Favorable prognostic value of tissue human kallikrein 11 (hK11) in patients with ovarian carcinoma

Borgoño, Carla A.; Fracchioli, Stefano; Yousef, George M.; Longrais, Irene A. Rigault de la; Luo, Liu‐Ying; Soosaipillai, Antoninus; Puopolo, Manuela; Grass, Linda; Scorilas, Andreas; Diamandis, Eleftherios P.; Katsaros, Dionyssios

doi:10.1002/ijc.11296

Cited by 61 publications

(57 citation statements)

References 55 publications

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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%

“…Two kallikreins, KLK9 ) and KLK14 (Yousef et al, 2003a), are markers of favourable prognosis. In addition, KLK8 (Borgono et al, 2006;Kountourakis et al, 2009), KLK11 (Borgono et al, 2003;Shigemasa et al, 2004), and KLK13 (Scorilas et al, 2004;White et al, 2009) have conflicting evidence on prognosis. A recent report showed a concordant higher expression of both KLK5 and KLK7 in ovarian carcinomas, especially late-stage serous carcinomas, compared with normal ovaries and benign adenomas (Dong et al, 2003).…”

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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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Section: Bioinformatic Analysismentioning

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

et al. 2010

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“…The human kallikreins are abundantly expressed in groups in many tissues, often in a sex-steroid hormonedependent manner, and they are up-regulated in disease states. For example, hK5, -6, and -14 are found at increased levels in the serum and/or ascites fluid of ovarian cancer patients (22)(23)(24)(25)(26) as well as in the serum of breast cancer patients (23,26). Kallikreins are also highly expressed at sites of inflammation (27,28).…”

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confidence: 99%

Proteinase-activated Receptors, Targets for Kallikrein Signaling

Οικονομοπούλου

Hansen

Saifeddine

et al. 2006

Journal of Biological Chemistry

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Serine proteinases like thrombin can signal to cells by the cleavage/activation of proteinase-activated receptors (PARs).Although thrombin is a recognized physiological activator of PAR 1 and PAR 4 , the endogenous enzymes responsible for activating PAR 2 in settings other than the gastrointestinal system, where trypsin can activate PAR 2 , are unknown. We tested the hypothesis that the human tissue kallikrein (hK) family of proteinases regulates PAR signaling by using the following: 1) a high pressure liquid chromatography (HPLC)-mass spectral analysis of the cleavage products yielded upon incubation of hK5, -6, and -14 with synthetic PAR N-terminal peptide sequences representing the cleavage/activation motifs of PAR 1 , PAR 2 , and PAR 4 ; 2) PAR-dependent calcium signaling responses in cells expressing PAR 1 , PAR 2 , and PAR 4 and in human platelets; 3) a vascular ring vasorelaxation assay; and 4) a PAR 4 -dependent rat and human platelet aggregation assay. We found that hK5, -6, and -14 all yielded PAR peptide cleavage sequences consistent with either receptor activation or inactivation/disarming. Furthermore, hK14 was able to activate PAR 1 , PAR 2 , and PAR 4 and to disarm/inhibit PAR 1 . Although hK5 and -6 were also able to activate PAR 2 , they failed to cause PAR 4 -dependent aggregation of rat and human platelets, although hK14 did. Furthermore, the relative potencies and maximum effects of hK14 and -6 to activate PAR 2 -mediated calcium signaling differed. Our data indicate that in physiological settings, hKs may represent important endogenous regulators of the PARs and that different hKs can have differential actions on PAR 1 , PAR 2 , and PAR 4 . Proteinase-activated receptors (PAR 1-4 )3 compose a unique family of four G-protein-coupled cell surface receptors for certain proteinases (1-9). Proteolytic cleavage within the extracellular N terminus reveals a tethered ligand that binds to the extracellular receptor domains to initiate cell signaling (5, 6, 9, 10). Proteinases that activate PARs include coagulation factors, enzymes from inflammatory cells, and proteinases from epithelial cells and neurons. These enzymes, generated and released during injury and inflammation, can cleave and activate PARs on many cell types from a variety of species (humans, rats, and mice) to regulate the critically important processes of hemostasis, inflammation, pain, and tissue repair. Other proteinases that cleave PARs downstream of the N-terminal tethered ligand sequence disable the receptors for further proteolytic activation, thus abrogating PAR signaling. It is of considerable interest to identify the proteinases that activate and/or disable PARs, in view of the emerging role that these receptors can play in diseases such as asthma, arthritis, inflammatory bowel disease, and cancer (5-7).In some systems, the proteinases that activate PARs have been established. For example, in the circulatory system, PAR 1 , PAR 3 , and PAR 4 are recognized physiological targets for thrombin (4), which does not efficiently acti...

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“…Semen liquefaction is under a tight regulatory control by a number of endogenous inhibitors, such the protein C inhibitor (PCI), as well as inhibitory Zn 2ϩ (25)(26)(27). Several other KLKs, including KLK1, -11, and -14, are known to be expressed in varying levels in seminal plasma (20,28,29) and may be involved in a common activation pathway.…”

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Human Kallikrein-related Peptidase 14 (KLK14) Is a New Activator Component of the KLK Proteolytic Cascade

Emami¹,

Diamandis²

2008

Journal of Biological Chemistry

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Human kallikrein-related peptidases (KLKs) are a family of 15 serine proteases mainly known for their biomarker utility in various neoplastic and non-neoplastic diseases. Despite significant progress in understanding their clinical application, little is known about the activation mechanism(s) of this important family of enzymes. Emerging evidence indicates that KLKs are activated in a stepwise manner, which is a characteristic of proteolytic cascades. Thus far, KLK cascades have been implicated in semen liquefaction and skin desquamation. Many members of the KLK family have been reported to be active in seminal plasma and/or skin, suggesting their involvement in common proteolytic cascades. KLK14, in particular, is highly active and has recently been proposed as one of the key trypsin-like proteases involved in skin desquamation. This study aims to elucidate a probable cascade-mediated role of KLK14 by 1) examining KLK14-mediated cleavage of a heptapeptide library encompassing activation sites of the 15 KLKs and 2) verifying activation of certain candidate downstream targets of KLK14 (i.e. pro-KLK1, -KLK3, and -KLK11). Heptapeptides encompassing activation motifs of KLK2, -3, -5, and -11 were cleaved with a high (>85%) cleavage efficiency. Activation of these candidates was confirmed using full-length recombinant proteins. Pro-KLK11, -KLK3, and -KLK1 were rapidly activated in a concentration-dependent manner. Pro-KLK3 regulation was bidirectional because activation was followed by inactivation via internal cleavage of active KLK3. We are proposing a putative cascade model, operating through multiple KLKs. Identification of novel members of such proteolytic cascades will aid in further defining mechanisms involved in seminal/skin homeostasis.Proteases are a major group of enzymes participating in a multitude of physiological processes, including coagulation, apoptosis, and immune responses (1). Due to the irreversible nature of proteolytic activation, proteases often remain as inactive zymogens in quiescent conditions. Activation is often triggered by an external stimulus and mediated by highly orchestrated cascades (2). Within a cascade, proteases function coordinately to ensure sequential activation of protease zymogens. The result is a rapid amplification of signal, in response to a minute amount of stimulus (2).Proteolytic cascades are tightly regulated through a series of highly orchestrated feedback loops, internal cleavages, and (auto)degradations. Also, inhibitors play a major role by targeting activated proteases (2). These multiple regulatory points are critical in preventing deleterious effects due to uncontrolled protease activation. Dysregulated protease activation has been implicated in several pathological conditions, such as amyloidogenesis in Alzheimer disease, intravascular coagulation in sepsis, and desquamation in various skin disorders as well as tumor metastasis, invasion, and angiogenesis in cancer (2-5).KLKs 2 belong to a subgroup of secreted serine proteases within the S1 family of clan ...

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Favorable prognostic value of tissue human kallikrein 11 (hK11) in patients with ovarian carcinoma

Cited by 61 publications

References 55 publications

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

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

Proteinase-activated Receptors, Targets for Kallikrein Signaling

Human Kallikrein-related Peptidase 14 (KLK14) Is a New Activator Component of the KLK Proteolytic Cascade

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