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

Shan, Shubham; Scorilas, Andreas; Katsaros, Dionyssios; Diamandis, Eleftherios P.

doi:10.1038/sj.bjc.6603556

Cited by 40 publications

(39 citation statements)

References 46 publications

(51 reference statements)

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“…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). Ovarian serous tumours of borderline and low grade are thought to arise from a step-wise progression from adenoma to borderline tumour to carcinoma through the Ras-Raf signalling pathway (Bell, 2005).…”

Section: Discussionsupporting

confidence: 90%

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: 90%

KLK6 and KLK13 predict tumor recurrence in epithelial ovarian carcinoma

et al. 2009

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“…Hormonal control is another postulated mechanism (Yousef and Diamandis, 1999;Shaw and Diamandis, 2008;Lai et al, 2009). However, there are also reports that suggest that other regulatory mechanism exists for KLK expression in cancers (Shan et al, 2007). Our findings highlight the possibility that miRNAs represent a potential regulatory mechanism for controlling kallikrein expression at the post-transcriptional level.…”

Section: Discussionmentioning

confidence: 62%

“…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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“…Ovarian cancer cells that either constitutively overexpress active Akt/AKT1 or exhibit AKT2 gene amplification are highly resistant to paclitaxel compared with cells with low AKT levels 23. Overexpression of KLK6 24, EGFR 25, LMX1B 26, BMP8B and ATP13A4 27, because of gene amplification or high copy number gains, is associated with worse PFS and OS in patients with ovarian cancer. In contrast, an increased copy number of GAB2 is associated with improved PFS and OS and correlates with enhanced sensitivity to the dual PI3K/mTOR inhibitor PF‐04691502 in vitro 27.…”

Section: Molecular Portraits Underlying Th Of Eocmentioning

confidence: 99%

Genetic and epigenetic heterogeneity of epithelial ovarian cancer and the clinical implications for molecular targeted therapy

Bai

Cao

Yang

et al. 2016

J Cellular Molecular Medi

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Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy, and tumoural heterogeneity (TH) has been blamed for treatment failure. The genomic and epigenomic atlas of EOC varies significantly with tumour histotype, grade, stage, sensitivity to chemotherapy and prognosis. Rapidly accumulating knowledge about the genetic and epigenetic events that control TH in EOC has facilitated the development of molecular‐targeted therapy. Poly (ADP‐ribose) polymerase (PARP) inhibitors, designed to target homologous recombination, are poised to change how breast cancer susceptibility gene (BRCA)‐related ovarian cancer is treated. Epigenetic treatment regimens being tested in clinical or preclinical studies could provide promising novel treatment approaches and hope for improving patient survival.

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

Cited by 40 publications

References 46 publications

KLK6 and KLK13 predict tumor recurrence in epithelial ovarian carcinoma

KLK6 and KLK13 predict tumor recurrence in epithelial ovarian carcinoma

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

Genetic and epigenetic heterogeneity of epithelial ovarian cancer and the clinical implications for molecular targeted therapy

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