Characterisation of human kallikrein 6/protease M expression in ovarian cancer

Ni, Xiaoling; Zhang, W; Huang, K.C.; Wang, Y; Ng, Shu Kay; Mok, S. C.; Rs, Berkowitz; Ng, S-W

doi:10.1038/sj.bjc.6602041

Cited by 52 publications

(41 citation statements)

References 24 publications

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“…High KLK6 mRNA expression was associated with the presence of serous ovarian cancer and late stage disease. These results are similar to previous studies, which found increased KLK6 expression in ovarian cancers when compared to normal ovarian tissue (Anisowicz et al, 1996;Tanimoto et al, 2001;Ni et al, 2004). Interestingly, previous studies have also associated high KLK6 serum levels with advanced ovarian cancer (stage III/IV) and serous tumour histology (Hoffman et al, 2002;Shan et al, 2007).…”

Section: Discussionsupporting

confidence: 82%

KLK6 and KLK13 predict tumor recurrence in epithelial ovarian carcinoma

et al. 2009

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BACKGROUND: The human kallikrein-related peptidase family consists of 15 genes. Twelve of these genes are overexpressed in ovarian cancer and may represent potential markers for diagnosis, prognosis, and/or response to treatment. The aim of this study was to determine the prognostic significance of kallikrein-related peptidase 6 (KLK6) and kallikrein-related peptidase 13 (KLK13) in epithelial ovarian cancer by quantifying gene expression levels with tumour pathology and patient survival data. METHODS: Total RNA was isolated from 106 patients diagnosed with primary ovarian cancer, as well as 8 normal ovary controls. Samples were analysed by quantitative real-time PCR for KLK6 and KLK13 expression. Correlation between kallikrein gene expression and clinical characteristics was evaluated with the w 2 -test. Survival analysis was performed using Kaplan -Meier and Cox proportional hazards regression models. RESULTS: Expression levels of both KLK6 and KLK13 mRNA were significantly increased in invasive cancers relative to normal ovaries (P ¼ 0.002 and 0.039 respectively). High KLK6 and KLK13 expression was an indicator of poor prognosis, with patients having a shorter recurrence-free survival (P ¼ 0.002 and 0.027 respectively). High KLK6 expression was also significantly associated with lower overall survival (P ¼ 0.011). When subjected to multivariate analysis, patients with either high KLK6 or KLK13 were 3-and 2.2-fold, respectively, more likely to have a recurrence than patients with low kallikrein expression. CONCLUSION: These data show increased mRNA expression of KLK6 and KLK13 in ovarian cancer compared to normal ovarian tissues. High KLK6 or KLK13 expression in primary ovarian tumours can significantly predict prognosis in terms of recurrence-free survival and overall survival. In all, this study shows KLK6 and KLK13 as potential biomarkers and may be therapeutic targets for treatment of ovarian cancer.

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Section: Discussionsupporting

confidence: 82%

KLK6 and KLK13 predict tumor recurrence in epithelial ovarian carcinoma

et al. 2009

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“…Lastly, chromosome 19q13 is reportedly rearranged in numerous types of solid tumours (Whang-Peng et al, 1984;Tanaka et al, 1989;Bello and Rey, 1990;Pejovic et al, 1991Pejovic et al, , 1992Jenkins et al, 1993). Potential gene amplification of KLK6 in ovarian cancer has also been suggested (Ni et al, 2004). Therefore, the role of chromosomal rearrangements of the KLK locus in cancer should be examined in future investigations.…”

Section: Discussionmentioning

confidence: 98%

Transcriptional upregulation of human tissue kallikrein 6 in ovarian cancer: clinical and mechanistic aspects

et al. 2007

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The human tissue kallikrein family (KLK for protein; KLK for gene) includes 15 members. Twelve kallikreins, including KLK6, are concurrently upregulated in ovarian cancer. However, the mechanism of this phenomenon remains unclear. In this study, we measured KLK6 expression in a large series of ovarian tissue cytosols and examined possible mechanisms of KLK6 up-regulation in ovarian cancer. Using a newly developed enzyme-linked immunosorbent assay (ELISA) with two monoclonal antibodies, we quantified KLK6 expression in ovarian tissue cytosols, and confirmed the upregulation of KLK6 in ovarian cancer and its unfavourable prognostic value. We then examined KLK6 mRNA expression using reverse transcription -polymerase chain reaction and established its good concordance with KLK6 protein expression. This finding suggested that the KLK6 gene is under transcriptional regulation. We then scrutinised a few mechanisms that could explain KLK6 upregulation. The relative abundance of two KLK6 mRNA transcripts was studied; we found the same differential expression pattern in all samples, regardless of KLK6 levels. Genomic mutation screening of all exons and the 5 0 -flanking region of the KLK6 gene identified two linked single-nucleotide polymorphisms in the 5 0 -untranslated region, but neither correlated with KLK6 expression. Ovarian cell lines were separately treated with five steroid hormones. None of the treatments produced significant effects on KLK6 expression. We conclude that KLK6 is transcriptionally upregulated in ovarian cancer, but probably not through alternative mRNA transcript expression, genomic mutation, or steroid hormone induction.

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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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Characterisation of human kallikrein 6/protease M expression in ovarian cancer

Cited by 52 publications

References 24 publications

KLK6 and KLK13 predict tumor recurrence in epithelial ovarian carcinoma

KLK6 and KLK13 predict tumor recurrence in epithelial ovarian carcinoma

Transcriptional upregulation of human tissue kallikrein 6 in ovarian cancer: clinical and mechanistic aspects

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

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