Research IndicatorsGraph generated 30 August 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex
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).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: KLK10 (cancer-related)
Panagopoulou M, Karaglani M, Balgkouranidou I, et al.Circulating cell-free DNA in breast cancer: size profiling, levels, and methylation patterns lead to prognostic and predictive classifiers.
Oncogene. 2019; 38(18):3387-3401 [PubMed
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Blood circulating cell-free DNA (ccfDNA) is a suggested biosource of valuable clinical information for cancer, meeting the need for a minimally-invasive advancement in the route of precision medicine. In this paper, we evaluated the prognostic and predictive potential of ccfDNA parameters in early and advanced breast cancer. Groups consisted of 150 and 16 breast cancer patients under adjuvant and neoadjuvant therapy respectively, 34 patients with metastatic disease and 35 healthy volunteers. Direct quantification of ccfDNA in plasma revealed elevated concentrations correlated to the incidence of death, shorter PFS, and non-response to pharmacotherapy in the metastatic but not in the other groups. The methylation status of a panel of cancer-related genes chosen based on previous expression and epigenetic data (KLK10, SOX17, WNT5A, MSH2, GATA3) was assessed by quantitative methylation-specific PCR. All but the GATA3 gene was more frequently methylated in all the patient groups than in healthy individuals (all p < 0.05). The methylation of WNT5A was statistically significantly correlated to greater tumor size and poor prognosis characteristics and in advanced stage disease with shorter OS. In the metastatic group, also SOX17 methylation was significantly correlated to the incidence of death, shorter PFS, and OS. KLK10 methylation was significantly correlated to unfavorable clinicopathological characteristics and relapse, whereas in the adjuvant group to shorter DFI. Methylation of at least 3 or 4 genes was significantly correlated to shorter OS and no pharmacotherapy response, respectively. Classification analysis by a fully automated, machine learning software produced a single-parametric linear model using ccfDNA plasma concentration values, with great discriminating power to predict response to chemotherapy (AUC 0.803, 95% CI [0.606, 1.000]) in the metastatic group. Two more multi-parametric signatures were produced for the metastatic group, predicting survival and disease outcome. Finally, a multiple logistic regression model was constructed, discriminating between patient groups and healthy individuals. Overall, ccfDNA emerged as a highly potent predictive classifier in metastatic breast cancer. Upon prospective clinical evaluation, all the signatures produced could aid accurate prognosis.
Reyes I, Reyes N, Suriano R, et al.Gene expression profiling identifies potential molecular markers of papillary thyroid carcinoma.
Cancer Biomark. 2019; 24(1):71-83 [PubMed
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BACKGROUND: Thyroid cancer is the most common endocrine malignancy worldwide, with the predominant form papillary thyroid carcinoma (PTC) representing approximately 80% of cases.
OBJECTIVE: This study was addressed to identify potential genes and pathways involved in the pathogenesis of PTC and potential novel biomarkers for this disease.
METHODS: Gene expression profiling was carried out by DNA microarray technology. Validation of microarray data by qRT-PCR, western blot, and enzyme linked immunosorbent assay was also performed in a selected set of genes and gene products, with the potential to be used as diagnostic or prognostic biomarkers, such as those associated with cell adhesion, extracellular matrix (ECM) remodeling and immune/inflammatory response.
RESULTS: In this study we found that upregulation of extracellular activities, such as proteoglycans, ECM-receptor interaction, and cell adhesion molecules, were the most prominent feature of PTC. Significantly over-expressed genes included SDC1 (syndecan 1), SDC4 (syndecan 4), KLK7 (kallikrein-related peptidase 7), KLK10 (kallikrein-related peptidase 10), SLPI (secretory leukocyte peptidase inhibitor), GDF15 (growth/differentiation factor-15), ALOX5 (arachidonate 5-lipoxygenase), SFRP2 (secreted Frizzled-related protein 2), among others. Further, elevated KLK10 levels were detected in patients with PTC. Many of these genes belong to KEGG pathway "Proteoglycans in cancer".
CONCLUSIONS: Using DNA microarray analysis allowed the identification of genes and pathways with known important roles in malignant transformation, and also the discovery of novel genes that may be potential biomarkers for PTC.
The comprehensive screening of intracellular and extracellular microRNAs was performed to identify novel tumor suppressors. We found that miR-8073 was present in exosome and predominantly exported from colorectal cancer cells. Treatment with a synthetic miR-8073 mimic resulted in a dramatic decrease in the proliferation of various types of cancer cells, which was not observed in similarly treated normal cells. As little is known about the biological functions of miR-8073, its target mRNAs were analyzed by both mRNA expression and in silico sequence analyses, leading to five probable target candidates (FOXM1, MBD3, CCND1, KLK10, and CASP2) that enhance survival during the regulation of the cell cycle, cell proliferation, and apoptosis. We experimentally confirmed that miR-8073 binds the 3'-UTR of each of these mRNA target candidates and that the introduction of a synthetic miR-8073 mimic into cancer cells reduced levels of protein expression. Finally, the antiproliferative effects of miR-8073 were validated in vivo: the subcutaneous injection of a synthetic miR-8073 mimic suppressed colorectal tumor volume to 43% in tumor-bearing xenografted mice. These results suggest that because miR-8073 binds, and thus reduces the levels of, these oncogenic targets, cancer cells must actively downregulate miR-8073 as a survival mechanism. The introduction of miR-8073 into tumors could thus inhibit tumor growth, indicating its great potential for cancer therapeutics.
Xu LJ, Duan Y, Wang P, Yin HQMiR-199b-5p promotes tumor growth and metastasis in cervical cancer by down-regulating KLK10.
Biochem Biophys Res Commun. 2018; 503(2):556-563 [PubMed
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MiR-199 b-5p and kallikrein-related peptidase 10 (KLK10) are related to various disease processes and pathogenesis. However, little is known about the molecular mechanisms of miR-199 b-5p and KLK10 in human cervical cancer. In the present study, we found that miR-199 b-5p was highly expressed in cervical cancer tissues and cell lines, and was positively correlated with overall survival (OS) and progression-free survival (PFS), higher incidences of larger tumor sizes, late International Federation of Gynecology and Obstetrics (FIGO) stages and preoperative metastasis. Further, we found that transfecting miR-199 b-5p mimics into cervical cancer cells promoted tumor progression through enhancing the cell viability, migration, and suppressing apoptosis by using 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT), wound healing and flow cytometry analysis. Luciferase reporter assays indicated that miR-199 b-5p targeted the 3'-untranslated region (3'-UTR) of KLK10. Over-expressing KLK10 reversed the role of miR-199 b-5p in accelerating cervical cancer progression. Suppressing miR-199 b-5p expressions improved apoptosis and reduced the cell viability, while the process was reversed in KLK10-knockdown cervical cancer cells. In vivo analysis verified the effects of miR-199 b-5p on promoting cervical cancer progression, accompanied with reduced KLK10 expressions. In summary, we identified that miR-199 b-5p played as a tumor promoter in cervical cancer cell growth by targeting KLK10, and miR-199 b-5p might function as a novel biomarker for diagnosis or therapeutic targets of human cervical cancer.
BACKGROUND: KLK10 exon 3 hypermethylation correlated to tumor-specific lack of KLK10 expression in cancer cell lines and primary tumors. In the present study we investigate the possible role of KLK10 exon 3 methylation in ovarian tumor diagnosis and prognosis.
RESULTS: Qualitative methylation-specific PCR (MSP) results did not show statistically significant differences in patient group samples (normal and tumor) where all samples were positive only for the unmethylated-specific PCR except for two malignant samples that were either doubly positive (serous carcinoma) or doubly negative (Sertoli-Leydig cell tumor) for the two MSP tests. However, KLK10 exon 3 unmethylated PCR product concentration (ng/μl) showed statistically significant differences in benign and malignant patient group samples; mean ± SD (n): tumor: 0.077 ± 0.035 (14) and 0.047 ± 0.021 (15), respectively, p-value = 0.011; and normal: 0.094 ± 0.039 (7) and 0.046 ± 0.027 (6), respectively, p-value = 0.031. Moreover, ROC curve analysis of KLK10 exon 3 unmethylated PCR product concentration in overall patient group samples showed good diagnostic ability (AUC = 0.778; p-value = 0.002). Patient survival (living and died) showed statistically significant difference according to preoperative serum CA125 concentration (U/ml); median (n): 101.25 (10) and 1252 (5), respectively, p-value = 0.037, but not KLK10 exon 3 unmethylated PCR product concentration (ng/μl) in overall malignant patient samples; mean ± SD (n): 0.042 ± 0.015 (14) and 0.055 ± 0.032 (7), p-value = 0.228.
CONCLUSION: To the best of our knowledge, this is the first report on KLK10 exon 3 unmethylated PCR product concentration as potential early epigenetic diagnostic marker in primary ovarian tumors. Taken into account the limitations in our study (small sample size and semi-quantitative PCR product analysis) further studies are strongly recommended.
Cao XY, Zhang XX, Yang MW, et al.Aberrant upregulation of KLK10 promotes metastasis via enhancement of EMT and FAK/SRC/ERK axis in PDAC.
Biochem Biophys Res Commun. 2018; 499(3):584-593 [PubMed
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Pancreatic Ductal Adenocarcinoma (PADC) metastasis is the leading cause of morality of this severe malignant tumor. Proteases are key players in the degradation of extracellular matrix which promotes the cascade of tumor metastasis. As a kind of serine proteases, the kallikrein family performs vital function on the cancer proteolysis scene, which have been proved in diverse malignant tumors. However, the specific member of kallikrein family and its function in PDAC remain unexplored. In this study, by data mining of GEO datasets, we have identified KLK10 is upregulated gene in PDAC. We found that KLK10 was significantly overexpressed in tissues of pancreatic intraepithelial neoplasia (PanIN) and PDAC from Pdx1-Cre; LSL-Kras
Tang L, Long Z, Zhao N, et al.NES1/KLK10 promotes trastuzumab resistance via activation of PI3K/AKT signaling pathway in gastric cancer.
J Cell Biochem. 2018; 119(8):6398-6407 [PubMed
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Trastuzumab, a humanized antibody targeting human epidermal growth factor receptor 2 (HER2), exhibits remarkable therapeutic efficacy against HER2-positive gastric cancer. Acquired resistance to trastuzumab remains a barrier to patient survival and the mechanisms underlying this are still not well understood. The normal epithelial cell-specific-1 (NES1) gene, also named as KLK10, is recognized as a potential therapeutic target for reversing trastuzumab resistance. The aim of this study was to explore the potential role of KLK10 in trastuzumab resistance (TR) gastric cancer cells. We found that KLK10 was significantly upregulated in trastuzumab-resistant cell lines, SGC7901-TR and BGC-823-TR. In addition, down regulation of KLK10 reversed the resistance in trastuzumab resistant cells. Overexpression of KLK10 induced trastuzumab resistance, and activated the PI3K/AKT signaling pathway, while downregulation of KLK10 presented the opposite effects. Moreover, when the PI3K/AKT signaling pathway was inhibited, the effect of KLK10 on resistance was diminished. Furthermore, combination of trastuzumab and PI3K/AKT inhibitor XL147 effectively inhibited tumor growth in KLK10-overexpressing xenografts. Taken together, our findings show that KLK10 promotes trastuzumab resistance, at least in part, through the PI3K/AKT signaling pathway, suggesting that KLK10 is a potentially target to overcome trastuzumab resistance, and the combination might overcome trastuzumab resistance in KLK10-overexpressed gastric cancer patients.
Immunotherapies, particularly checkpoint inhibitors, have set off a revolution in cancer therapy by releasing the power of the immune system. However, only little is known about the antigens that are essentially presented on cancer cells, capable of exposing them to immune cells. Large-scale HLA ligandome analysis has enabled us to exhaustively characterize the immunopeptidomic landscape of epithelial ovarian cancers (EOCs). Additional comparative profiling with the immunopeptidome of a variety of benign sources has unveiled a multitude of ovarian cancer antigens (MUC16, MSLN, LGALS1, IDO1, KLK10) to be presented by HLA class I and class II molecules exclusively on ovarian cancer cells. Most strikingly, ligands derived from mucin 16 and mesothelin, a molecular axis of prognostic importance in EOC, are prominent in a majority of patients. Differential gene-expression analysis has allowed us to confirm the relevance of these targets for EOC and further provided important insights into the relationship between gene transcript levels and HLA ligand presentation.
Trastuzumab, the first antibody widely used in anti-HER2 targeted therapy, dramatically improved the overall outcome of HER2 positive breast cancer patients. However, trastuzumab resistance emerged as a major problem in its clinical application. In order to explore mechanisms underlying trastuzumab resistance, we performed RNA-Seq to analyze the gene expression variation in trastuzumab resistant breast cancer cell line. The sequencing result was then combined with the relevant data in TCGA database to conduct a co-expression analysis. We found a series of differentially expressed genes with potential contributions to trastuzumab resistance. Among them, KLK10 was verified to be a potential therapeutic target for reversing trastuzumab resistance. In summary, this study provides a new clue to screen molecular targets and predictive biomarkers for trastuzumab resistance.
Teo CR, Casey PJ, Rasheed SAThe GNA13-RhoA signaling axis suppresses expression of tumor protective Kallikreins.
Cell Signal. 2016; 28(10):1479-88 [PubMed
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Gα13 (encoded by GNA13 gene) is the alpha subunit of a heterotrimeric G-protein that mediates signaling through specific G-protein-coupled receptors (GPCRs). Increased GNA13 expression has been observed in metastatic breast cancer cells. Recently, we have shown that enhanced GNA13 signaling in MCF-10a cells, a benign breast cancer cell line increased its invasiveness. Previous studies have reported that Kallikrein-related peptidases (KLKs 1-15) are down-regulated in breast tumors and may have a tumor protective function. However, the mechanisms that lead to the down-regulation of KLK genes in breast cancer are yet to be elucidated. We found that enhanced GNA13 signaling represses KLK gene expression in breast cancer, and undertook examination of the mechanisms involved. A microarray analysis revealed down-regulation of several members of the Kallikrein-related peptidases (KLK) gene family, namely KLK5, KLK6, KLK7, KLK8 and KLK10, in MCF-10a lines with enhanced GNA13 protein expression. Using real-time PCR and promoter analysis, we identified that the mRNA expression and promoter activities of these KLKs are suppressed upon enforced expression of GNA13 in MCF-10a cells. Using Rhotekin pull-down assays, we identified that GNA13 suppressed Rho-A activation and protein levels in MCF-10a cells. Blocking Rho-A activation using C3-toxin or by inhibiting its down-stream effector, Rho-associated kinase (ROCK), reduced the above-mentioned KLK mRNAs in MCF-10A cells. Importantly, in a metastatic breast cancer cell line MDA-MB-157, knock down of GNA13 alone was sufficient to induce the expression KLK mRNAs. Taken together, our findings suggested that enhanced GNA13 signaling down-regulates KLK gene transcription. The ability of enhanced GNA13 signaling to suppress KLK gene expression appears at least in part due to the ability of enhanced GNA13 signaling to negatively impact Rho/ROCK-signaling.
The normal epithelial cell-specific-1 (NES1) gene, also named as KLK10, is recognised as a novel putative tumour suppressor in breast cancer, but few studies have focused on the function of KLK10 in human prostate cancer. Our study confirms that the expression of KLK10 in prostate cancer tissue and cell lines (PC3, DU145, and LNCaP clone FGC) is low. Given that the androgen-independent growth characteristic of the PC3 cell line is more similar to clinical castration-resistant prostate cancer, we studied the role of KLK10 in PC3. In vitro and in vivo assays showed that over-expressing KLK10 in PC3 could decelerate tumour proliferation, which was accompanied with an increase in apoptosis and suppression of glucose metabolism. The related proteins, such as Bcl-2 and HK-2, were down-regulated subsequently. Furthermore, by up-regulating Bcl-2 or HK-2 respectively in the PC3-KLK10 cell line, we observed a subsequent increase of cell proliferation and a synchronous up-regulation of HK-2 and Bcl-2. Besides, KLK10 expression was also increased by Bcl-2 and HK-2, which suggests that there is a negative feedback loop between KLK10 and Bcl-2/HK-2. Thus, our results demonstrated that KLK10 may function as a tumour suppressor by repressing proliferation, enhancing apoptosis and decreasing glucose metabolism in PC3 cells.
Li L, Xu N, Fan N, et al.Upregulated KLK10 inhibits esophageal cancer proliferation and enhances cisplatin sensitivity in vitro.
Oncol Rep. 2015; 34(5):2325-32 [PubMed
] Related Publications
The kallikrein-related peptidase 10 (KLK10) gene has tumor-suppressive function in various types of human cancer. However, previous studies showed that KLK10 also acts as an oncogene and is upregulated in gastrointestinal tumors. The role of KLK10 in human esophageal cancer (EC) remains unclear. In the present study, the expression of KLK10 in human esophageal and non-esophageal cancer tissues was investigated by immunohistochemistry. Quantitative RT-PCR and western blot analysis were utilized to detect KLK10 mRNA and protein expression in human esophageal cancer cell lines (TE-1 and Eca-109). Small interference RNA was utilized to specifically knockdown KLK10 expression in Eca-109 and TE-1 cells. Cell proliferation, cell cycle analysis as well as CDDP-dependent apoptosis were determined using a CCK-8 assay and flow cytometry. The results showed that, KLK10 was positive in 67 out of 83 (80.72%) human EC and positive in 3 out of 11 (27.27%) normal tissues (P=0.001). The present study indicated that KLK10 potentially plays a crucial role in Eca-109 cell growth. Additionally, the downregulation of KLK10 induced S-phase arrest and promoted cisplatin-induced apoptosis. The resutls of the present study suggested that KLK10 is a promising novel marker for the diagnostic and therapeutic target of esophageal cancer.
Jimenez L, Sharma VP, Condeelis J, et al.MicroRNA-375 Suppresses Extracellular Matrix Degradation and Invadopodial Activity in Head and Neck Squamous Cell Carcinoma.
Arch Pathol Lab Med. 2015; 139(11):1349-61 [PubMed
] Free Access to Full Article Related Publications
CONTEXT: Head and neck squamous cell carcinoma (HNSCC) is a highly invasive cancer with an association with locoregional recurrence and lymph node metastasis. We have previously reported that low microRNA-375 (miR-375) expression levels correlate with poor patient survival, increased locoregional recurrence, and distant metastasis. Increasing miR-375 expression in HNSCC cell lines to levels found in normal cells results in suppressed invasive properties. HNSCC invasion is mediated in part by invadopodia-associated degradation of the extracellular matrix.
OBJECTIVE: To determine whether elevated miR-375 expression in HNSCC cell lines also affects invadopodia formation and activity.
DESIGN: For evaluation of the matrix degradation properties of the HNSCC lines, an invadopodial matrix degradation assay was used. The total protein levels of invadopodia-associated proteins were measured by Western blot analyses. Immunoprecipitation experiments were conducted to evaluate the tyrosine phosphorylation state of cortactin. Human protease arrays were used for the detection of the secreted proteases. Quantitative real time-polymerase chain reaction measurements were used to evaluate the messenger RNA (mRNA) expression of the commonly regulated proteases.
RESULTS: Increased miR-375 expression in HNSCC cells suppresses extracellular matrix degradation and reduces the number of mature invadopodia. Higher miR-375 expression does not reduce cellular levels of selected invadopodia-associated proteins, nor is tyrosine phosphorylation of cortactin altered. However, HNSCC cells with higher miR-375 expression had significant reductions in the mRNA expression levels and secreted levels of specific proteases.
CONCLUSIONS: MicroRNA-375 regulates invadopodia maturation and function potentially by suppressing the expression and secretion of proteases.
Di Meo A, Rotondo F, Kovacs K, et al.Human kallikrein 10 expression in surgically removed human pituitary corticotroph adenomas: an immunohistochemical study.
Appl Immunohistochem Mol Morphol. 2015; 23(6):433-7 [PubMed
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Human kallikrein 10 (hk10), a secreted serine protease, was reported to function as a tumor suppressor. hK10 immunoexpression has been demonstrated in lactrotrophs and corticotrophs of the nontumorous human adenohypophysis. In the present study, for the first time we report hK10 immunoexpression in various surgically removed corticotroph adenoma subtypes. Specimens were fixed in formalin and embedded in paraffin. Immunostaining was performed using the streptavidin-biotin-peroxidase complex method with an hK10-specific rabbit polyclonal antibody. Results showed that the endocrinologically active adrenocorticotropic hormone (ACTH)-producing pituitary tumors and the silent subtypes were immunopositve for hK10. Intensity of staining varied between the different subtypes. Intensity was lowest in the silent subtypes (silent corticotroph subtypes 1 and 2) compared with nontumorous human adenohypophysial corticotrophs, whereas the endocrinologically active subtypes (ACTH-secreting adenomas, corticotroph carcinomas, Crooke cell adenomas, Crooke cell carcinomas), showed the highest hK10 immunoexpression. Immunopositivity in the nuclei of the ACTH-secreting adenomas and carcinomas, as well as dual cytoplasmic and nuclear localization of hK10 in some of the secreting tumor types was an intriguing finding. Immunoexpression of hK10 in the ACTH-secreting tumors as well as in the Crooke cell tumors was significantly increased when compared with the nonfunctioning tumors and in the corticotrophs of nontumorous pituitaries.
AIM: To analyze the expression of kallikrein gene 10 (KLK10) in gastric cancer and to determine whether KLK10 has independent prognostic value in gastric cancer.
METHODS: We studied KLK10 expression in 80 histologically confirmed gastric cancer samples using real-time quantitative reverse transcription-PCR and hK10 expression using immunohistochemistry. Correlations with clinicopathological variables (lymph node metastasis, depth of invasion and histology) and with outcomes (disease-free survival and overall survival) during a median follow-up period of 31 mo were assessed. Gastric cancer tissues were then classified as KLK10 positive or negative.
RESULTS: KLK10 was found to be highly expressed in 57/80 (70%) of gastric cancer samples, while its expression was very low in normal gastric tissues. Positive relationships between KLK10 expression and lymph node metastasis (P = 0.048), depth of invasion (P = 0.034) and histology (P = 0.015) were observed. Univariate survival analysis revealed that gastric cancer patients with positive KLK10 expression had an increased risk for relapse/metastasis and death (P = 0.005 and 0.002, respectively). Cox multivariate analysis indicated that KLK10 was an independent prognostic indicator of disease-free survival and overall survival in patients with gastric cancer.
CONCLUSION: KLK10 expression is an independent biomarker of unfavorable prognosis in patients with gastric cancer.
Alexopoulou DK, Papadopoulos IN, Scorilas AClinical significance of kallikrein-related peptidase (KLK10) mRNA expression in colorectal cancer.
Clin Biochem. 2013; 46(15):1453-61 [PubMed
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OBJECTIVES: Colorectal cancer (CRC) is one of the three most common cancers in both genders. Even though several biomarkers are in use in diagnosis and prognosis of the disease, they are marred by limited specificity and sensitivity. The human kallikrein-related peptidase 10 (KLK10) gene is a member of the human tissue kallikrein family. Because prostate specific antigen (PSA), the best biomarker for detecting and monitoring prostate cancer, is a member of this family, many other members, including KLK10, have been widely examined as novel biomarkers for different cancer types. In previous studies, KLK10 has been proposed as a diagnostic biomarker for ovarian carcinoma, while its methylation on exon 3 has been proposed as a prognostic marker for early-stage breast cancer patients. The purpose of this study was to analyse KLK10 mRNA expression and examine its prognostic value and potential clinical application as a novel molecular tissue biomarker in CRC.
DESIGN AND METHODS: The study group consisted of 190 colorectal samples. Total RNA was extracted from pulverised tissues and cDNA was prepared by reverse transcription. KLK10 was amplified by real-time PCR. B2M was used as a reference gene and HT-29 cells as positive control.
RESULTS: KLK10 expression was significantly higher in cancer tissues (P<0.001). Tumours of advanced TNM and Dukes' stage showed high KLK10 expression status (P=0.036; P=0.025). Patients with high KLK10 expression had a shorter disease-free and overall survival rates (P=0.014; P=0.020).
CONCLUSION: Our results suggest that KLK10 may serve as a new marker of unfavourable prognosis of colorectal cancer.
Treeck O, Schüler S, Häring J, et al.icb-1 Gene counteracts growth of ovarian cancer cell lines.
Cancer Lett. 2013; 335(2):441-6 [PubMed
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Human gene icb-1 has been originally identified to be involved in differentiation processes of cancer cells. To examine the function of icb-1 in ovarian cancer, we knocked down its expression in three ovarian cancer cell lines and performed microarray-based gene expression profiling with subsequent gene network modeling. Loss of icb-1 expression accelerated proliferation of SK-OV-3, OVCAR-3 and OAW-42 cells and led to upregulation of ovarian cancer biomarkers like KLK10 and CLDN16. Most of the upregulated genes were part of oncogenic pathways regulated by ERα or TNF. Our data suggest that icb-1 gene inhibits growth and progression of ovarian cancer cells.
Wang YY, Lin YC, Hung HC, et al.Polymorphisms in Kallikrein7 and 10 genes and oral cancer risks in Taiwan betel quid chewers and smokers.
Oral Dis. 2013; 19(8):824-32 [PubMed
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OBJECTIVES: We investigated the association between mRNA levels, polymorphisms of Kallikrein7 (KLK7) and Kallikrein10 (KLK10), and the development of oral squamous cell carcinoma (OSCC).
MATERIALS AND METHODS: We recruited 217 OSCC patients and 138 healthy controls. All were men, betel quid chewers, cigarette smokers, and Minnan ethnicity. Genotyping was performed using a TaqMan probe genotyping assay. Gene expression levels were determined using real-time polymerase chain reactions (PCRs) for 20 pairs of cancerous and non-cancerous tissues.
RESULTS: Kallikrein10 rs3745535G>T polymorphisms were significantly associated with OSCC development [adjusted OR (AOR) = 1.62, 95% CI = 1.02-2.59], but KLK7 polymorphisms were not. The KLK7 rs10581213(wt/ins + ins/ins) genotypes were significantly associated with early-stage cancer (AOR = 0.34, 95% CI = 0.14-0.78), but KLK10 polymorphisms were not. Relative expression analysis indicated that an increase in KLK7 and KLK10 mRNA levels was found in cancerous tissues (2(-ΔΔCT) = 25.23 ± 8.85 and 10.89 ± 4.97, respectively). A significantly higher level of KLK7 was expressed in early-stage cancer with the rs10581213(wt/ins + ins/ins) genotypes, but there was no significant difference in the mRNA levels of KLK7 and KLK10 between early- and advanced-stage cancers.
CONCLUSIONS: This is the first correlation of OSCC with KLK10 rs3745535G>T polymorphisms. Early-stage OSCC and high KLK7 mRNA levels were correlated with the rs10581213(wt/ins + ins/ins) genotypes. More studies with large sample sizes are needed to verify our findings.
Bayani J, Kuzmanov U, Saraon P, et al.Copy number and expression alterations of miRNAs in the ovarian cancer cell line OVCAR-3: impact on kallikrein 6 protein expression.
Clin Chem. 2013; 59(1):296-305 [PubMed
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BACKGROUND: Kallikrein-related peptidase 6 (KLK6), a member of the serine protease family of kallikrein (KLK) genes, is dysregulated in ovarian carcinomas (OCa) and its overexpression is associated with poor prognosis. Regulation of its expression is poorly understood and is likely to be influenced by multiple mechanisms. The KLK locus is subject to copy number changes and heterogeneity in serous OCas. These copy number imbalances generally correlate with KLK6 protein expression; however, this is not always the case. In this study we explored the role of miRNAs in the posttranscriptional control of KLK6 expression and the contributions of copy numbers, not only of the KLK locus, but also of the miRNAs predicted to regulate it.
METHODS AND RESULTS: By miRNA profiling of the KLK6-overexpressing OCa cell line, OVCAR-3, we identified overexpressed and underexpressed miRNAs. Publically available miRNA databases identified the human miRNA lethal 7 (hsa-let-7) family members as putative regulating miRNAs, from which hsa-let-7a was chosen for functional analysis. The transient transfection of hsa-let-7a to OVCAR-3 resulted in a decrease of KLK6 secreted protein. Moreover, such transfection was also able to weakly affect the expression of another member of the KLK gene family, KLK10 (kallikrein-related peptidase 10). Cytogenomic analysis, including array comparative genomic hybridization, fluorescence in situ hybridization, and spectral karyotyping revealed the overall net copy number losses of hsa-let-7a and other miRNAs predicted to target KLK6.
CONCLUSIONS: The hsa-let-7 family member hsa-let-7a is a modulator of KLK6 protein expression that is independent of the KLK6 copy number status.
Olkhov-Mitsel E, Van der Kwast T, Kron KJ, et al.Quantitative DNA methylation analysis of genes coding for kallikrein-related peptidases 6 and 10 as biomarkers for prostate cancer.
Epigenetics. 2012; 7(9):1037-45 [PubMed
] Free Access to Full Article Related Publications
DNA methylation plays an important role in carcinogenesis and is being recognized as a promising diagnostic and prognostic biomarker for a variety of malignancies including Prostate cancer (PCa). The human kallikrein-related peptidases (KLKs) have emerged as an important family of cancer biomarkers, with KLK3, encoding for Prostate Specific Antigen, being most recognized. However, few studies have examined the epigenetic regulation of KLKs and its implications to PCa. To assess the biological effect of DNA methylation on KLK6 and KLK10 expression, we treated PC3 and 22RV1 PCa cells with a demethylating drug, 5-aza-2'deoxycytidine, and observed increased expression of both KLKs, establishing that DNA methylation plays a role in regulating gene expression. Subsequently, we have quantified KLK6 and KLK10 DNA methylation levels in two independent cohorts of PCa patients operated by radical prostatectomy between 2007-2011 (Cohort I, n = 150) and 1998-2001 (Cohort II, n = 124). In Cohort I, DNA methylation levels of both KLKs were significantly higher in cancerous tissue vs. normal. Further, we evaluated the relationship between DNA methylation and clinicopathological parameters. KLK6 DNA methylation was significantly associated with pathological stage only in Cohort I while KLK10 DNA methylation was significantly associated with pathological stage in both cohorts. In Cohort II, low KLK10 DNA methylation was associated with biochemical recurrence in univariate and multivariate analyses. A similar trend for KLK6 DNA methylation was observed. The results suggest that KLK6 and KLK10 DNA methylation distinguishes organ confined from locally invasive PCa and may have prognostic value.
White NM, Youssef YM, Fendler A, et al.The miRNA-kallikrein axis of interaction: a new dimension in the pathogenesis of prostate cancer.
Biol Chem. 2012; 393(5):379-89 [PubMed
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Kallikrein-related peptidases (KLKs) are a family of serine proteases that were shown to be useful cancer biomarkers. KLKs have been shown to be dysregulated in prostate cancer (PCa). microRNAs (miRNAs) are short RNA nucleotides that negatively regulate gene expression and have been reportedly dysregulated in PCa. We compiled a comprehensive list of 55 miRNAs that are differentially expressed in PCa from previous microarray analysis and published literature. Target prediction analyses showed that 29 of these miRNAs are predicted to target 10 KLKs. Eight of these miRNAs were predicted to target more than one KLK. Quantitative real-time (qRT)-PCR demonstrated that there was an inverse correlation pattern in the expression (normal vs. cancer) between dysregulated miRNAs and their target KLKs. In addition, we experientially validated the miRNA-KLK interaction by transfecting miR-331-3p and miR-143 into a PCa cell line. Decreased expression of targets KLK4 and KLK10, respectively, and decreased cellular growth were observed. In addition to KLKs, dysregulated miRNAs were predicted to target other genes involved in the pathogenesis of PCa. These data show that miRNAs can contribute to KLK regulation in PCa. The miRNA-KLK axis of interaction projects a new element in the pathogenesis of PCa that may have therapeutic implications.
Petraki C, Youssef YM, Dubinski W, et al.Evaluation and prognostic significance of human tissue kallikrein-related peptidase 10 (KLK10) in colorectal cancer.
Tumour Biol. 2012; 33(4):1209-14 [PubMed
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The prognosis of patients with colorectal cancer (CRC) is assessed through conventional clinicopathological parameters, which are not always accurate. Members of the human kallikrein-related peptidases gene family represent potential cancer biomarkers. The aim of this study was to investigate the expression of human tissue kallikrein-related peptidase 10 (KLK10) by immunohistochemistry in CRC, to correlate this expression with various histopathological and clinical variables, and to evaluate its significance as a predictor of disease outcome. KLK10 expression was evaluated by immunohistochemistry and a combined expression score was calculated for each case based on intensity and percentage of positivity. A statistically significant positive association was observed between KLK10 and tumor stage and liver metastases (p = 0.015 and p = 0.035, respectively). Paradoxically, a negative association was observed between KLK10 and tumor grade (p = 0.009). Kaplan-Meier survival curves and univariate analysis showed that both KLK10 expression and stage had statistically significant correlations with disease-free survival (DFS) (p = 0.030 and p < 0.001, respectively) and overall survival (p = 0.010 and p = 0.001, respectively). Cox multivariate analysis showed that both KLK10 expression and stage were independent predictors of unfavorable DFS (p = 0.057 and p = 0.001, respectively) and overall survival (p = 0.009 and p = 0.001, respectively). In conclusion, KLK10 immunostaining is an independent prognostic marker in patients with CRC.
Methyl cytosine binding domain protein 2 (MBD2) has been shown to bind to and mediate repression of methylated tumor suppressor genes in cancer cells, where repatterning of CpG methylation and associated gene silencing is common. We have investigated the role of MBD2 in breast cancer cell growth and tumor suppressor gene expression. We show that stable short hairpin RNA (shRNA)-mediated knockdown of MBD2 leads to growth suppression of cultured human mammary epithelial cancer lines, SK-BR-3, MDA-MB-231, and MDA-MB-435. The peak antiproliferative occurs only after sustained, stable MBD2 knockdown. Once established, the growth inhibition persists over time and leads to a markedly decreased propensity for aggressive breast cancer cell lines to form in vivo xenograft tumors in Bagg Albino (BALB)/C nu/nu mice. The growth effects of MBD2 knockdown are accompanied by derepression of tumor suppressor genes, including DAPK1 and KLK10. Chromatin immunoprecipitation assays and bisulfite sequencing show MBD2 binding directly to the hyper methylated and CpG-rich promoters of both DAPK1 and KLK10. Remarkably, the promoter CpG island-associated methylation of these genes remained stable despite robust transcriptional activation in MBD2 knockdown cells. Expression of a shRNA-resistant MBD2 protein resulted in restoration of growth and resilencing of the MBD2-dependent tumor suppressor genes. Our data suggest that uncoupling CpG methylation from repressive chromatin remodeling and histone modifications by removing MBD2 is sufficient to initiate and maintain tumor suppressor gene transcription and suppress neoplastic cell growth. These results show a role for MBD2 in cancer progression and provide support for the prospect of targeting MBD2 therapeutically in aggressive breast cancers.
Talieri M, Alexopoulou DK, Scorilas A, et al.Expression analysis and clinical evaluation of kallikrein-related peptidase 10 (KLK10) in colorectal cancer.
Tumour Biol. 2011; 32(4):737-44 [PubMed
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Kallikrein-related peptidases (KLKs) represent a serine protease family having 15 members. KLK10 is a secreted protease with a trypsin-like activity. The function of KLK10 is poorly understood, although it has been suggested that KLK10 may function as a tumor suppressor gene. In human cancer, KLK10 gene shows organ-specific up- or down-regulation. Since KLKs are promising tumor biomarkers, the examination of KLK10 mRNA expression and its association with colorectal cancer (CRC) progression was studied using semi-quantitative PCR. One hundred and nineteen primary CRC specimens were examined for which follow-up information was available for a median period of 29 months (range, 1-104 months). KLK10 expression was found to be significantly associated with TNM stage (p=0.028). Cox proportional hazard regression model using univariate analysis revealed for the first time that high status KLK10 expression is a significant factor for disease-free survival (DFS; p=0.002) and overall survival (OS; p=0.026) of patients. Kaplan-Meier survival curves demonstrated that KLK10 expression of low status is significantly associated with longer DFS (p=0.001) as well as OS (p=0.021), suggesting that KLK10 gene expression may be used as a marker of unfavorable prognosis for CRC. As the epigenetics of cancer are unraveled, KLK10 may represent not only a novel biomarker, but also a promising future therapeutic target for the disease.
Zhang Y, Wang R, Song H, et al.Methylation of multiple genes as a candidate biomarker in non-small cell lung cancer.
Cancer Lett. 2011; 303(1):21-8 [PubMed
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Aberrant DNA methylation is a common phenomenon in human cancer. The aims of this study were to investigate the methylation profiles of non-small cell lung cancer (NSCLC) in the Chinese population. Twenty tumor suppressor genes (TSGs) were determined of the methylation status using methylation-specific PCR in 78 paired NSCLC specimens and adjacent normal tissues, as well as in 110 Stage I/II NSCLC and 50 cancer-free plasmas. The results showed that, nine genes (APC, CDH13, KLK10, DLEC1, RASSF1A, EFEMP1, SFRP1, RARβ and p16(INK4A)) demonstrated a significantly higher frequency of methylation in NSCLC compared with the normal tissues (P≤0.001), while the others (RUNX3, hMLH1, DAPK, BRCA1, p14(ARF), MGMT, NORE1A, FHIT, CMTM3, LSAMP and OPCML) showed relatively low sensitivity or specificity. Furthermore, methylation of multiple genes was more frequentin cancerous tissue, CpG island methylator phenotype positive (CIMP+) cases were detected in 65.38% of (51/78) NSCLC while only in 1.28% (1/78) of adjacent normal tissues (P<0.001), and CIMP+ was associated with advanced stage (P=0.017), lymphatic metastasis (P=0.001) and adverse 2-year progression-free survival (P=0.027). The nine genes validated in tissues also showed a significantly higher frequency of tumor-specific hypermethylation in NSCLC plasma, as compared with the cancer-free plasmas, and a 5-gene set (APC, RASSF1A, CDH13, KLK10 and DLEC1) achieved a sensitivity of 83.64% and a specificity of 74.0% for cancer diagnosis. Thus, the results indicated that methylated alteration of multiple genes plays an important role in NSCLC pathogenesis and a panel of candidate epigenetic biomarkers for NSCLC detection in the Chinese population was identified.
Li M, Zhao ZW, Zhang Y, Xin YOver-expression of Ephb4 is associated with carcinogenesis of gastric cancer.
Dig Dis Sci. 2011; 56(3):698-706 [PubMed
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BACKGROUND: Gastric cancer is one of the most frequently diagnosed malignancies in the world. The gene expression profile and molecular grouping of gastric cancer has been a challenging task due to its inherent complexity and variation among individuals.
AIMS: To determine the molecular mechanism associated with gastric carcinogenesis.
METHODS: We analyzed the gene expression profiles of 20 cancerous tissues and their tumor-adjacent tissue from patients with gastric cancer by using a 14 K cDNA microarray. The differentially expressed genes and their products were verified by semiquantitative reverse transcription PCR (RT-PCR), western blotting and immunohistochemistry of gastric cancer and normal tissue samples.
RESULTS: A total of 69 genes were found to be differentially regulated in the cancerous tissue. Among them, genes such as CDH17, ETV4, S100A6, S100A11, Ephb4, and KLK10 were confirmed by RT-PCR to be up-regulated, while genes such as NK4 and PPP2R1B were down-regulated. Western blotting and immunohistochemistry indicated that Ephb4 was over-expressed and localized to the cytoplasm of gastric cancer cells. Moreover, Ephb4 protein was observed as being significantly related to tumor size and pN category (p = 0.001 and 0.007, respectively).
CONCLUSIONS: These newly identified genes might provide a valuable resource for understanding the molecular mechanism associated with the carcinogenesis of gastric cancer and for finding potential diagnostic markers of gastric cancer.
Batra J, Tan OL, O'Mara T, et al.Kallikrein-related peptidase 10 (KLK10) expression and single nucleotide polymorphisms in ovarian cancer survival.
Int J Gynecol Cancer. 2010; 20(4):529-36 [PubMed
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INTRODUCTION: Kallikrein-related peptidase 10 (KLK10) overexpression is a predictor of poor disease outcome in women with late-stage ovarian cancer. We aimed to identify whether KLK10 overexpression could be attributed to genetic variants, in particular, in hormone response elements or transcription factor binding sites.
METHODS: Cox regression analysis was used to assess the association between 2 tag and 1 exonic KLK10 single nucleotide polymorphisms (SNPs) and the survival of 319 patients with ovarian cancer. Four different ovarian cancer cell lines were investigated for KLK10 expression after hormone stimulation, and sequence variation in the 3.6-Kb upstream of the KLK10 start site. In silico analyses of SNPs in cell lines and from published databases were undertaken to identify further research novel and potentially functional SNPs that are not covered by tag SNPs.
RESULTS: The KLK10 SNPs investigated were not associated with ovarian cancer survival. However, steroid hormone treatment of ovarian cell lines showed KLK10 up-regulation in response to estrogen and estrogen plus progesterone treatments in the aggressive cell line PEO1 and affirmed a role for KLK10 in aggressive ovarian cancer. Potentially functional KLK10 SNPs were identified by cell line sequencing and bioinformatic analysis.
CONCLUSION: Potentially functional candidate KLK10 SNPs require investigation in future association studies of ovarian cancer risk and survival, including rs3760738 identified in aggressive ovarian cancer cell lines and predicted to affect transcription factor binding sites.
Tong WG, Wierda WG, Lin E, et al.Genome-wide DNA methylation profiling of chronic lymphocytic leukemia allows identification of epigenetically repressed molecular pathways with clinical impact.
Epigenetics. 2010; 5(6):499-508 [PubMed
] Free Access to Full Article Related Publications
We performed a genome-wide analysis of aberrant DNA methylation in chronic lymphocytic leukemia (CLL) using methylated CpG island amplification (MCA) coupled with a promoter microarray. We identified 280 potential targets of aberrant DNA methylation in CLL. These genes were located more frequently in chromosomes 19 (16%, p=0.001), 16 (11%, p=0.001), 17 (10%, p=0.02) and 11 (9%, p=0.02) and could be grouped in several functional networks. Methylation status was confirmed for 22 of these genes (SOX11, DLX1, FAM62C, SOX14, RSPO1, ADCY5, HAND2,SPOCK, MLL, ING1, PRIMA1, BCL11B, LTBP2, BNC1, NR2F2, SALL1, GALGT2, LHX1, DLX4, KLK10, TFAP2 and APP) in 78 CLL patients by pyrosequencing. As a proof of principle, we analyzed the expression of 2 genes, PRIMA1 and APP, in primary cells and of GALGT2, TFAP2C and PRIMA1 in leukemia cells. There was an inverse association between methylation and gene expression. This could be reversed by treatment with 5-aza-2'-deoxycytidine in cell lines. Treatment in a clinical trial with 5-azacitidine resulted in decreased methylation of LINE, DLX4 and SALL1 in the peripheral blood B-cells of patients with CLL. IgVH mutational status or ZAP-70 expression were not associated with specific methylation profiles. By multivariate analysis, methylation of LINE and APP was associated with shorter overall survival (p = 0.045 and 0.0035, respectively). This study demonstrates that aberrant DNA methylation is common and has potential prognostic and therapeutic value in CLL.
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
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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.
BACKGROUND: Kallikrein-related peptidases (KLKs) are a family of serine proteases that have been shown to be dysregulated in several malignancies including ovarian cancer. The control of kallikrein genes and their physiological function in cancer is not well understood. We hypothesized that microRNAs (miRNAs) represent a novel mechanism for post-transcriptional control of KLK expression in cancer.
METHODS: We first analysed miRNA expression in ovarian cancer in silico. A total of 98 miRNAs were reported to have altered expression in ovarian cancer. Three of these miRNAs were predicted to target KLK10. We experimentally verified the predicted miR-KLK10 interaction using two independent techniques, a luciferase assay with a construct containing the KLK10 3' untranslated region (UTR), pMIR-KLK10, and measuring KLK10 protein levels after transfection with miRNA.
RESULTS: When we co-transfected cells with pMIR-KLK10 and either let-7f, miR-224, or mR-516a, we saw decreased luciferase signal, suggesting that these miRNAs can target KLK10. We then examined the effect of these three miRNAs on KLK10 protein expression and cell growth. Transfection of all miRNAs, let-7f, miR-224, and miR-516a led to a decrease in protein expression and cellular growth. This effect was shown to be dose dependent. The KLK10 protein levels were partially restored by co-transfecting let-7f and its inhibitor. In addition, there was a slight decrease in KLK10 mRNA expression after transfection with let-7f.
CONCLUSION: Our results confirm that KLKs can be targeted by more than one miRNA. Increased expression of certain miRNAs in ovarian cancer can lead to decreased KLK protein expression and subsequently have a negative effect on cell proliferation. This dose-dependent effect suggests that a 'tweaking' or 'fine-tuning' mechanism exists in which the expression of one KLK can be controlled by multiple miRNAs. These data together suggest that miRNA may be used as potential therapeutic options and further studies are required.