Gene Summary

Gene:KLK14; kallikrein related peptidase 14
Aliases: KLK-L6
Summary:This gene encodes a member of the kallikrein subfamily of serine proteases that have diverse physiological functions such as regulation of blood pressure and desquamation. The altered expression of this gene is implicated in the progression of different cancers including breast and prostate tumors. The encoded protein is a precursor that is proteolytically processed to generate the functional enzyme. This gene is one of the fifteen kallikrein subfamily members located in a cluster on chromosome 19. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2015]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 30 August, 2019


What does this gene/protein do?
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Cancer Overview

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Publications Per Year (1994-2019)
Graph generated 30 August 2019 using data from PubMed using criteria.

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Specific Cancers (5)

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: KLK14 (cancer-related)

Dettmar L, Ahmed N, Kotzsch M, et al.
Advanced high-grade serous ovarian cancer: inverse association of KLK13 and KLK14 mRNA levels in tumor tissue and patients' prognosis.
J Cancer Res Clin Oncol. 2018; 144(6):1109-1118 [PubMed] Related Publications
PURPOSE: Gene expression of a variety of the 15 members of the KLK serine protease family is dysregulated in ovarian cancer. We aimed at determining the clinical relevance of KLK13 and KLK14 mRNA expression in tumor tissues of a homogeneous patient cohort afflicted with advanced high-grade serous ovarian cancer (FIGO stage III/IV).
METHODS: mRNA expression levels of KLK13 and KLK14 were assessed by quantitative PCR in tumor tissue of 91 patients and related with clinical factors and patients' outcome.
RESULTS: There was no significant association of KLK13 and KLK14 mRNA expression with the clinical factors ascitic fluid volume or residual tumor mass. In univariate Cox regression analysis, elevated KLK13 mRNA levels were significantly linked with shorter progression-free (PFS; hazard ratio [HR] = 1.97, P = 0.020) and overall survival (OS; HR = 1.81, P = 0.041). High KLK14 mRNA levels were significantly associated with prolonged PFS (HR = 0.44, P = 0.017) and showed a trend towards significance for OS (HR = 0.55, P = 0.070). In multivariable analysis, including the factors age, residual tumor mass, ascitic fluid volume, KLK13, and KLK14, both KLKs, apart from residual tumor mass, remained statistically independent predictive markers: patients with high KLK13 mRNA expression levels displayed a more than twofold increase risk for shorter PFS (HR = 2.14, P = 0.020) as well as OS (HR = 2.05, P = 0.028), whereas elevated KLK14 mRNA values were found to be significant for both, prolonged PFS (HR = 0.36, P = 0.007) and OS (HR = 0.46, P = 0.037).
CONCLUSION: These results indicate that in advanced high-grade serous ovarian cancer KLK13 may become proficient for tumor-supporting functions, whereas KLK14 may have adopted tumor-suppressing activity.

Kontos CK, Adamopoulos PG, Papageorgiou SG, et al.
mRNA overexpression of kallikrein-related peptidase 14 (KLK14) is an independent predictor of poor overall survival in chronic lymphocytic leukemia patients.
Clin Chem Lab Med. 2016; 54(2):315-24 [PubMed] Related Publications
BACKGROUND: Tissue kallikrein and kallikrein-related peptidases (KLKs) compose a family of serine endopeptidases with much clinical interest in oncology, as their potential as diagnostic and/or prognostic molecular biomarkers in several human malignancies has already been evidenced. However, none of the members of this family has ever been studied in hematological malignancies. Based on our preliminary results regarding the differential mRNA expression of several KLK genes in peripheral blood mononuclear cells (PBMCs) of patients with chronic lymphocytic leukemia (CLL) compared to healthy blood donors, we decided to study the diagnostic and prognostic potential of KLK14 mRNA expression in CLL.
METHODS: Total RNA was isolated from 69 CLL patients and 31 non-leukemic blood donors. After reverse transcription of poly(A)-RNA, KLK14 mRNA levels were quantified using a sensitive and accurate quantitative real-time PCR (qPCR) methodology.
RESULTS: According to ROC analysis, KLK14 mRNA overexpression successfully discriminated CLL patients from normal population (area under the curve [AUC] 0.89, 95% confidence interval [CI] 0.83-0.95, p<0.001). Moreover, although not clearly related to clinical staging or other prognostic factors including IGHV mutational status and CD38 expression, strong KLK14 mRNA expression was shown to predict reduced overall survival of CLL patients (p=0.026) using Kaplan-Meier survival analysis. The unfavorable prognostic value of KLK14 mRNA overexpression in CLL patients' PBMCs was independent of established prognostic factors of the disease, as shown by multivariate Cox regression analysis (hazard ratio [HR] 14.65, 95% CI 1.81-118.36, p=0.012).
CONCLUSIONS: KLK14 mRNA expression merits further investigation as a potential prognostic biomarker of overall survival of patients with CLL.

Walker F, Nicole P, Jallane A, et al.
Kallikrein-related peptidase 7 (KLK7) is a proliferative factor that is aberrantly expressed in human colon cancer.
Biol Chem. 2014; 395(9):1075-86 [PubMed] Related Publications
Emerging evidence indicates that serine proteases of the tissue kallikrein-related peptidases family (KLK) are implicated in tumorigenesis. We recently reported the ectopic expression of KLK4 and KLK14 in colonic cancers and their signaling to control cell proliferation. Human tissue kallikrein-related peptidase 7 (KLK7) is often dysregulated in many cancers; however, its role in colon tumorigenesis has not yet been established. In the present study, we analyzed expression of KLK7 in 15 colon cancer cell lines and in 38 human colonic tumors. In many human colon cancer cells, KLK7 mRNA was observed, which leads to KLK7 protein expression and secretion. Furthermore, KLK7 was detected in human colon adenocarcinomas, but it was absent in normal epithelia. KLK7 overexpression in HT29 colon cancer cells upon stable transfection with a KLK7 expression plasmid resulted in increased cell proliferation. Moreover, subcutaneous inoculation of transfected cells into nude mice led to increased tumor growth that was associated with increased tumor cell proliferation as reflected by a positive Ki-67 staining. Our results demonstrate the aberrant expression of KLK7 in colon cancer cells and tissues and its involvement in cell proliferation in vitro and in vivo. Thus, KLK7 may represent a potential therapeutic target for human colon tumorigenesis.

Samaan S, Lichner Z, Ding Q, et al.
Kallikreins are involved in an miRNA network that contributes to prostate cancer progression.
Biol Chem. 2014; 395(9):991-1001 [PubMed] Related Publications
MicroRNAs (miRNAs) are short RNA nucleotides that negatively regulate their target genes. They are differentially expressed in prostate cancer. Kallikreins are genes that encode serine proteases and are dysregulated in cancer. We elucidated a miRNA-kallikrein network that can be involved in prostate cancer progression. Target prediction identified 23 miRNAs that are dysregulated between high and low risk biochemical failure and are predicted to target five kallikreins linked to prostate cancer; KLK2, KLK3, KLK4, KLK14 and KLK15. We also identified 14 miRNAs that are differentially expressed between Gleason grades and are predicted to target these kallikreins. This demonstrates that kallikreins are downstream effectors through which miRNAs influence tumor progression. We show, through in-silico and experimental analysis, that miR-378/422a and its gene targets PIK3CG, GRB2, AKT3, KLK4 and KLK14 form an integrated circuit in prostate cancer. Our analysis shows that a minisatellite sequence in the kallikrein locus consists of a number of microsatellite repeats that represent predicted miRNA response elements. A number of kallikrein and non-kallikrein prostate cancer-related genes share these microsatellite repeats. We validated some of these interactions in prostate cancer cell lines. Finally, we provide preliminary evidence on the presence of a miRNA-mediated cross-talk between kallikreins, including a kallikrein pseudogene.

Devetzi M, Trangas T, Scorilas A, et al.
Parallel overexpression and clinical significance of kallikrein-related peptidases 7 and 14 (KLK7KLK14) in colon cancer.
Thromb Haemost. 2013; 109(4):716-25 [PubMed] Related Publications
Currently available colon cancer (CC) markers lack sensitivity and specificity. Kallikrein-related peptidases (KLKs) present a new class of biomarkers under investigation for diverse diseases, including cancer. KLKs are co-expressed in various tissues participating in proteolytic cascades. KLK7 in human tumours facilitates metastasis by degrading components of the extracellular matrix. KLK14 promotes tumourigenesis by activating proteinase-activated receptors. In the present study we examined the concomitant expression of KLK7 and KLK14 in245 colonic tissue specimens from 175 patients; 70 were pairs of cancerous-normal tissues, 31 were cancerous tissues and 74 were colonic adenomas. We used quantitative real-time PCR and proved that both genes are up-regulated in CC at the mRNA level. Receiver-operating characteristic (ROC) analysis of our results showed that both genes have discriminatory value between CC and adenoma tissues, with KLK14 obtaining greater distinguishing power (area under the curve [AUC]=0.708 for KLK14; AUC=0.669 for KLK7). Current work showed that the two genes are fairly co-expressed in all three types of colon tissues examined (normal rs=0.667, p<0.001, adenomas rs=0.373, p=0.001, carcinomas rs=0.478, p<0.001). KLK14 is associated with shorter disease-free survival (DFS) and overall survival (OS) of patients (p=0.003, p=0.016 respectively), whereas KLK7only with shorter DFS (p=0.004). KLK7 and KLK14 gene expression can be regarded as markers of poor prognosis for CC patients with discriminating power between CC and adenoma patients.

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.

Chung H, Hamza M, Oikonomopoulou K, et al.
Kallikrein-related peptidase signaling in colon carcinoma cells: targeting proteinase-activated receptors.
Biol Chem. 2012; 393(5):413-20 [PubMed] Related Publications
We hypothesized that kallikrein-related peptidase 14 (KLK14) is produced by colonic tumors and can promote tumorigenesis by activating proteinase-activated receptors (PARs). We found that KLK14 is expressed in human colon adenocarcinoma cells but not in adjacent cancer-free tissue; KLK14 mRNA, present in colon cancer, leads to KLK14 protein expression and secretion; and KLK14 signals viaPAR-2 in HT-29 cells to cause (1) receptor activation/internalization, (2) increases in intracellular calcium, (3) stimulation of ERK1/2/MAP kinase phosphorylation, and (4) cell proliferation. We suggest that KLK14, acting via PAR-2, represents an autocrine/paracrine regulator of colon tumorigenesis.

Lose F, Lawrence MG, Srinivasan S, et al.
The kallikrein 14 gene is down-regulated by androgen receptor signalling and harbours genetic variation that is associated with prostate tumour aggressiveness.
Biol Chem. 2012; 393(5):403-12 [PubMed] Related Publications
Kallikrein 14 (KLK14) has been proposed as a useful prognostic marker in prostate cancer, with expression reported to be associated with tumour characteristics such as higher stage and Gleason score. KLK14 tumour expression has also shown the potential to predict prostate cancer patients at risk of disease recurrence after radical prostatectomy. The KLKs are a remarkably hormone-responsive family of genes, although detailed studies of androgen regulation of KLK14 in prostate cancer have not been undertaken to date. Using in vitro studies, we have demonstrated that unlike many other prostatic KLK genes that are strictly androgen responsive, KLK14 is more broadly expressed and inversely androgen regulated in prostate cancer cells. Given these results and evidence that KLK14 may play a role in prostate cancer prognosis, we also investigated whether common genetic variants in the KLK14 locus are associated with risk and/or aggressiveness of prostate cancer in approximately 1200 prostate cancer cases and 1300 male controls. Of 41 single nucleotide polymorphisms assessed, three were associated with higher Gleason score (≥7): rs17728459 and rs4802765, both located upstream of KLK14, and rs35287116, which encodes a p.Gln33Arg substitution in the KLK14 signal peptide region. Our findings provide further support for KLK14 as a marker of prognosis in prostate cancer.

Zhang R, Shi H, Chen Z, et al.
Effects of kallikrein-related peptidase 14 gene inhibition by small interfering RNA in ovarian carcinoma cells.
Mol Med Rep. 2012; 5(1):256-9 [PubMed] Related Publications
Kallikrein-related peptidase 14 (KLK14) is a member of the tissue kallikrein family of proteases, which are associated with the pathogenesis of malignant tumors and are over-expressed in ovarian carcinoma. However, the mechanism through which KLK14 is implicated in ovarian cancer remains unclear. The aim of the present study was to investigate the effects of KLK14 gene inhibition by small interfering RNA (siRNA) on the growth, apoptosis and invasion of ovarian carcinoma cells in vitro. KLK14 siRNA was transiently transfected into SK-OV-3 and OVCAR-3 ovarian carcinoma cells for 48 h. The expression of KLK14 was determined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. Cell proliferation, apoptosis and invasion were examined by MTT, flow cytometry and Matrigel assay, respectively. The expression of survivin, caspase 9, cleaved caspase 3 and MMP2 protein was measured by Western blot analysis. The expression of KLK14 was significantly downregulated by siRNA in SK-OV-3 and OVCAR-3 cells at both the mRNA and protein levels. Following transfection with KLK14 siRNA, cell growth and invasion were significantly suppressed, and cell apoptosis was markedly induced. The expression of survivin and MMP2 was decreased, while the espression of caspase 9 and cleaved caspase 3 was increased. These results indicate that KLK14 is implicated in the malignant behavior of ovarian carcinoma cells in vitro, and that KLK14 may serve as a target for therapy of ovarian carcinoma.

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] Free Access to Full Article 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.

Papachristopoulou G, Avgeris M, Charlaftis A, Scorilas A
Quantitative expression analysis and study of the novel human kallikrein-related peptidase 14 gene (KLK14) in malignant and benign breast tissues.
Thromb Haemost. 2011; 105(1):131-7 [PubMed] Related Publications
Human kallikrein-related peptidase 14 gene (KLK14) is regulated by androgens and progestins. This gene is expressed in the central nervous system and endocrine tissues such as the breast, prostate and ovary. The differential KLK14 mRNA expression levels are related to several human neoplasias, among them breast cancer. The aim of this study was to analyse the KLK14 expression in breast tissues and to investigate its differential diagnostic and prognostic value in the mammary carcinomas. For this purpose, we isolated total RNA from 70 malignant and 33 benign specimens. After testing RNA quality, we synthesised cDNA by reverse transcription and applied a highly sensitive quantitative real-time PCR (qRT-PCR) method for KLK14 mRNA quantification using the SYBR Green® chemistry. HPRT1 was used as a reference gene and the BT20 breast cancer cell line as a calibrator. Relative quantification analysis was performed using the comparative CT method 2-ΔΔCT. KLK14 expression was detected in both types of breast tumours. However, a statistically significant increase of the KLK14 mRNA level was observed in the malignant, compared to the benign tumour samples (p<0.001), highlighting its value in discriminating these breast lesions. Elevated KLK14 expression profiles were associated with higher tumour grade (p=0.043) and size (p=0.007) in cancerous samples. Furthermore, KLK14 mRNA expression showed negative correlation in a statistically significant manner with estrogen receptor status (p=0.024). In accordance with logistic regression models (p=0.012) and receiver-operating-characteristics analysis (p<0.001), KLK14 gene expression could be evaluated as a putative independent diagnostic biomarker in breast tumour biopsies.

Ricciardelli C, Bianco-Miotto T, Jindal S, et al.
Comparative biomarker expression and RNA integrity in biospecimens derived from radical retropubic and robot-assisted laparoscopic prostatectomies.
Cancer Epidemiol Biomarkers Prev. 2010; 19(7):1755-65 [PubMed] Related Publications
BACKGROUND: Knowledge of preanalytic conditions that biospecimens are subjected to is critically important because novel surgical procedures, tissue sampling, handling, and storage might affect biomarker expression or invalidate tissue samples as analytes for some technologies.
METHODS: We investigated differences in RNA quality, gene expression by quantitative real-time PCR, and immunoreactive protein expression of selected prostate cancer biomarkers between tissues from retropubic radical prostatectomy (RRP) and robot-assisted laparoscopic prostatectomy (RALP). Sections of tissue microarray of 23 RALP and 22 RRP samples were stained with antibodies to androgen receptor (AR) and prostate-specific antigen (PSA) as intersite controls, and 14 other candidate biomarkers of research interest to three laboratories within the Australian Prostate Cancer BioResource tissue banking network. Quantitative real-time PCR was done for AR, PSA (KLK3), KLK2, KLK4, and HIF1A on RNA extracted from five RALP and five RRP frozen tissue cores.
RESULTS: No histologic differences were observed between RALP and RRP tissue. Biomarker staining grouped these samples into those with increased (PSA, CK8/18, CKHMW, KLK4), decreased (KLK2, KLK14), or no change in expression (AR, ghrelin, Ki67, PCNA, VEGF-C, PAR2, YB1, p63, versican, and chondroitin 0-sulfate) in RALP compared with RRP tissue. No difference in RNA quality or gene expression was detected between RALP and RRP tissue.
CONCLUSIONS: Changes in biomarker expression between RALP and RRP tissue exist at the immunoreactive protein level, but the etiology is unclear.
IMPACT: Future studies should account for changes in biomarker expression when using RALP tissues, and mixed cohorts of RALP and RRP tissue should be avoided.

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.

Angelopoulou K, Prassas I, Yousef GM
The canine kallikrein-related peptidase 14: structural characterization, alternative splicing and differential expression in mammary cancer.
Gene. 2009; 446(2):68-74 [PubMed] Related Publications
Human kallikrein-related peptidases (KLKs) represent a family of 15 serine proteases with diverse roles in many physiological and pathological processes, including carcinogenesis. In the dog, only two KLK genes are known; dKLK1 and canine arginine esterase. Recently, 12 other genes have been predicted using computational methods, but none of them has ever been experimentally validated in canine tissues. In this study we investigated the expression of Canis familiaris KLK14, (CANFA)KLK14, in normal and cancerous mammary tissues. First, it was demonstrated that the in-silico determined canine KLK14 mRNA (GenBank accession no: XM_541464) has been wrongfully predicted on its 5'-end (nucleotides 1-88). The (CANFA)KLK14 mRNA sequence presented here, has high homology to its human counterpart and exhibits all defining-KLK features. In addition to the classical form of the gene, five splice variants were also identified. The splicing events involved 5'-truncation or complete elimination of exon 4 and/or retention of intron I. All encoded protein products of the splice variants were predicted to be truncated and catalytically inactive. The classical form and variant 3 were almost ubiquitously expressed in both normal and neoplastic tissues. Variant 1 was predominantly detected in normal tissues. The classical form and variants 1 and 2 exhibited lower expression levels in tumor compared to normal tissues. Moreover, an Ile155Asn polymorphism was identified. This is the first report on the structural characterization, alternative splicing and tissue expression of canine KLK14 mRNA. These findings may form the basis for the establishment of comparative studies investigating KLK functions in health and disease using the dog as a model.

Paliouras M, Diamandis EP
Androgens act synergistically to enhance estrogen-induced upregulation of human tissue kallikreins 10, 11, and 14 in breast cancer cells via a membrane bound androgen receptor.
Mol Oncol. 2008; 1(4):413-24 [PubMed] Free Access to Full Article Related Publications
The regulation of gene expression by steroid hormones plays an important role in the normal development and function of many organs, as well as in the pathogenesis of endocrine-related cancers, especially breast cancer. However, clinical data suggest that combined testosterone and estrogen treatments on post-menopausal women increase the risk of breast cancer. Experiments have shown that many, if not all kallikreins are under steroid hormone regulation in breast cancer cell lines. Their implication as prognostic and diagnostic markers has also been well-documented. Thus, we investigated the effect of combined hormone stimulation with androgens and 17beta-estradiol on the ductal caricinoma cell line BT474. This cell line has been shown to be sensitive to both, androgens (secreting PSA) and estrogens (secreting a number of kallikreins including KLK10, 11, and KLK14). We found that PSA expression was downregulated upon combined hormone stimulation, confirming reports that estrogen can antagonize and block the activity of the androgen receptor. Upon analysis of estrogen-sensitive kallikreins 10, 11, and 14, all showed to be synergistically enhanced in their expression three- to fourfold, upon joint hormone treatment versus individual hormone stimulation. The enhancement is dependent upon the action of androgens as treatment with the androgen receptor antagonist cyproterone actetate normalized the expression of KLK10, 11, and KLK14 to estrogen-stimulation levels. The synergistic effects between estrogens and androgens on estrogen-sensitive genes may have implications on the role of the kallikreins in associated risk of breast cancer and progression.

Lai J, Myers SA, Lawrence MG, et al.
Direct progesterone receptor and indirect androgen receptor interactions with the kallikrein-related peptidase 4 gene promoter in breast and prostate cancer.
Mol Cancer Res. 2009; 7(1):129-41 [PubMed] Related Publications
Kallikrein 4 (KLK4) is a member of the human KLK gene family of serine proteases, many of which are implicated in hormone-dependent cancers. Like other KLKs, such as KLK3/PSA and KLK2, KLK4 gene expression is also regulated by steroid hormones in hormone-dependent cancers, although the transcriptional mechanisms are ill defined. Here, we have investigated the mechanisms mediating the hormonal regulation of KLK4 in breast (T47D) and prostate (LNCaP and 22Rv1) cancer cells. We have shown that KLK4 is only expressed in breast and prostate cancers that express the progesterone receptor (PR) and androgen receptor (AR), respectively. Expression analysis in PR- and AR-positive cells showed that the two predominant KLK4 variants that use either TIS1 or TIS2a/b are both up-regulated by progesterone in T47D cells and androgens in LNCaP cells. Two putative hormone response elements, K4.pPRE and K4.pARE at -2419 bp and -1005 bp, respectively, were identified in silico. Electrophoretic mobility shift assays and luciferase reporter experiments suggest that neither K4.pARE nor approximately 2.8 kb of the KLK4 promoter interacts directly with the AR to mediate KLK4 expression in LNCaP and 22Rv1 cells. However, we have shown that K4.pPRE interacts directly with the PR to up-regulate KLK4 gene expression in T47D cells. Further, chromatin immunoprecipitation experiments showed a time-dependent recruitment of the PR to the KLK4 promoter (-2496 to -2283), which harbors K4.pPRE. This is the first study to show that progesterone-regulated KLK4 expression in T47D cells is mediated partly by a hormone response element (K4.pPRE) at -2419 bp.

Planque C, Bléchet C, Ayadi-Kaddour A, et al.
Quantitative RT-PCR analysis and immunohistochemical localization of the kallikrein-related peptidases 13 and 14 in lung.
Biol Chem. 2008; 389(6):781-6 [PubMed] Related Publications
Expression of the KLK13 and KLK14 genes was examined at the mRNA and protein levels in a cohort of 57 patients with non-small-cell lung cancer (NSCLC). The mRNA levels, assessed by real-time RT-PCR, were significantly different in malignant tissues compared to adjacent non-malignant tissues (KLK13, p=0.006; KLK14, p=0.022). KLK13 and KLK14 mRNA overexpression in tumors (1/3 of the patients) was associated with a positive nodal status in multivariate analysis (p=0.018 and p=0.069, respectively). KLK13 and KLK14 were localized in the cytoplasm of epithelial cells of normal bronchus and NSCLC, as determined by immunohistochemistry. Moreover, positive staining was significantly associated with adenocarcinoma histotype (KLK13, p=0.014) and tumor size (KLK14, p=0.048). Although the results are marginally significant, patients with high KLK13 expression at the mRNA or protein level had lower overall survival.

Paliouras M, Diamandis EP
Intracellular signaling pathways regulate hormone-dependent kallikrein gene expression.
Tumour Biol. 2008; 29(2):63-75 [PubMed] Related Publications
OBJECTIVES: Our aim was to examine how certain signal transduction pathways influence the regulation of hormone-dependent kallikrein (KLK) gene expression in androgen-sensitive breast cancer cell lines.
METHODS: We used the breast cancer cell lines T47D and BT474, treated with steroid hormones or various pathway inhibitors. KLKs were quantified by ELISA. RT-PCR, Western blots and immunoprecipitations were used to assess transcript and protein levels.
RESULTS: PSA, KLK10, KLK11, KLK13 and KLK14 are upregulated upon androgen stimulation in the T47D cell line. The expression of PSA, KLK10 and KLK11 was repressed by the MEK1/2 inhibitor U0126 and the PI3K inhibitor Wortmannin in the presence of the hormone, thus implicating the RAS/MEK/ERK and PI3K/AKT signaling pathways in regulating hormone-dependent KLK gene activation. Analysis of inhibitor-treated cells revealed changes in c-MYC expression with a pattern parallel to KLK gene expression. Chromatin immunoprecipitations identified androgen-dependent recruitment of specific transcription factors to the KLK proximal promoters, including c-MYC binding to PSA and KLK11.
CONCLUSION: The hormone-specific upregulation of PSA, KLK10 and KLK11 in the breast cancer cell line T47D is dependent on major intracellular signaling pathways. This work provides a new dimension to the regulation of these cancer-related genes and the potential for new therapeutic targeting strategies.

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.

Rajapakse S, Takahashi T
Expression and enzymatic characterization of recombinant human kallikrein 14.
Zoolog Sci. 2007; 24(8):774-80 [PubMed] Related Publications
Human kallikrein 14 (KLK14) is a member of the human kallikrein gene family of serine proteases, and its protein, hK14, has recently been suggested to serve as a new ovarian and breast cancer marker. To gain insights into hK14's physiological functions, the active recombinant enzyme was obtained in an enzymatically pure state for biochemical and enzymatic characterizations. We studied its substrate specificity and behavior to various protease inhibitors, and identified candidate physiological substrates. hK14 had trypsin-like activity with a strong preference for Arg over Lys in the P1 position, and its activity was inhibited by typical serine protease inhibitors. The protease degraded casein, fibronectin, gelatin, collagen type I, collagen type IV, fibrinogen, and high-molecular-weight kininogen. Furthermore, it rapidly hydrolyzed insulin-like growth factor binding protein-3 (IGFBP-3). These findings suggest that hK14 may be implicated in tumor progression in ovarian carcinoma.

Yousef GM, Borgoño CA, Michael IP, et al.
Molecular cloning of a new gene which is differentially expressed in breast and prostate cancers.
Tumour Biol. 2004 May-Jun; 25(3):122-33 [PubMed] Related Publications
OBJECTIVE: The chromosomal region 19q13 is non-randomly rearranged in many solid tumors.
METHODS: Using the positional candidate gene approach, we cloned a new gene, tentatively named cancer-associated gene (CAG), which is differentially expressed in breast and prostate cancers.
RESULTS: The gene is formed of 3 exons and 2 intervening introns. Its coding region is 1,047 bp in length and is predicted to encode a 348-amino-acid polypeptide. The new gene maps to chromosome 19q13.4 and is located 14 kb telomeric to the kallikrein gene locus (KLK14 gene) and 17 kb centromeric from the Siglec family of genes (Siglec-9). The gene is expressed in a wide variety of tissues including the brain, colon, kidney and pancreas. The CAG protein shows a high degree of conservation among species and phylogenetically is most closely related to its mouse ortholog. In silico analysis indicates that this gene is differentially expressed in a variety of tumors including brain, colon, ovarian and prostate cancers.
CONCLUSIONS: Our preliminary experimental data show that CAG is upregulated in prostate cancer tissues compared to normal prostatic tissues. CAG also appears to be downregulated in breast cancer tissues. The physiological function of the CAG protein is currently unknown.

Borgoño CA, Grass L, Soosaipillai A, et al.
Human kallikrein 14: a new potential biomarker for ovarian and breast cancer.
Cancer Res. 2003; 63(24):9032-41 [PubMed] Related Publications
Human kallikrein gene 14 (KLK14) is a recently discovered member of the tissue kallikrein family of secreted serine proteases, which includes hK3/prostate-specific antigen, the best cancer biomarker to date. Given that KLK14 is hormonally regulated, differentially expressed in endocrine-related cancers, and a prognostic marker for breast and ovarian cancer at the mRNA level, we hypothesize that its encoded protein, hK14, like hK3/prostate-specific antigen, may constitute a new biomarker for endocrine-related malignancies. The objective of this study was to generate immunological reagents for hK14, to develop an ELISA and immunohistochemical techniques to study its expression in normal and cancerous tissues and biological fluids. Recombinant hK14 was produced in Pichia pastoris, purified by affinity chromatography, and injected into mice and rabbits for polyclonal antibody generation. Using the mouse and rabbit antisera, a sandwich-type immunofluorometric ELISA and immunohistochemical methodologies were developed for hK14. The ELISA was sensitive (detection limit of 0.1 micro g/liter), specific for hK14, linear from 0 to 20 micro g/liter with between-run and within-run coefficients of variation of <10%. hK14 was quantified in human tissue extracts and biological fluids. Highest levels were observed in the breast, skin, prostate, seminal plasma, and amniotic fluid, with almost undetectable levels in normal serum. hK14 concentration was higher in 40% of ovarian cancer tissues compared with normal ovarian tissues. Serum hK14 levels were elevated in a proportion of patients with ovarian (65%) and breast (40%) cancers. Immunohistochemical analyses indicated strong cytoplasmic staining of hK14 by the epithelial cells of normal and malignant skin, ovary, breast, and testis. In conclusion, we report the first ELISA and immunohistochemical assays for hK14 and describe its distribution in tissues and biological fluids. Our preliminary data indicate that hK14 is a potential biomarker for breast and ovarian cancers.

Yousef GM, Stephan C, Scorilas A, et al.
Differential expression of the human kallikrein gene 14 (KLK14) in normal and cancerous prostatic tissues.
Prostate. 2003; 56(4):287-92 [PubMed] Related Publications
BACKGROUND: Many members of the human kallikrein gene family are differentially expressed in cancer and a few have potential as diagnostic/prognostic markers. KLK14 is a newly discovered human kallikrein gene that is mainly expressed in the central nervous system and endocrine tissues. Since KLK14 was found to be regulated by steroid hormones in prostate cancer cell lines, we hypothesized that it will be differentially expressed in prostate cancer tissues compared to their normal counterparts.
METHODS: Matched prostate tissue samples from the cancerous and non-cancerous parts of the same prostates were obtained from 100 patients who underwent radical prostatectomy. Quantitative analysis of KLK14 expression levels were performed by real-time RT-PCR using SYBR Green I dye on the LightCycler trade mark system. Associations with clinico-pathological parameters were analyzed.
RESULTS: KLK14 overexpression in the cancerous compared to non-cancerous tissue was found in 74% of patients (P < 0.001). Mean level of expression was 154 arbitrary units (Au) in cancerous tissues and 14.2 Au in the non-cancerous tissues. The ratio of the cancerous to non-cancerous KLK14 expression values was higher in patients with late stage (stage III) compared to stage II (P = 0.002), and in grade 3 compared to grade 1/2 tumors (P = 0.001). A statistically significant increase was also observed in patients with higher in Gleason score (>6) compared to Gleason score = 6 tumors (P = 0.027). No correlation was found between KLK14 tissue expression levels and serum prostate-specific antigen.
CONCLUSIONS: KLK14 expression is significantly higher in cancerous compared to non-cancerous prostatic tissue. The up-regulation of the KLK14 gene in advanced and more aggressive tumors may indicate a possible role for the hK14 protein in tumor spread and opens the possibility of hK14 being a candidate new marker for prostate cancer diagnosis and prognosis.

Luo LY, Yousef G, Diamandis EP
Human tissue kallikreins and testicular cancer.
APMIS. 2003; 111(1):225-32; discussion 232-3 [PubMed] Related Publications
Human tissue kallikreins are fifteen homologous genes encoding for secreted serine proteases and residing tandemly on chromosome 19q13.4. These enzymes are highly expressed in a variety of tissues and participate in diverse physiological processes. Human tissue kallikreins were found to be associated with several malignancies, especially endocrine-related cancers, including prostate, ovarian, breast and testicular cancer. In testicular germ cell tumors, some tissue kallikrein genes, including KLK5, KLK10, KLK13 and KLK14, were found to be significantly down-regulated. Tissue-specific splice variant forms of some kallikreins have been identified in the testis. In this paper, the expression of KLK5, KLK10, KLK13 and KLK14 in testicular cancer and their possible roles during testicular cancer development, as well as their clinical applications are briefly reviewed.

Yousef GM, Polymeris ME, Yacoub GM, et al.
Parallel overexpression of seven kallikrein genes in ovarian cancer.
Cancer Res. 2003; 63(9):2223-7 [PubMed] Related Publications
Recent evidence suggests that many members of the human kallikrein (KLK) gene family are differentially regulated in ovarian cancer and have potential as diagnostic and/or prognostic markers. We used the serial analysis of gene expression and expressed sequence tag databases of the Cancer Genome Anatomy Project to perform in silico analyses of the expression pattern of the 15 human KLK genes in normal and cancerous ovarian tissues and cell lines. We found that seven KLK genes (KLK5, KLK6, KLK7, KLK8, KLK10, KLK11, and KLK14) are up-regulated in ovarian cancer. Probing 2 normal and 10 ovarian cancer serial analysis of gene expression libraries with gene-specific tags for each KLK indicated that whereas no expression was detected in any normal libraries (with the exception of KLK10 and KLK11), these KLKs were found to be expressed with moderate densities (103-408 tags per million) in 40-60% of the ovarian cancer libraries analyzed. These data were verified by screening the expressed sequence tag databases, where 78 of 79 mRNA clones isolated for these genes were from ovarian cancer libraries. X-profiler comparison of the pools of normal and cancerous ovaries identified a significant difference in expression levels for six of the seven KLKs. We experimentally verified the overexpression of six KLK proteins in cancer versus normal or benign tissues with highly sensitive and specific immunofluorometric assays. A statistically significant stepwise increase in protein levels was found among normal, benign, and cancerous ovarian tissues. The expression of five KLKs showed a strong degree of correlation at the protein level, suggesting the existence of a common mechanism or pathway that controls the expression of this group of adjacent genes during ovarian cancer progression.

Yousef GM, Fracchioli S, Scorilas A, et al.
Steroid hormone regulation and prognostic value of the human kallikrein gene 14 in ovarian cancer.
Am J Clin Pathol. 2003; 119(3):346-55 [PubMed] Related Publications
To study KLK14 gene expression in endocrine-related cancers, we studied its hormonal regulation in breast and ovarian cancer cell lines. Our kinetic and blocking experiments suggest that this up-regulation is mediated through the androgen receptor. We then studied the expression of KLK14 by quantitative reverse transcriptase-polymerase chain reaction in 155 consecutive ovarian tumors and correlated these findings with clinicopathologic parameters, response to chemotherapy, and survival. A stepwise reduction was observed in the levels of KLK14 messenger RNA in normal, benign, and cancerous tissues (P < .001). Expression levels were significantly higher in patients with early stage disease and optimal debulking and in patients who responded to chemotherapy. Kaplan-Meier survival curves demonstrated longer progression-free and overall survival in patients with KLK14-positive tumors than in patients with KLK14-negative tumors (P < .001). When all other prognostic variables were controlled in the multivariate analysis, KLK14 retained its prognostic significance (progression-free and overall survival, respectively, hazard ratios, 0.43 and 0.53; P = .027 and .014). A weak negative correlation was found between KLK14 expression and serum CA-125. KLK14 is a new, independent, and favorable prognostic marker for ovarian cancer.

Kyriakopoulou LG, Yousef GM, Scorilas A, et al.
Prognostic value of quantitatively assessed KLK7 expression in ovarian cancer.
Clin Biochem. 2003; 36(2):135-43 [PubMed] Related Publications
BACKGROUND: Among females, ovarian cancer is the sixth most common malignancy. Women with ovarian cancer have poor overall survival rates, largely because the disease is often diagnosed at an advanced, less curable stage. Several lines of evidence suggest that members of the kallikrein family are involved in various malignancies such as prostate (PSA, KLK2, KLK15), ovarian (KLK4, KLK5, KLK6, KLK8, KLK10), and breast cancer (KLK10, KLK13, KLK14). Recent evidence has indicated that expression of KLK7 appears to be increased in ovarian cancer. We hypothesized that overexpression of the KLK7 gene in ovarian cancer may serve as a prognostic marker of the disease.
METHODS: Using the LightCycler technology we quantified the level of KLK7 mRNA expression in 125 ovarian tumors. Different disease stages and tumor grades were analyzed. Univariate and multivariate analyses were performed to establish the associations between clinicopathological parameters and KLK7 expression.
RESULTS: We here report that patients with KLK7-negative tumors have a significantly higher disease-free survival than patients with KLK7-positive tumors. KLK7 expression levels were significantly higher in patients with grade 3 than in patients with grade 1 to 2 tumors (p = 0.030). KLK7 status also correlated with size of residual tumor postsurgery. KLK7 expression is an independent predictor of both disease-free and overall survival for patients with low grade tumors. In this subgroup of patients the hazard ratios for disease-free and overall survival were 3.28 and 3.09, respectively. Similarly, patients who had undergone optimal debulking but harbored KLK7-positive tumors had a high hazard ratio (HR) for relapse (HR = 8.2) and death (HR = 4.6).
CONCLUSIONS: We conclude that higher KLK7 expression in ovarian cancer tissue is associated with poorer prognosis of ovarian cancer patients, especially those with lower grade disease and those who have been optimally debulked.

Yousef GM, Borgoño CA, Scorilas A, et al.
Quantitative analysis of human kallikrein gene 14 expression in breast tumours indicates association with poor prognosis.
Br J Cancer. 2002; 87(11):1287-93 [PubMed] Free Access to Full Article Related Publications
KLK14 (formerly known as KLK-L6) is a recently identified member of the human kallikrein gene family. This family harbours several genes aberrantly expressed in various cancers as well as established (PSA/hK3, hK2) and potential (hK6, hK10) cancer markers. Similar to other kallikrein genes, KLK14 was found to be regulated by steroid hormones, particularly androgens and progestins, in breast and ovarian cancer cell lines. Preliminary studies indicated that KLK14 is differentially expressed in breast, ovarian, prostatic and testicular tumours. Given the above, we determined the prognostic significance of KLK14 expression in breast cancer. We studied KLK14 expression in 178 histologically confirmed epithelial breast carcinomas by quantitative reverse transcription-polymerase chain reaction and correlated with clinicopathological variables (tumour stage, grade, histotype etc.) and with outcome (disease-free survival and overall survival), monitored over a median of 76 months. KLK14 mRNA levels ranged from 0 to 1,219 arbitrary units in breast cancer tissues, with a mean+/-s.e. of 136+/-22. An optimal cutoff value of 40.5 arbitrary units was selected, to categorise tumours as KLK14-positive or negative. Higher concentrations of KLK14 mRNA were more frequently found in patients with advanced stage (III) disease (P=0.032). No statistically significant association was found between KLK14 and the other clinicopathological variables. KLK14 overexpression was found to be a significant predictor of decreased disease-free survival (hazard ratio of 2.31, P=0.001) and overall survival (hazard ratio of 2.21, P=0.005). Cox multivariate analysis indicated that KLK14 was an independent prognostic indicator of disease-free survival and overall survival. KLK14 also has independent prognostic value in subgroups of patients with a tumour size

Yousef GM, Magklara A, Chang A, et al.
Cloning of a new member of the human kallikrein gene family, KLK14, which is down-regulated in different malignancies.
Cancer Res. 2001; 61(8):3425-31 [PubMed] Related Publications
Kallikreins (KLKs) belong to the serine protease family of proteolytic enzymes. Human pancreatic/renal KLK (KLK1) encodes for an enzyme that is involved in posttranslational processing of polypeptide precursors. The function of the other members of this gene family is currently unknown, but growing evidence suggests that many KLKs are implicated in carcinogenesis. By using the positional candidate approach, we were able to identify a new human KLK-like gene, KLK14 (also known as KLK-L6). This new gene maps to chromosome 19q13.3-q13.4 and is formed of seven exons (two untranslated and five coding exons) and six intervening introns. KLK14 was defined as a KLK gene based on structural and mapping criteria, in relation to other known KLK genes. KLK14 is expressed in a variety of tissues, but the highest levels of KLK14 are found in the central nervous system, including brain, cerebellum, and spinal cord. Our preliminary results show that KLK14 is down-regulated, at the mRNA level, in breast, testicular, prostatic, and ovarian cancer.

Diamandis EP, Yousef GM, Luo LY, et al.
The new human kallikrein gene family: implications in carcinogenesis.
Trends Endocrinol Metab. 2000; 11(2):54-60 [PubMed] Related Publications
The traditional human kallikrein gene family consists of three genes, namely KLK1 [encoding human kallikrein 1 (hK1) or pancreatic/renal kallikrein], KLK2 (encoding hK2, previously known as human glandular kallikrein 1) and KLK3 [encoding hK3 or prostate-specific antigen (PSA)]. KLK2 and KLK3 have important applications in prostate cancer diagnostics and, more recently, in breast cancer diagnostics. During the past two to three years, new putative members of the human kallikrein gene family have been identified, including the PRSSL1 gene [encoding normal epithelial cell-specific 1 gene (NES1)], the gene encoding zyme/protease M/neurosin, the gene encoding prostase/KLK-L1, and the genes encoding neuropsin, stratum corneum chymotryptic enzyme and trypsin-like serine protease. Another five putative kallikrein genes, provisionally named KLK-L2, KLK-L3, KLK-L4, KLK-L5 and KLK-L6, have also been identified. Many of the newly identified kallikrein-like genes are regulated by steroid hormones, and a few kallikreins (NES1, protease M, PSA) are known to be downregulated in breast and possibly other cancers. NES1 appears to be a novel breast cancer tumor suppressor protein and PSA a potent inhibitor of angiogenesis. This brief review summarizes recent developments and possible applications of the newly defined and expanded human kallikrein gene locus.

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