Kallikrein-related peptidases 4, 5, 6 and 7 regulate tumour-associated factors in serous ovarian cancer

Wang, Ping; Magdolen, Viktor; Seidl, Christof; Dorn, Julia; Drecoll, Enken; Kotzsch, Matthias; Yang, Feng; Schilling, Oliver; Rockstroh, Anja; Clements, Judith A.; Loessner, Daniela

doi:10.1038/s41416-018-0260-1

Cited by 32 publications

(28 citation statements)

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“…KLK5 and L1CAM play important roles in cancer progression (including cell proliferation, migration, angiogenesis, invasion, and metastasis) (34, 35), and their expression levels are associated with prognosis. KLK5 not only regulates KRT19 expression to increase the malignancy of ovarian cancer cells strongly (36), but also induces miRNA-mediated anti-oncogenic pathways in breast cancer (37). However, KLK5 plays different roles in different cancers (38, 39).…”

Section: Discussionmentioning

confidence: 99%

Integrated Transcriptome Analysis Reveals KLK5 and L1CAM Predict Response to Anlotinib in NSCLC at 3rd Line

et al. 2019

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The oral multi-targeted tyrosine kinase inhibitor (TKI) anlotinib is effective for non-small cell lung cancer (NSCLC) in clinical trials at 3rd line. However, a fraction of patients remains non-responsive, raising the need of how to identify anlotinib-responsive patients. In the present study, we aimed to screen potential biomarkers for anlotinib-responsive stratification via integrated transcriptome analysis. Comparing with the anlotinib-sensitive lung cancer cell NCI-H1975, we found 1,315 genes were differentially expressed in anlotinib-resistant NCI-H1975 cells. Among the enriched angiogenesis-related genes, we observed high expression of KLK5 and L1CAM was mostly associated with poor clinical outcomes in NSCLC patients through Kaplan-Meier survival analysis in a TCGA cohort. Moreover, an independent validation in a cohort of ALTER0303 (NCT02388919) indicated that high serum levels of KLK5 and L1CAM were also associated with poor anlotinib response in NSCLC patients at 3rd line. Lastly, we demonstrated that knockdown of KLK5 and L1CAM increases anlotinib-induced cytotoxicity in anlotinib-resistant NCI-H1975 cells. Collectively, our study suggested serum levels of KLK5 and L1CAM potentially serve as biomarkers for anlotinib-responsive stratification in NSCLC patients at 3rd line.

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Section: Discussionmentioning

confidence: 99%

Integrated Transcriptome Analysis Reveals KLK5 and L1CAM Predict Response to Anlotinib in NSCLC at 3rd Line

et al. 2019

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“…Many of the identified differentially expressed proteins are involved in cell-cell communication, including TGF-ß [24]. Furthermore, KLK4-7 regulate gene expression of other cancerrelated factors: simultaneous overexpression of these four KLKs lead, e.g., to a distinct up-regulation of moesin and keratin 19 mRNA and protein expression, while keratin 7 is strongly down-regulated [41]. In fact, under physiological conditions, several members of the KLK family are known to interact with each other in different tissues [42].…”

Section: Discussionmentioning

confidence: 99%

Quantitative assessment and clinical relevance of kallikrein-related peptidase 5 mRNA expression in advanced high-grade serous ovarian cancer

et al. 2019

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Background: In ovarian cancer, dysregulation of mRNA expression of several components of the family of the kallikrein-related peptidases (KLKs) is observed. In this study, we have analyzed the KLK5 mRNA expression pattern in tumor tissue of patients suffering from high-grade serous ovarian cancer stage FIGO III/IV. Moreover, we have correlated the KLK5 mRNA levels with clinical outcome. Methods: We assessed the mRNA expression levels of KLK5 in tumor tissue of 138 patients using quantitative PCR (qPCR). The mRNA levels were correlated with KLK5 antigen tumor tissue levels measured by ELISA (available for 41 of the 138 patients), established clinical features as well as patients' outcome, using Chi-square-tests, Mann-Whitney U-tests and Spearman rank calculations as well as Cox regression models, Kaplan-Meier survival analysis and the log-rank test. Results: A highly significant correlation between the mRNA expression levels and protein levels of KLK5 in tumor tissues was observed (r s = 0.683, p < 0.001). In univariate Cox regression analysis, elevated KLK5 mRNA expression was remarkably associated with reduced progression-free survival (PFS; p = 0.047), but not with overall survival (OS). Association of KLK5 mRNA expression with PFS was validated in silico using The Cancer Genome Atlas. For this, Affymetrix-based mRNA data (n = 377) were analyzed applying the Kaplan-Meier Plotter tool (p = 0.027). In multivariable Cox analysis, KLK5 mRNA values revealed a trend towards statistical significance for PFS (p = 0.095), whereas residual tumor mass (0 mm vs. > 0 mm), but not ascites fluid volume (≤500 ml vs. > 500 ml), remained an independent indicator for both OS and PFS (p < 0.001, p = 0.005, respectively). Conclusions: These results obtained with a homogenous patient group with all patients suffering from advanced high-grade serous ovarian cancer support previous results suggesting elevated KLK5 mRNA levels as an unfavorable marker in ovarian cancer.

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“…Hsa_circ_0051240, derived from the gene CEACAM5, is another circRNA that is upregulated in OvCa. This highly expressed circRNA was reported to enhance cell proliferation, invasion and migration by targeting miR-637 to regulate the expression of Kallikrein-related peptidases 4 (KLK4), and KLK4 was reported to be involved in many steps of OvCa tumorigenesis and progression and to exert modulatory effects on a subset of cancer-related genes and proteins in several cancers [62,63].…”

Section: Hsa_circ_0051240mentioning

confidence: 99%

The emerging roles of circular RNAs in ovarian cancer

et al. 2020

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Circular RNA (circRNA) is a novel class of regulatory noncoding RNA (ncRNA) molecules with a unique covalently closed loop structure. Next-generation sequencing shows that thousands of circRNAs are widely and stably expressed in multiple eukaryotes. As novel regulatory ncRNAs, circRNAs possess several specific molecular functions, including regulating gene transcription and translation, acting as miRNA sponges, and interacting with functional proteins. Ovarian cancer (OvCa) is one of the most aggressive malignant diseases affecting the lives of thousands of women worldwide, and the majority of OvCa cases are diagnosed at advanced stages. Accumulating evidence has revealed the significant roles of circRNAs in the occurrence and progression of OvCa, indicating the function of circRNAs as promising biomarkers and their therapeutic relevance in this disease. This review aims to summarize the mechanisms by which circRNAs mediate OvCa progression as well as their diagnostic and prognostic values in OvCa.

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Kallikrein-related peptidases 4, 5, 6 and 7 regulate tumour-associated factors in serous ovarian cancer

Cited by 32 publications

References 50 publications

Integrated Transcriptome Analysis Reveals KLK5 and L1CAM Predict Response to Anlotinib in NSCLC at 3rd Line

Integrated Transcriptome Analysis Reveals KLK5 and L1CAM Predict Response to Anlotinib in NSCLC at 3rd Line

Quantitative assessment and clinical relevance of kallikrein-related peptidase 5 mRNA expression in advanced high-grade serous ovarian cancer

The emerging roles of circular RNAs in ovarian cancer

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