Kallikreins as microRNA targets: an<i>in silico</i>and experimental-based analysis

Chow, Tsz-fung F.; Crow, Megan; Earle, Tammy; El-Said, Hala; Diamandis, Eleftherios P.; Yousef, George M.

doi:10.1515/bc.2008.071

Cited by 45 publications

(44 citation statements)

References 19 publications

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“…All KLKs, except KLK14, were predicted to be targets for ovarian cancer-dysregulated miRNAs. As reported earlier, multiple miRNAs were predicted to target the same KLK and the same miRNA was predicted to target multiple KLKs (Chow et al, 2008;Yousef, 2008). There were no miRNAs that were predicted to target more than five KLKs.…”

Section: In Silico Analysis Of Klks As Mirna Targets In Ovarian Cancersupporting

confidence: 58%

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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: In Silico Analysis Of Klks As Mirna Targets In Ovarian Cancersupporting

confidence: 58%

“…We have recently published the first manuscript of in silico and experimental-based analysis of the potential of KLK regulation by miRNAs (Chow et al, 2008). We also provided preliminary experimental validation of the miRNA target prediction analysis.…”

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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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“…It is hypothesized that, in part, this regulation may be posttranscriptional through miRNAs (Chow et al , 2008 ;Yousef , 2008 ). We showed evidence indicating that miRNAs can contribute to KLK dysregulation in PCa through two independent lines of evidence.…”

Section: Discussionmentioning

confidence: 67%

“…The interaction between miRNAs and KLKs is emerging in the literature as a potential new dimension of regulation of carcinogenesis in many tumors including ovarian and kidney cancers (Chow et al , 2008 ;Yousef , 2008 ;White et al , 2010a,b ). Recognizing this relationship will enhance our understanding of the mechanisms that control KLK dysregulation in PCa and will also shed the light on the downstream effector pathways through which miRNAs can affect tumor formation and progression.…”

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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“…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%

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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Kallikreins as microRNA targets: anin silicoand experimental-based analysis

Cited by 45 publications

References 19 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

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

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

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