The role of proteases in epithelial-to-mesenchymal cell transitions in cancer

Mitschke, Julia; Burk, Ulrike; Reinheckel, Thomas

doi:10.1007/s10555-019-09808-2

Cited by 37 publications

(29 citation statements)

References 143 publications

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“…The epithelial-mesenchymal transition (EMT) is mainly regulated by a small number of transcription factors (TFs). They belong to the Snail (SNAIL, SLUG), basic helix-loop-helix (TWIST1 TWIST2), and ZEB (ZEB1, ZEB2) families [48,49]. Individual EMT-TFs regulate in turn the expression of common, but also specific, target genes, which they can either repress or activate [48,49].…”

Section: Klf7 Knockdown Suppresses Expression Of Emt-inducer Genesmentioning

confidence: 99%

KLF7: a new candidate biomarker and therapeutic target for high-grade serous ovarian cancer

Donato

Babini

Mozzetti

et al. 2020

J Exp Clin Cancer Res

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Background In spite of great progress in the surgical and clinical management, until now no significant improvement in overall survival of High-Grade Serous Ovarian Cancer (HGSOC) patients has been achieved. Important aspects for disease control remain unresolved, including unclear pathogenesis, high heterogeneity and relapse resistance after chemotherapy. Therefore, further research on molecular mechanisms involved in cancer progression are needed to find new targets for disease management. The Krüppel-like factors (KLFs) are a family of transcriptional regulators controlling several basic cellular processes, including proliferation, differentiation and migration. They have been shown to play a role in various cancer-relevant processes, in a context-dependent way. Methods To investigate a possible role of KLF family members as prognostic biomarkers, we carried out a bioinformatic meta-analysis of ovarian transcriptome datasets in different cohorts of late-stage HGSOC patients. In vitro cellular models of HGSOC were used for functional studies exploring the role of KLF7 in disease development and progression. Finally, molecular modelling and virtual screening were performed to identify putative KLF7 inhibitors. Results Bioinformatic analysis highlighted KLF7 as the most significant prognostic gene, among the 17 family members. Univariate and multivariate analyses identified KLF7 as an unfavourable prognostic marker for overall survival in late-stage TCGA-OV and GSE26712 HGSOC cohorts. Functional in vitro studies demonstrated that KLF7 can play a role as oncogene, driving tumour growth and dissemination. Mechanistic targets of KLF7 included genes involved in epithelial to mesenchymal transition, and in maintaining pluripotency and self-renewal characteristics of cancer stem cells. Finally, in silico analysis provided reliable information for drug-target interaction prediction. Conclusions Results from the present study provide the first evidence for an oncogenic role of KLF7 in HGSOC, suggesting it as a promising prognostic marker and therapeutic target.

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Section: Klf7 Knockdown Suppresses Expression Of Emt-inducer Genesmentioning

confidence: 99%

KLF7: a new candidate biomarker and therapeutic target for high-grade serous ovarian cancer

Donato

Babini

Mozzetti

et al. 2020

J Exp Clin Cancer Res

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“…A recent study showed that EMT is associated with immunity in human cancers (Gugnoni et al, 2017;Mitschke, Burk & Reinheckel, 2019;Yeung & Yang, 2017). Increased expression of EMT markers in breast tumors is associated with increased immune infiltration into the tumor microenvironment (Kotiyal & Bhattacharya, 2014;Yeung & Yang, 2017).…”

Section: Introductionmentioning

confidence: 99%

EMT-related gene expression is positively correlated with immunity and may be derived from stromal cells in osteosarcoma

Peng

Qin

et al. 2020

PeerJ

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Background Osteosarcoma is the most common type of bone cancer in children and young adults. Recent studies have shown a correlation between epithelial–mesenchymal transition (EMT)-related gene expression and immunity in human cancers. Here, we investigated the relationship among EMT, immune activity, stromal activity and tumor purity in osteosarcoma. Methods We defined EMT gene signatures and evaluated immune activity and stromal activity based on the gene expression and clinical data from three independent microarray datasets. These factors were evaluated by single sample Gene Set Enrichment Analyses and the ESTIMATE tool. Finally, we analyzed the key source of EMT gene expression in osteosarcoma using microarray datasets from the Gene Expression Omnibus and human samples that we collected. Results EMT-related gene expression was positively correlated with immune and stromal activity in osteosarcoma. Tumor purity was negatively correlated with EMT, immune activity and stromal cells. We further demonstrated that high EMT gene expression could significantly predict poor overall survival (OS) and recurrence-free survival (RFS) in osteosarcoma patients, while high immune activity cannot. However, combining these factors could have further prognostic value for osteosarcoma patients in terms of OS and RFS. Finally, we found that stromal cells may serve as a key source of EMT gene expression in osteosarcoma. Conclusion The results of this study reveal that the expression of EMT genes and immunity are positively correlated, but these signatures convey disparate prognostic information. Furthermore, the results indicate that EMT-related gene expression may be derived from stromal rather than epithelial cancer cells.

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“…MMP-7 is known to bind to and inhibit the FAS-cleavage, inhibiting apoptosis and thereby contributing to carcinogenesis [ 24 ]. Various MMPs have been known to cleave the extracellular domain of E-cadherin that interacts with β-catenin to anchor the cells to surrounding parenchyma [ 25 ]. MMP-based ECM-protein cleavage results in detachment of cells from the surrounding parenchyma essential to allow them to metastasize.…”

Section: Introductionmentioning

confidence: 99%

Bioinformatics and Molecular Insights to Anti-Metastasis Activity of Triethylene Glycol Derivatives

Malik

Garg

Afzal

et al. 2020

IJMS

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The anti-metastatic and anti-angiogenic activities of triethylene glycol derivatives have been reported. In this study, we investigated their molecular mechanism(s) using bioinformatics and experimental tools. By molecular dynamics analysis, we found that (i) triethylene glycol dimethacrylate (TD-10) and tetraethylene glycol dimethacrylate (TD-11) can act as inhibitors of the catalytic domain of matrix metalloproteinases (MMP-2, MMP-7 and MMP-9) by binding to the S1’ pocket of MMP-2 and MMP-9 and the catalytic Zn ion binding site of MMP-7, and that (ii) TD-11 can cause local disruption of the secondary structure of vascular endothelial growth factor A (VEGFA) dimer and exhibit stable interaction at the binding interface of VEGFA receptor R1 complex. Cell-culture-based in vitro experiments showed anti-metastatic phenotypes as seen in migration and invasion assays in cancer cells by both TD-10 and TD-11. Underlying biochemical evidence revealed downregulation of VEGF and MMPs at the protein level; MMP-9 was also downregulated at the transcriptional level. By molecular analyses, we demonstrate that TD-10 and TD-11 target stress chaperone mortalin at the transcription and translational level, yielding decreased expression of vimentin, fibronectin and hnRNP-K, and increase in extracellular matrix (ECM) proteins (collagen IV and E-cadherin) endorsing reversal of epithelial–mesenchymal transition (EMT) signaling.

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The role of proteases in epithelial-to-mesenchymal cell transitions in cancer

Cited by 37 publications

References 143 publications

KLF7: a new candidate biomarker and therapeutic target for high-grade serous ovarian cancer

KLF7: a new candidate biomarker and therapeutic target for high-grade serous ovarian cancer

EMT-related gene expression is positively correlated with immunity and may be derived from stromal cells in osteosarcoma

Bioinformatics and Molecular Insights to Anti-Metastasis Activity of Triethylene Glycol Derivatives

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