Human Tissue Kallikreins: From Gene Structure to Function and Clinical Applications

Yousef, George M.; Obiezu, Christina V.; Luo, Liu‐Ying; Magklara, Angeliki; Borgoño, Carla A.; Kishi, Tadaaki; Memari, Nader; Michael, Iacovos P.; Sidiropoulos, Michael; Kurlender, Lisa; Economopolou, Katerina; Kapadia, Carl; Komatsu, Naoya; Petraki, Constantina; Elliott, Marc B.; Scorilas, Andreas; Katsaros, Dionyssios; Levesque, Michael A.; Diamandis, Eleftherios P.

doi:10.1016/s0065-2423(04)39002-5

Cited by 63 publications

(37 citation statements)

References 223 publications

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“…At least seven kallikrein proteins are up-regulated in ovarian cancer compared with normal ovarian tissues (Yousef et al, 2003b). The prognostic value of at least 11 out of 15 members of the human kallikrein family in ovarian cancer has been also published (Clements et al, 2004;Yousef et al, 2005;Prezas et al, 2006;Dorn et al, 2007). Six kallikreins, KLK4, KLK5, KLK6, KLK7, KLK10, and KLK15 (Kim et al, 2001;Kyriakopoulou et al, 2003;Shvartsman et al, 2003;Yousef et al, 2003c;Kountourakis et al, 2008), are markers of poor prognosis in ovarian cancer.…”

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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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confidence: 99%

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

et al. 2010

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“…Local recurrence is found in 40-60% [1] and is often limiting for curative treatment and survival. While 5-year overall survival for cutaneous melanoma is up to 80%, the literature describes a dismal prognosis for MMHN with an OS in the range between 12 and 25% [1,15]. Most of the primary MMHN are located in the nasal cavity and the nasal sinus, followed by the oral cavity, the larynx and the pharynx [16].…”

Section: Discussionmentioning

confidence: 99%

“…Due to the discovery of Kallikrein-related peptidase 3 (PSA) as a diagnostic marker for prostate cancer, the Kallikrein gene family has gained increasing interest in the past decades [14,15]. Kallikreins (KLKs) are a group of serine proteases with diverse physiological functions, and several KLKs, including KLK6 have been implicated in neoplastic transformation and malignant progression [16].…”

Section: Introductionmentioning

confidence: 99%

“…However, recent studies questioned the general oncogenic role of KLK6 and stressed the importance to consider its context-dependent, tumor-protective function, as exemplified in breast and renal cancer as well as squamous cell carcinoma of the head and neck (HNSCC) [21,22]. Although KLK6 has been related to neoplastic transformation and malignant progression, the regulation and function of KLK6 under physiological and pathological settings is poorly understood, and is most likely influenced by multiple mechanisms, including gene copy number imbalances [17], exposure to steroid hormones [15,23], epigenetic events such as gene promoter hyper-methylation, oncogenic signaling [24,25] and posttranscriptional control by miRNAs [17,26,27].…”

Section: Introductionmentioning

confidence: 99%

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Expression of Kallikrein-Related Peptidase 6 in Primary Mucosal Malignant Melanoma of the Head and Neck

Thierauf

Veit

Lennerz

et al. 2016

Head and Neck Pathol

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Mucosal melanomas of the head and neck (MMHN) are aggressive tumors with poor prognosis, different opposed to cutaneous melanoma. In this study, we characterized primary mucosal malignant melanoma for the expression of Kallikrein-related peptidase 6 (KLK6), a member of the KLK family with relevance to the malignant phenotype in various cancer types including cutaneous melanoma. Paraffin-embedded MMHN of 22 patients were stained immunohistochemically for KLK6 and results were correlated with clinical and pathological data. In 77.3% (17/22) of MMHN cases, positive KLK6 staining was found. Staining pattern for tumor cells showed a predominant cytoplasmic staining. However, in six cases we also observed a prominent nuclear staining. MMHN with a high KLK6 expression showed significantly better outcome concerning local recurrence-free survival (p = 0.013) and nuclear KLK6 staining was significantly associated with the survival status (p = 0.027). Overexpression of KLK6 was detected in more than 70% of MMHN and approximately 40% of tumors showed a strong expression pattern. Correlation between clinical outcome of MMHN patients and overexpression of KLK6 has not been addressed so far. Our data demonstrate for the first time increased levels of KLK6 in MMHN and strengthen the hypothesis that there might be a context-specific regulation and function of KLK6 in mucosal melanoma.

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“…Sequential cleavage of the signal-and the pro-peptides results in the secretion and the activation of the mature serine protease . The expression of KLKs has been detected in a large number of human tissues and cell lines, implicating the family in a broad spectrum of physiological roles, such as blood pressure regulation, skin desquamation, seminal clot liquefaction, tissue remodeling, peptide hormone processing and inflammatory cascades Yousef et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Kallikrein-related peptidase genes as promising biomarkers for prognosis and monitoring of human malignancies

Avgeris

Mavridis

Scorilas

2010

Biological Chemistry

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Tissue kallikrein (KLK1) and the kallikrein-related peptidase (KLK2-15) genes encode for a subgroup of 15 homologous secreted serine proteases possessing numerous physiological roles, such as the regulation of blood pressure, hormone processing and tissue remodeling. The expression of KLKs is detected in a broad spectrum of human tissues where it has been found to be regulated mainly by steroids hormones. The aberrant expression of KLKs, presented in many human malignancies, highlights the significance of this gene family for early diagnosis, prognosis and monitoring of cancer patients, as it is strongly emphasized by the routine use of PSA (KLK3) for prostate cancer management. Here, we review the presently known data regarding the role of KLKs as cancer biomarkers, giving emphasis on novel information about the subject.

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Human Tissue Kallikreins: From Gene Structure to Function and Clinical Applications

Cited by 63 publications

References 223 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

Expression of Kallikrein-Related Peptidase 6 in Primary Mucosal Malignant Melanoma of the Head and Neck

Kallikrein-related peptidase genes as promising biomarkers for prognosis and monitoring of human malignancies

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