Kallikrein 4 is a Predominantly Nuclear Protein and Is Overexpressed in Prostate Cancer

Xi, Zhijun; Klokk, Tove Irene; Korkmaz, Kemal; Kurys, Piotr; Elbi, Cem; Risberg, Bjørn; Danielsen, Håvard E.; Loda, Massimo; Saatcioglu, Fahri

doi:10.1158/0008-5472.can-03-2025

Cited by 102 publications

(104 citation statements)

References 35 publications

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“…In an attempt to confirm their results, we did assess MMP20 and KLK4 expression in ALCs by use of quantitative real-time PCR, but we did not reach the cycle thresholds for MMP20 and KLK4 transcripts by our 35-cycle cutoff point. This is why we used the human prostate carcinoma cell line LNCaP, which expresses KLK4 (Xi et al, 2004), for our TGF-β1/KLK4 expression-level studies.…”

Section: Discussionmentioning

confidence: 99%

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Fluoride Affects Enamel Protein Content via TGF-β1-mediated KLK4 Inhibition

Suzuki¹,

Shin²,

Simmer

et al. 2014

J Dent Res

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Dental fluorosis is caused by chronic high-level fluoride (F -) exposure during enamel development, and fluorosed enamel has a higher than normal protein content. Matrix metalloproteinase 20 cleaves enamel matrix proteins during the secretory stage, and KLK4 further cleaves these proteins during the maturation stage so that the proteins can be reabsorbed from the hardening enamel. We show that transforming growth factor β1 (TGF-β1) can induce Klk4 expression, and we examine the effect of F -on TGF-β1 and KLK4 expression. We found that in vivo F -inhibits Klk4 but not Mmp20 transcript levels. LacZ-C57BL/6-Klk4 +/LacZ mice have LacZ inserted in frame at the Klk4 translation initiation site so that the endogenous Klk4 promoter drives LacZ expression in the same temporal/spatial way as it does for Klk4. KLK4 protein levels in rat enamel and β-galactosidase staining in LacZ-C57BL/6-Klk4 +/LacZ mouse enamel were both significantly reduced by F -treatment. Since TGF-β1 induces KLK4 expression, we tested and found that F -significantly reduced Tgf-β1 transcript levels in rat enamel organ. These data suggest that F --mediated downregulation of TGF-β1 expression contributes to reduced KLK4 protein levels in fluorosed enamel and provides an explanation for why fluorosed enamel has a higher than normal protein content.

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Section: Discussionmentioning

confidence: 99%

“…The human prostate carcinoma cell line (LNCaP) was purchased from ATCC (Manassas, VA, USA) because it expresses KLK4 (Xi et al, 2004). These cells were cultured at pH 7.4 in modified (ATCC) RPMI1640 medium (Invitrogen) supplemented with 10% fetal bovine serum.…”

Section: Cell Culturementioning

confidence: 99%

Fluoride Affects Enamel Protein Content via TGF-β1-mediated KLK4 Inhibition

Suzuki¹,

Shin²,

Simmer

et al. 2014

J Dent Res

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“…Assessment of KLK protein dysregulation in ovarian cancer was compiled from the results of 17 studies (Dong et al, 2001;Luo et al, 2001Luo et al, , 2003Tanimoto et al, 2001;Hoffman et al, 2002;Yousef et al, , 2003bBorgono et al, 2003;Diamandis et al, 2003;Ni et al, 2004;Scorilas et al, 2004;Xi et al, 2004;Prezas et al, 2006;Shan et al, 2007;Bayani et al, 2008;Shaw and Diamandis, 2008). Chromosomal aberration in ovarian cancer was extracted from the Progenetix comparative genomic hybridisation database available as of January 2009 (Baudis and Cleary, 2001).…”

Section: Bioinformatic Analysismentioning

confidence: 99%

Three dysregulated miRNAs control kallikrein 10 expression and cell proliferation in ovarian cancer

et al. 2010

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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 0 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. CONCLUSIONS: 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.

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“…Diagnostic tests that combine serum KLK2 with total PSA (Recker et al , 2000 ) and free PSA (Stephan et al , 2006 ) have improved the sensitivity and specifi city of detection. In addition, KLK4 mRNA was shown to be upregulated in PCa tissues (Yousef et al , 1999 ;Obiezu et al , 2002 ;Xi et al , 2004 ;Avgeris et al , 2011 ) and may play a role in epithelial to mesenchymal transition (Veveris -Lowe et al, 2005 ). On the other hand, studies showed that KLK10, a potential tumor suppressor, was downregulated in more aggressive PCa s (Luo and Diamandis , 2000 ).…”

Section: Introductionmentioning

confidence: 99%

The miRNA-kallikrein axis of interaction: a new dimension in the pathogenesis of prostate cancer

White¹,

Youssef

Fendler³

et al. 2012

Biological Chemistry

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AbstractKallikrein-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.

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Kallikrein 4 is a Predominantly Nuclear Protein and Is Overexpressed in Prostate Cancer

Cited by 102 publications

References 35 publications

Fluoride Affects Enamel Protein Content via TGF-β1-mediated KLK4 Inhibition

Fluoride Affects Enamel Protein Content via TGF-β1-mediated KLK4 Inhibition

Three dysregulated miRNAs control kallikrein 10 expression and cell proliferation in ovarian cancer

The miRNA-kallikrein axis of interaction: a new dimension in the pathogenesis of prostate cancer

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