLK5 re-expression leads to reduced cellular cholesterol and fatty acid synthesis and enhanced uptake of LDL-cholesterol. Suppression of the mevalonate pathway in KLK5 transfectants was further shown by reduced synthesis of isoprenoids. Indeed, we found diminished levels of active RhoA, a signaling oncoprotein that requires prenylation for activation. We propose that reduced RhoA activation plays a dominant role in suppression of malignancy by KLK5, since geranylgeranyl pyrophosphate restored active RhoA in KLK5-reverted cells resulting in increased malignancy. For the first time, we suggest that a protease may suppress breast cancer by modulating the mevalonate pathway.

Papachristopoulou G, Talieri M, Scorilas A
Significant alterations in the expression pattern of kallikrein-related peptidase genes KLK4, KLK5 and KLK14 after treatment of breast cancer cells with the chemotherapeutic agents epirubicin, docetaxel and methotrexate.
Tumour Biol. 2013; 34(1):369-78 [PubMed] Related Publications
Given that 1.3 million new cases of breast cancer are universally registered among women and approximately 36 % of the patients die annually, the revelation of new predictive markers for treatment efficiency is of vital importance. Recently, our group has depicted that KLK4, KLK5, and KLK14 are differentially expressed in breast carcinoma. The objective of this study was to determine and investigate the expression pattern of the KLK4, KLK5, and KLK14 genes in breast cancer cells after treatment with established chemotherapeutic agents. We evaluated these genes' expression after treatment of the BT-20 cells with epirubicin, docetaxel and methotrexate, determining their cytotoxic effect by MTT and trypan blue assays. The relative quantification of genes' mRNA levels was performed by using the SYBR Green® chemistry, and the HPRT1 served as an endogenous control gene. The drugs triggered apoptosis in treated cells and induced deregulations in the expression of the above KLKs. The most significant alterations were a 12-fold and tenfold increase of KLK5 in docetaxel and methotrexate-treated cells, respectively, while the KLK4 levels decreased by ten-fold in epirubicin, five-fold in docetaxel and twenty-fold in methotrexate treated-cells, compared to the untreated ones. In the case of KLK14 levels, a twofold increase in epirubicin and threefold decrease in methotrexate-treated cells were observed. Present significant alterations in the expression pattern of KLK4, KLK5, and KLK14 could comprise an initial stage for predicting chemotherapy response in breast cancer and should be further investigated as predictive markers in the future.

Loessner D, Quent VM, Kraemer J, et al.
Combined expression of KLK4, KLK5, KLK6, and KLK7 by ovarian cancer cells leads to decreased adhesion and paclitaxel-induced chemoresistance.
Gynecol Oncol. 2012; 127(3):569-78 [PubMed] Related Publications
OBJECTIVE: Chemoresistance is a critical feature of advanced ovarian cancer with only 30% of patients surviving longer than 5 years. We have previously shown that four kallikrein-related (KLK) peptidases, KLK4, KLK5, KLK6 and KLK7 (KLK4-7), are implicated in peritoneal invasion and tumour growth, but underlying mechanisms were not identified. We also reported that KLK7 overexpression confers chemoresistance to paclitaxel, and cell survival via integrins. In this study, we further explored the functional consequenses of overexpression of all four KLKs (KLK4-7) simultaneously in the ovarian cancer cell line, OV-MZ-6, and its impact on integrin expression and signalling, cell adhesion and survival as contributors to chemoresistance and metastatic progression.
METHODS: Quantitative gene and protein expression analyses, confocal microscopy, cell adhesion and chemosensitivity assays were performed.
RESULTS: Expression of α5β1/αvβ3 integrins was downregulated upon combined stable KLK4-7 overexpression in OV-MZ-6 cells. Accordingly, the adhesion of these cells to vitronectin and fibronectin, the extracellular matrix binding proteins of α5β1/αvβ3 integrins and two predominant proteins of the peritoneal matrix, was decreased. KLK4-7-transfected cells were more resistant to paclitaxel (10-100 nmol/L: 38-54%), but not to carboplatin, which was associated with decreased apoptotic stimuli. However, the KLK4-7-induced paclitaxel resistance was not blocked by the MEK1/2 inhibitor, U0126.
CONCLUSIONS: This study demonstrates that combined KLK4-7 expression by ovarian cancer cells promotes reduced integrin expression with consequently less cell-matrix attachment, and insensitivity to paclitaxel mediated by complex integrin and MAPK independent interactions, indicative of a malignant phenotype and disease progression suggesting a role for these KLKs in this process.

Lose F, Batra J, O'Mara T, et al.
Common variation in Kallikrein genes KLK5, KLK6, KLK12, and KLK13 and risk of prostate cancer and tumor aggressiveness.
Urol Oncol. 2013; 31(5):635-43 [PubMed] Related Publications
The human tissue Kallikrein family consists of 15 genes with the majority shown to be differentially expressed in cancers and/or indicators of cancer prognosis. We sought to elucidate the role of common genetic variation in four of the Kallikrein genes, KLK5, KLK6, KLK12, and KLK13, in prostate cancer risk and tumor aggressiveness. Genotyping of all 22 tagging single nucleotide polymorphisms (tagSNPs) in the KLK5, KLK6, KLK12, and KLK13 genes was performed in approximately 1,000 prostate cancer cases and 1,300 male controls from Australia. Data from any positive results were also accessed for 1,844 cases and 1,886 controls from a previously published prostate cancer genome-wide association study set from the United Kingdom. For one SNP in KLK12, rs3865443, there was evidence for association with prostate cancer risk of similar direction and magnitude in the replication set to that seen in the Australian cohort. We conducted genotyping of a further 309 prostate cancer cases, and combined analyses revealed an increased risk of prostate cancer for carriers of the rare homozygous genotype for rs3865443 (OR 1.28, 95% CI 1.04-1.57; P = 0.018). No other tagSNPs in the KLK5, KLK6, and KLK13 genes were consistently associated with prostate cancer risk or tumor aggressiveness. Analysis of a combined sample of 3,153 cases and 3,199 controls revealed the KLK12 tagSNP rs3865443 to be marginally statistically significantly associated with risk of prostate cancer. Considering the total number of SNPs investigated in this study, this finding should be interpreted cautiously and requires additional validation from very large datasets such as those of the Prostate Cancer Association group to investigate cancer associated alterations (PRACTICAL) Consortium.

Guillon-Munos A, Oikonomopoulou K, Michel N, et al.
Kallikrein-related peptidase 12 hydrolyzes matricellular proteins of the CCN family and modifies interactions of CCN1 and CCN5 with growth factors.
J Biol Chem. 2011; 286(29):25505-18 [PubMed] Article available free on PMC after 25/03/2017 Related Publications
Kallikrein-related peptidases (KLKs) are an emerging group of secreted serine proteases involved in several physiological and pathological processes. We used a degradomic approach to identify potential substrates of KLK12. MDA-MB-231 cells were treated either with KLK12 or vehicle control, and the proteome of the overlying medium was analyzed by mass spectrometry. CCN1 (cyr61, ctgf, nov) was among the proteins released by the KLK12-treated cells, suggesting that KLK12 might be responsible for the shedding of this protein from the cell surface. Fragmentation of CCN1 by KLK12 was further confirmed in vitro, and the main cleavage site was localized in the hinge region between the first and second half of the recombinant protein. KLK12 can target all six members of the CCN family at different proteolytic sites. Limited proteolysis of CCNs (cyr61, ctgf, nov) was also observed in the presence of other members of the KLK family, such as KLK1, KLK5, and KLK14, whereas KLK6, KLK11, and KLK13 were unable to fragment CCNs. Because KLK12 seems to have a role in angiogenesis, we investigated the relations between KLK12, CCNs, and several factors known to be involved in angiogenesis. Solid phase binding assays showed that fragmentation of CCN1 or CCN5 by KLK12 prevents VEGF(165) binding, whereas it also triggers the release of intact VEGF and BMP2 from the CCN complexes. The KLK12-mediated release of TGF-β1 and FGF-2, either as intact or truncated forms, was found to be concentration-dependent. These findings suggest that KLK12 may indirectly regulate the bioavailability and activity of several growth factors through processing of their CCN binding partners.

Jiang R, Shi Z, Johnson JJ, et al.
Kallikrein-5 promotes cleavage of desmoglein-1 and loss of cell-cell cohesion in oral squamous cell carcinoma.
J Biol Chem. 2011; 286(11):9127-35 [PubMed] Article available free on PMC after 25/03/2017 Related Publications
Oral squamous cell carcinoma (OSCC) ranks among the top 8 causes of cancer death worldwide, with only a 60% 5-year survival rate, highlighting the need for discovery of novel biomarkers and therapeutic targets. We have previously reported that expression of a panel of serine proteinase kallikreins (KLK 5, 7, 8, and 10) is correlated with formation of more aggressive OSCC tumors in a murine orthotopic OSCC model and is elevated in human OSCC. Current studies focus on understanding the potential role of KLK5 in OSCC progression. In initial studies, KLK levels in malignant OSCC cells (SCC25) were compared with cells from normal oral mucosa (OKF/6) and pre-malignant oral keratinocytes (pp126) using qPCR. A marked elevation of all KLKs was observed in aggressive SCC25 cells relative to OKF/6 cells. In normal skin, KLKs are involved in desquamation during epidermal differentiation via proteolytic cleavage of the desmosomal cadherin component desmoglein 1 (Dsg1). As loss of cell-cell cohesion is prevalent in tumor metastasis, Dsg1 integrity was evaluated. Results show that SCC25 cells exhibit cleavage of Dsg1, which is blocked by proteinase inhibitor treatment as well as by siRNA silencing of KLK5 expression. Furthermore, cell-cell aggregation assays demonstrate that silencing of KLK5 enforces cell-cell adhesion; conversely, overexpression of KLK5 in normal oral mucosal cells (OKF/6) enhances cell dispersal. These data suggest that KLK5 may promote metastatic dissemination of OSCC by promoting loss of junctional integrity through cleavage of desmoglein 1.

Angelopoulou K, Karagiannis GS
Structural characterization and expression of five novel canine kallikrein-related peptidases in mammary cancer.
Mamm Genome. 2010; 21(9-10):516-24 [PubMed] Related Publications
Kallikrein-related peptidases (KLKs) constitute a major family of proteolytic enzymes implicated in the pathogenesis of many diseases, including cancer. Recently, we have suggested that the dog might represent a useful animal model for in vivo KLK studies and sought to investigate the expression patterns of the largely unknown canine KLK family. Along the same lines, in the present report we experimentally characterized five previously unidentified (CANFA)KLKs and investigated their expression in normal and tumorous mammary tissues. We demonstrated that the GenBank sequences that were predicted in silico to represent the canine orthologs of human KLK5, KLK6, KLK7, and KLK8 mRNAs were correct, whereas the one corresponding to the canine KLK4 had a major inconsistency within its 5'-terminus. More specifically, two internal segments of the first intron of KLK4, 78 and 97 bp long, respectively, were wrongfully determined to constitute the initial 175-nucleotide sequence of the KLK4 coding region. (CANFA)KLK8 was further shown to undergo alternative splicing that generated an mRNA transcript missing exon 4 (variant 1). All five (CANFA)KLKs were almost ubiquitously expressed in both cancerous and noncancerous mammary tissues. Lower positivity rates were identified for (CANFA)KLK8 variant 1. A trend for upregulation in tumors was observed for (CANFA)KLK5, (CANFA)KLK7, and (CANFA)KLK8, whereas (CANFA)KLK8 variant 1 tended to be downregulated in cancer. Moreover, a parallel expression of the studied canine KLKs was observed, which suggested a possible participation of the encoded enzymes in interrelated proteolytic cascades taking place in the mammary gland.

Planque C, Choi YH, Guyetant S, et al.
Alternative splicing variant of kallikrein-related peptidase 8 as an independent predictor of unfavorable prognosis in lung cancer.
Clin Chem. 2010; 56(6):987-97 [PubMed] Related Publications
BACKGROUND: A relatively unexplored area for biomarker identification is alternative splice variants. We undertook this study to evaluate the usefulness of mRNA isoforms encoded by the KLK8 (kallikrein-related peptidase 8) gene as prognostic markers for lung cancer.
METHODS: Real-time reverse-transcription PCR was used to analyze the mRNAs encoded by KLK8 (particularly 2 mRNA splice variants, KLK8-T3 and KLK8-T4) in 60 non-small-cell lung cancer (NSCLC) tumors and in paired unaffected tissues. The ratios of these mRNAs to those encoded by the KLK5, KLK6, KLK7, KLK10, KLK11, KLK13, and KLK14 genes were also determined and analyzed for correlations with various clinicopathologic variables.
RESULTS: KLK8-T3 and KLK8-T4 were the most abundant of the 6 mRNA isoforms identified in lung tissues. The overall expression of the KLK8 gene and the amounts of the KLK8-T3 and KLK8-T4 mRNAs were significantly increased in lung tumor tissue (P < 0.0001). Univariate survival analysis revealed significant relationships of the relative concentrations of mRNA splice variants KLK8 (P = 0.043), KLK8-T3 (P = 0.037), and KLK8-T4 (P = 0.009) with overall survival (OS). Cox multivariate analysis indicated that the amount of KLK8-T4 mRNA was an independent prognostic factor for OS (relative risk = 3.90; P = 0.016) and that high KLK8-T4/KLK7, KLK8-T4/KLK10, and KLK8-T4/KLK11 mRNA ratios in NSCLC indicated increased risk of death. The increase was approximately 5-fold for the KLK8-T4/KLK7 and KLK8-T4/KLK10 ratios (P = 0.006, and P = 0.011, respectively) and 8-fold for the KLK8-T4/KLK11 ratio (P = 0.001).
CONCLUSIONS: The KLK8-T4 alternative splice variant, alone or in combination, may be a new independent marker of unfavorable prognosis in lung cancer.

Beaufort N, Plaza K, Utzschneider D, et al.
Interdependence of kallikrein-related peptidases in proteolytic networks.
Biol Chem. 2010; 391(5):581-7 [PubMed] Related Publications
Human kallikrein-related peptidases (KLKs) are 15 homologous serine proteases involved in several (patho)physiological processes, including cancer. Secreted as precursors, they are activated upon proteolytic release of a short pro-peptide. We searched for interconnection of KLKs within extracellular proteolytic networks leading to activation of protease zymogens and found that (i) pro-KLK activation by other KLKs is scarce, with the exception of pro-KLK11, which is efficiently activated by KLK4 and 5; (ii) pro-KLK4 is activated by matrix metalloproteinase 3; and (iii) trypsin-like KLKs efficiently activate the serine protease urokinase. Our observations provide new insights into the regulation of these important tumor-associated proteases.

Davidson B, Stavnes HT, Holth A, et al.
Gene expression signatures differentiate ovarian/peritoneal serous carcinoma from breast carcinoma in effusions.
J Cell Mol Med. 2011; 15(3):535-44 [PubMed] Article available free on PMC after 25/03/2017 Related Publications
Ovarian/primary peritoneal carcinoma and breast carcinoma are the gynaecological cancers that most frequently involve the serosal cavities.With the objective of improving on the limited diagnostic panel currently available for the differential diagnosis of these two malignancies,as well as to define tumour-specific biological targets, we compared their global gene expression patterns. Gene expression profiles of 10 serous ovarian/peritoneal and eight ductal breast carcinoma effusions were analysed using the HumanRef-8 BeadChip from Illumina.Differentially expressed candidate genes were validated using quantitative real-time PCR and immunohistochemistry. Unsupervised hierarchical clustering using all 54,675 genes in the array separated ovarian from breast carcinoma samples. We identified 288 unique probes that were significantly differentially expressed in the two cancers by greater than 3.5-fold, of which 81 and 207 were overexpressed in breast and ovarian/peritoneal carcinoma, respectively. SAM analysis identified 1078 differentially expressed probes with false discovery rate less than 0.05. Genes overexpressed in breast carcinoma included TFF1, TFF3, FOXA1, CA12, GATA3, SDC1, PITX1, TH, EHFD1, EFEMP1, TOB1 and KLF2. Genes overexpressed in ovarian/peritoneal carcinoma included SPON1, RBP1, MFGE8, TM4SF12, MMP7, KLK5/6/7, FOLR1/3,PAX8, APOL2 and NRCAM. The differential expression of 14 genes was validated by quantitative real-time PCR, and differences in 5 gene products were confirmed by immunohistochemistry. Expression profiling distinguishes ovarian/peritoneal carcinoma from breast carcinoma and identifies genes that are differentially expressed in these two tumour types. The molecular signatures unique to these cancers may facilitate their differential diagnosis and may provide a molecular basis for therapeutic target discovery.

Mavridis K, Talieri M, Scorilas A
KLK5 gene expression is severely upregulated in androgen-independent prostate cancer cells after treatment with the chemotherapeutic agents docetaxel and mitoxantrone.
Biol Chem. 2010; 391(4):467-74 [PubMed] Related Publications
Kallikrein-related peptidases (KLKs), including KLK5, have been proposed as promising biomarkers for prostate cancer diagnosis and prognosis. In the present study, we report that distinct augmentations (up to 6.4-fold) of KLK5 mRNA expressional levels, calculated via quantitative real-time PCR, occur after treatment of DU145 cells with appropriate concentrations, determined by the MTT method, of docetaxel and mitoxantrone. Our data reveal the endogenous need of prostate cancer cells for modified KLK5 expression to cope with the administration of chemotherapeutic drugs. Furthermore, it is proposed that the expression profile of KLK5 could serve as a putative biomarker for monitoring the treatment response in hormone refractory prostate cancer patients.

Li X, Liu J, Wang Y, et al.
Parallel underexpression of kallikrein 5 and kallikrein 7 mRNA in breast malignancies.
Cancer Sci. 2009; 100(4):601-7 [PubMed] Related Publications
Kallikrein (KLK) 5 and KLK7 were reported to be overexpressed in several cancers, but underexpressed in prostate and breast cancers. However, the expression levels of KLK5 and KLK7 in benign breast tissues and metastases, and the relationship between KLK5 and KLK7, have not been reported. In addition, the value of KLK5 and KLK7 in the diagnosis and prognosis prediction of breast cancer patients is far from clear. To further determine their role and clinical significance in breast cancer and to explore the relationship between KLK5 and KLK7, the mRNA levels of KLK5 and KLK7 in normal breast tissues, benign breast tissues, primary tumors, and lymph node metastases were detected by real-time reverse transcription-polymerase chain reaction and microarray. The relationship between KLK5 and KLK7 expression and clinicopathological parameters, and the correlation between the mRNA levels of KLK5 and KLK7 as well as the 5'-uncoding regions of KLK5 and KLK7 were analyzed. The mRNA levels of KLK5 and KLK7 were both downregulated in breast cancers relative to normal and benign tissues, and downregulated in metastases compared to primary cancers. Underexpression of KLK5 and KLK7 was correlated with postmenopausal status and positive estrogen receptor status. The mRNA levels of KLK5 and KLK7 were positively correlated in breast malignancies. Moreover, four homologous sequences and 10 transcription factors as potential regulators were found on the control regions of both KLK5 and KLK7. Thus, KLK5 and KLK7 were underexpressed in parallel, potentially with the same regulation pathways, in breast malignancies, which might contribute to the carcinogenesis and development of breast cancer. They are potential biomarkers for breast cancer.

Korbakis D, Gregorakis AK, Scorilas A
Quantitative analysis of human kallikrein 5 (KLK5) expression in prostate needle biopsies: an independent cancer biomarker.
Clin Chem. 2009; 55(5):904-13 [PubMed] Related Publications
BACKGROUND: Kallikrein 5 (KLK5), a recently cloned member of the kallikrein family, codes for the secreted protein KLK5. Active KLK5 protein has a trypsin activity, and the expression of KLK5 gene seems to be regulated by steroid hormones. We performed an expression analysis and clinical evaluation of the KLK5 gene, at the mRNA level, in prostate needle biopsies.
METHODS: We examined KLK5 mRNA concentrations in 103 prostate tissue specimens. After testing of RNA quality, cDNA was prepared by reverse transcription. A highly sensitive quantitative real-time PCR (qRT-PCR) method for KLK5 mRNA quantification was developed using the SYBR Green chemistry. GAPDH was used as a housekeeping gene.
RESULTS: Specimens from patients with benign prostatic hyperplasia (BPH) showed higher levels of KLK5 mRNA expression than those from patients with prostate cancer (PCa) (P = 0.024). ROC analysis demonstrated that KLK5 expression had significant discriminatory value between BPH and PCa (AUC 0.64; P = 0.016). KLK5 mRNA expression showed a statistically significant negative correlation with the total PSA serum concentration in the PCa patients (P = 0.003). Early-stage tumors showed higher KLK5 expression than late-stage ones (P = 0.014), whereas KLK5 expression was negatively correlated to Gleason score (P = 0.005).
CONCLUSIONS: KLK5 mRNA, analyzed by quantitative PCR in prostate needle biopsies, could be an independent biomarker for the differential diagnosis and prognosis in prostate cancer.

Thomadaki H, Mavridis K, Talieri M, Scorilas A
Treatment of PC3 prostate cancer cells with mitoxantrone, etoposide, doxorubicin and carboplatin induces distinct alterations in the expression of kallikreins 5 and 11.
Thromb Haemost. 2009; 101(2):373-80 [PubMed] Related Publications
Several of the novel kallikrein-related peptidases (tissue kallikreins; KLKs) are emerging new serum and/or tissue biomarkers for prostate cancer (CaP) diagnosis, prognosis and monitoring. In the present research approach, our objective was to investigate the possible alterations in the mRNA expression levels of KLK5 and KLK11 genes in prostate cancer cells PC3 as a response to treatment with mitoxantrone, etoposide, doxorubicin and carboplatin. Viability was assessed with the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay after cell treatment with either mitoxantrone (2 microM), etoposide (20 microM), doxorubicin (1 microM), or carboplatin (15 microM), for 24, 48 and 72 hours. Additionally, trypan blue staining revealed that in PC3 cells all drugs displayed almost the same limited necrotic effects which appeared mainly at 72 hours of treatment. PC3 prostate cancer cells showed a concentration- and time-dependent increased cytotoxicity to the drugs under study which was mainly due to reduction of cell proliferation efficiency. Distinct modulations of KLK5 and KLK11 genes, at the mRNA level, were observed, supporting a drug-dependent cell response. Our experimental data demonstrate that the molecular profile mainly of KLK5 gene may serve as a new potential molecular biomarker predicting treatment response in CaP cells.

Pettus JR, Johnson JJ, Shi Z, et al.
Multiple kallikrein (KLK 5, 7, 8, and 10) expression in squamous cell carcinoma of the oral cavity.
Histol Histopathol. 2009; 24(2):197-207 [PubMed] Article available free on PMC after 25/03/2017 Related Publications
Oral squamous cell carcinoma (OSCC) represents 3% of all cancer deaths in the U.S. and is ranked one of the top 10 cancers worldwide. The 5-year survival rate has remained at a low 50% for the past several decades, necessitating discovery of novel biomarkers of aggressive disease and therapeutic targets. As overexpression of urinary type plasminogen activator and receptor (uPA/R) in OSCC is associated with malignant progression and poor outcome, cell lines were generated with either overexpression (SCC25-uPAR+) or silencing (SCC25-uPAR-KD) of uPAR. As SCC25-uPAR+ tumors behaved more aggressively both in vitro and in vivo, comparative cDNA microarray analysis was used to identify additional genes that may be associated with aggressive tumors. Four members of the human tissue kallikrein family (KLK 5, 7, 8, and 10) were identified and real-time RT-PCR (qPCR) was used to verify and quantify gene expression. qPCR analysis revealed 2.8-, 5.3-, 4.0-, and 3.5-fold increases in gene expression for KLK5, 7, 8, and 10, respectively, in SCC25-uPAR+ versus SCC25-uPAR-KD. Immunohistochemical analysis demonstrated strong reactivity for KLKs 5, 7, 8 and 10 in both orthotopic murine tumors and human OSCC tissues. Control experiments show lack of reactivity against KLK3 (prostate specific antigen). These results demonstrate that kallikreins 5, 7, 8, and 10 are abundantly expressed in human OSCC and may be implicated in malignant progression.

Guy M, Kote-Jarai Z, Giles GG, et al.
Identification of new genetic risk factors for prostate cancer.
Asian J Androl. 2009; 11(1):49-55 [PubMed] Article available free on PMC after 25/03/2017 Related Publications
There is evidence that a substantial part of genetic predisposition to prostate cancer (PCa) may be due to lower penetrance genes which are found by genome-wide association studies. We have recently conducted such a study and seven new regions of the genome linked to PCa risk have been identified. Three of these loci contain candidate susceptibility genes: MSMB, LMTK2 and KLK2/3. The MSMB and KLK2/3 genes may be useful for PCa screening, and the LMTK2 gene might provide a potential therapeutic target. Together with results from other groups, there are now 23 germline genetic variants which have been reported. These results have the potential to be developed into a genetic test. However, we consider that marketing of tests to the public is premature, as PCa risk can not be evaluated fully at this stage and the appropriate screening protocols need to be developed. Follow-up validation studies, as well as studies to explore the psychological implications of genetic profile testing, will be vital prior to roll out into healthcare.

Prassas I, Paliouras M, Datti A, Diamandis EP
High-throughput screening identifies cardiac glycosides as potent inhibitors of human tissue kallikrein expression: implications for cancer therapies.
Clin Cancer Res. 2008; 14(18):5778-84 [PubMed] Related Publications
PURPOSE: Human tissue kallikreins (KLK) comprise a subgroup of 15 homologous secreted serine proteases. Primarily known for their clinical use as cancer biomarkers (e.g., PSA), KLKs have recently been directly implicated in cancer-related processes, including invasion, angiogenesis, and tumor growth regulation. Therefore, the identification of compounds that would modulate expression of KLKs might be of considerable therapeutic value.
EXPERIMENTAL DESIGN: A cell-based high-throughput screening (HTS) of three small molecule libraries ( approximately 4,500 compounds) was undertaken; KLK expression in the breast cancer cell line MDA-MB-468 was assessed with sensitive ELISAs.
RESULTS: The initial screening resulted in 66 "putative hits" that decreased KLK5 expression by at least 50% over control. Secondary screening and mini-dose-response assays resulted in 21 "validated hits." These 21 compounds were clustered in only three distinct functional families and were further analyzed in vitro to determine their effectiveness (IC(50)s). Hits that failed to show dose-responsiveness or interfered with the viability of the cells were excluded. Multiple members of the cardiac glycoside family were found to be novel inhibitors of KLK expression, acting at low concentrations (10-50 nmol/L). Furthermore, members of the same family induced marked decreases in c-MYC and c-FOS expression, in a dose-dependent manner that correlated the KLK inhibition, suggesting a transcriptional mechanism of regulation of KLK expression.
CONCLUSIONS: We conclude that cardiac glycosides can dramatically suppress the transcription of KLKs and that these effects may be linked to proto-oncogene (c-myc/fos) expression. These findings may partially explain the recently realized antineoplastic actions of cardiac glycosides.

Gho JW, Ip WK, Chan KY, et al.
Re-expression of transcription factor ATF5 in hepatocellular carcinoma induces G2-M arrest.
Cancer Res. 2008; 68(16):6743-51 [PubMed] Related Publications
Transcription factors represent an important class of genes that play key roles in controlling cellular proliferation, cell cycle modulation, and attractive targets for cancer therapy. Here, we report on the novel finding of common ATF5 down-regulations in hepatocellular carcinoma (HCC), a highly malignant tumor with a dismal clinical course. Array-based mapping in HCC highlighted a high and consistent incidence of transcription factor ATF5 repressions on regional chr.19q13. By quantitative reverse transcription-PCR, profound down-regulations of ATF5 were further suggested in 78% of HCC tumors (60 of 77 cases) compared to their adjacent nontumoral liver (P = 0.0004). Restoration of ATF5 expression in 3 nonexpressing HCC cell lines demonstrated a consistent growth inhibitory effect (P < 0.029) but minimal induction on cellular apoptosis. Subsequent flow cytometric investigations revealed a G(2)-M cell cycle arrest in HCC cells that were ectopically transfected with ATF5 (P < 0.002). The differential expressed genes from the functional effects of ATF5 were examined by array profiling. Over a hundred genes were identified, among which ID1 contains the ATF/CREB target binding sequences within its promoter region. An inverse relationship between ATF5 expressions with ID1 transcriptions was verified in HCC (P = 0.019), and a direct interaction of ATF5 on the promoter of ID1 was further demonstrated from electromobility shift assay. Examination of causal events underlying the silencing of ATF5 in HCC suggested copy number losses, promoter hypermethylation, histone deacetylation, and DNA mutations to be the likely inactivating mechanisms. In conclusion, our finding supports a tumor suppressive role for ATF5 in HCC, and highlighted ID1 as a potential downstream target.

Planque C, Li L, Zheng Y, et al.
A multiparametric serum kallikrein panel for diagnosis of non-small cell lung carcinoma.
Clin Cancer Res. 2008; 14(5):1355-62 [PubMed] Related Publications
PURPOSE: Human tissue kallikreins are a family of 15 secreted serine proteases. We have previously shown that the expression of several tissue kallikreins is significantly altered at the transcriptional level in lung cancer. Here, we examined the clinical value of 11 members of the tissue kallikrein family as potential biomarkers for lung cancer diagnosis.
EXPERIMENTAL DESIGN: Serum specimens from 51 patients with non-small cell lung cancer (NSCLC) and from 50 healthy volunteers were collected. Samples were analyzed for 11 kallikreins (KLK1, KLK4-8, and KLK10-14) by specific ELISA. Data were statistically compared and receiver operating characteristic curves were constructed for each kallikrein and for various combinations.
RESULTS: Compared with sera from normal subjects, sera of patients with NSCLC had lower levels of KLK5, KLK7, KLK8, KLK10, and KLK12, and higher levels of KLK11, KLK13, and KLK14. Expression of KLK11 and KLK12 was positively correlated with stage. With the exception of KLK5, expression of kallikreins was independent of smoking status and gender. KLK11, KLK12, KLK13, and KLK14 were associated with higher risk of NSCLC as determined by univariate analysis and confirmed by multivariate analysis. The receiver operating characteristic curve of KLK4, KLK8, KLK10, KLK11, KLK12, KLK13, and KLK14 combined exhibited an area under the curve of 0.90 (95% confidence interval, 0.87-0.97).
CONCLUSIONS: We propose a multiparametric panel of kallikrein markers for lung cancer diagnosis with relatively good accuracy. This model requires validation with a larger series and may be further improved by addition of other biomarkers.

Shinoda Y, Kozaki K, Imoto I, et al.
Association of KLK5 overexpression with invasiveness of urinary bladder carcinoma cells.
Cancer Sci. 2007; 98(7):1078-86 [PubMed] Related Publications
Array-based comparative genomic hybridization (array-CGH) has powerful potential for high-throughput identification of genetic aberrations in cell genomes. We identified high-level amplification of kallikrein (KLK) genes, which are mapped to 19q13.3 and belong to the serine protease family, in the course of a program to screen a panel of urinary bladder carcinoma cell lines for genomic copy number aberrations using our in-house CGH-array. Expression levels of KLK5, -6, -8 and -9 were significantly increased in three cell lines with copy number gains of these KLK genes. Knockdown of these KLK transcripts by specific small interfering RNA significantly inhibited the invasion of a bladder carcinoma cell line through Matrigel in vitro. Reverse transcription-polymerase chain reaction analysis of 42 primary bladder tumor samples showed that increased expression of KLK5 was frequently observed in invasive tumors (pT2-pT4) (14.3%, 6/42) compared with superficial tumors (pTa, pT1) (0%, 0/42; P = 0.0052), and expression levels of KLK5, -6, -8 and -9 mRNA were higher in invasive tumors than in superficial tumors (P < 0.0001, P = 0.0043, P = 0.0790 and P = 0.0037, respectively). These observations indicate that KLK5, -6, -8 and -9 may be the most likely targets of the 19q13.3 amplification, and may play a crucial role in promoting cancer-cell invasion in bladder tumor.

Paliouras M, Borgono C, Diamandis EP
Human tissue kallikreins: the cancer biomarker family.
Cancer Lett. 2007; 249(1):61-79 [PubMed] Related Publications
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.

Prezas P, Arlt MJ, Viktorov P, et al.
Overexpression of the human tissue kallikrein genes KLK4, 5, 6, and 7 increases the malignant phenotype of ovarian cancer cells.
Biol Chem. 2006; 387(6):807-11 [PubMed] Related Publications
The human tissue kallikrein family of serine proteases (hK1-hK15 encoded by the genes KLK1-KLK15) is involved in several cancer-related processes. Accumulating evidence suggests that certain tissue kallikreins are part of an enzymatic cascade pathway that is activated in ovarian cancer and other malignant diseases. In the present study, OV-MZ-6 ovarian cancer cells were stably co-transfected with plasmids expressing hK4, hK5, hK6, and hK7. These cells displayed similar proliferative capacity as the vector-transfected control cells (which do not express any of the four tissue kallikreins), but showed significantly increased invasive behavior in an in vitro Matrigel invasion assay (p<0.01; Mann-Whitney U-test). For in vivo analysis, the cancer cells were inoculated into the peritoneum of nude mice. Simultaneous expression of hK4, hK5, hK6, and hK7 resulted in a remarkable 92% mean increase in tumor burden compared to the vector-control cell line. Five out of 14 mice in the 'tissue kallikrein overexpressing' group displayed a tumor/situs ratio greater than 0.198, while this weight limit was not exceeded at all in the vector control group consisting of 13 mice (p=0.017; chi2 test). Our results strongly support the view that tumor-associated overexpression of tissue kallikreins contributes to ovarian cancer progression.

Stavropoulou P, Gregorakis AK, Plebani M, Scorilas A
Expression analysis and prognostic significance of human kallikrein 11 in prostate cancer.
Clin Chim Acta. 2005; 357(2):190-5 [PubMed] Related Publications
BACKGROUND: Kallikrein 11 (KLK11) is a newly discovered human kallikrein gene that is mainly expressed in the central nervous system and endocrine tissues. KLK11 has two alternative splicing isoforms, known as the brain type and prostate type. Many members of the human kallikrein gene family are differentially expressed in cancer and a few have potential as diagnostic/prognostic markers.
METHODS: In the present study, the expression of prostate type variant of KLK11 gene was analyzed by RT-PCR in 66 prostate cancer tissues. Tumors were pulverized, total RNA was extracted, and cDNA was prepared by reverse transcription. KLK11 was amplified by PCR using gene specific primers and its identity was verified by sequencing. Prostate tissues were then classified as KLK5 positive or negative based on eithidium bromide staining in agarose gels and image analysis.
RESULTS: KLK11 was found to be highly expressed in 43/66 (65%) of prostate cancer samples. We found a significant negative relationship between KLK11 expression and Gleason score (p = 0.004) and disease stage (p = 0.038). Serum total PSA concentration was found to be lower in patients with overexpression of KLK11 (p = 0.044).
CONCLUSIONS: We conclude that down-regulation of the KLK11 gene in advanced and more aggressive tumors may open the possibility of being used as a future biological marker distinguishing the tumor aggressiveness as well as a useful prognostic biomarker for prostate cancer.

Planque C, de Monte M, Guyetant S, et al.
KLK5 and KLK7, two members of the human tissue kallikrein family, are differentially expressed in lung cancer.
Biochem Biophys Res Commun. 2005; 329(4):1260-6 [PubMed] Related Publications
Emerging data indicate that serine proteases of the kallikrein family (KLK) are implicated in various human diseases, including carcinoma; however, kallikrein gene expression has never been investigated in lung cancer. Using RT-PCR and Western blotting, we demonstrated the expression of both KLK5 and KLK7, and their respective proteins (hK5 and hK7) in tumoral and nontumoral lung tissues. Quantitative gene expression was then analyzed in a cohort of 56 patients with non-small cell lung cancer by real-time RT-PCR. KLK5 expression is significantly more expressed in squamous cell carcinoma than in matched nonmalignant lung tissue (P=0.02), whereas expression of KLK7 was decreased in adenocarcinoma (P=0.003). Multivariate analysis revealed diverse correlations between the KLK5 and KLK7 expression levels in nonmalignant and malignant tissues, and clinical parameters, including histotype, metastatic status, and grade. Our findings provide new insight into kallikrein gene expression in hormone-independent carcinoma. Altogether, our results suggest that variability in KLK5 and KLK7 gene expression might be involved in lung tumorigenesis and useful for clinical purposes.

Michael IP, Sotiropoulou G, Pampalakis G, et al.
Biochemical and enzymatic characterization of human kallikrein 5 (hK5), a novel serine protease potentially involved in cancer progression.
J Biol Chem. 2005; 280(15):14628-35 [PubMed] Related Publications
Human kallikrein 5 (KLK5) is a member of the human kallikrein gene family of serine proteases. Preliminary results indicate that the protein, hK5, may be a potential serological marker for breast and ovarian cancer. Other studies implicate hK5 with skin desquamation and skin diseases. To gain further insights on hK5 physiological functions, we studied its substrate specificity, the regulation of its activity by various inhibitors, and identified candidate physiological substrates. After producing and purifying recombinant hK5 in yeast, we determined the k(cat)/K(m) ratio of the fluorogenic substrates Gly-Pro-Arg-AMC and Gly-Pro-Lys-AMC, and showed that it has trypsin-like activity with strong preference for Arg over Lys in the P1 position. The serpins alpha(2)-antiplasmin and antithrombin were able to inhibit hK5 with an inhibition constant (k(+2)/K(i)) of 1.0 x 10(-) (2)and 4.2 x 10(-4) m(-1) min(-1), respectively. No inhibition was observed with the serpins alpha(1)-antitrypsin and alpha(1)-antichymotrypsin, although alpha(2)-macroglobulin partially inhibited hK5 at high concentrations. We also demonstrated that hK5 can efficiently digest the extracellular matrix components, collagens type I, II, III, and IV, fibronectin, and laminin. Furthermore, our results suggest that hK5 can potentially release (a) angiostatin 4.5 from plasminogen, (b) "cystatin-like domain 3" from low molecular weight kininogen, and (c) fibrinopeptide B and peptide beta15-42 from the Bbeta chain of fibrinogen. hK5 could also play a role in the regulation of the binding of plasminogen activator inhibitor 1 to vitronectin. Our findings suggest that hK5 may be implicated in tumor progression, particularly in invasion and angiogenesis, and may represent a novel therapeutic target.

Michael IP, Kurlender L, Memari N, et al.
Intron retention: a common splicing event within the human kallikrein gene family.
Clin Chem. 2005; 51(3):506-15 [PubMed] Related Publications
BACKGROUND: All human kallikrein (KLK) genes have at least one splice variant, some of which possess clinical utility in cancer diagnostics/prognostics. Given that introns <100 bp in length are retained in 95% of human genes and that splice variants of KLK3 and KLK4 retain intron III, we hypothesized that other proteins in this family, with a small intron III, may also retain it.
METHODS: Variant-specific reverse transcription-PCRs (RT-PCRs) for KLK1, KLK2, KLK5, and KLK15 were used to identify and clone the full coding sequence of intron III-containing splice variants. In addition, variant-specific RT-PCRs for the cloned KLK3 and KLK4 variants as well as for the "classical" forms of the six genes were used to determine their expression profiles in healthy tissues, their regulation by steroids, and their differential expression in prostate cancer.
RESULTS: KLK1, KLK2, KLK3, KLK4, KLK5, and KLK15 showed a common type of splice variant in which intron III is retained. Expression profiling of these splice variants revealed expression profiles similar to those of the classical mRNA forms, although the pattern of hormonal regulation was different. The KLK15 splice variant was up-regulated in 8 of 12 cancerous prostate tissues. All encoded variant proteins were predicted to be truncated and catalytically inactive because of a lack of the serine residue of the catalytic triad.
CONCLUSIONS: The first six centromeric members of the KLK gene family have splice variants that retain intron III. Some variants show tissue-specific expression. The KLK15 splice variant appears to be a candidate biomarker for prostate cancer.

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