miR-200c: a versatile watchdog in cancer progression, EMT, and drug resistance

MicroRNAs (miRNAs) are 20–22-nucleotide small endogenous non-coding RNAs which regulate gene expression at post-transcriptional level. In the last two decades, identification of almost 2600 miRNAs in human and their potential to be modulated opened a new avenue to target almost all hallmarks of cancer. miRNAs have been classified as tumor suppressors or oncogenes depending on the phenotype they induce, the targets they modulate, and the tissue where they function. miR-200c, an illustrious tumor suppressor, is one of the highly studied miRNAs in terms of development, stemness, proliferation, epithelial-mesenchymal transition (EMT), therapy resistance, and metastasis. In this review, we first focus on the regulation of miR-200c expression and its role in regulating EMT in a ZEB1/E-cadherin axis-dependent and ZEB1/E-cadherin axis-independent manner. We then describe the role of miR-200c in therapy resistance in terms of multidrug resistance, chemoresistance, targeted therapy resistance, and radiotherapy resistance in various cancer types. We highlight the importance of miR-200c at the intersection of EMT and chemoresistance. Furthermore, we show how miR-200c coordinates several important signaling cascades such as TGF-β signaling, PI3K/Akt signaling, Notch signaling, VEGF signaling, and NF-κB signaling. Finally, we discuss miR-200c as a potential prognostic/diagnostic biomarker in several diseases, but mainly focusing on cancer and its potential application in future therapeutics. © 2016, Springer-Verlag Berlin Heidelberg

MIR200C (microRNA 200c)

Review on MIR200C (microRNA 200c), with data on DNA, on the protein encoded, and where the gene is implicated

MiR-564 acts as a dual inhibitor of PI3K and MAPK signaling networks and inhibits proliferation and invasion in breast cancer

Dysregulation of PI3K and MAPK pathways promotes uncontrolled cell proliferation, apoptotic inhibition and metastasis. Individual targeting of these pathways using kinase inhibitors has largely been insufficient due to the existence of cross-talks between these parallel cascades. MicroRNAs are small non-coding RNAs targeting several genes simultaneously and controlling cancer-related processes. To identify miRNAs repressing both PI3K and MAPK pathways in breast cancer, we re-analyzed our previous miRNA mimic screen data with reverse phase protein array (RPPA) output, and identified miR-564 inhibiting both PI3K and MAPK pathways causing markedly decreased cell proliferation through G1 arrest. Moreover, ectopic expression of miR-564 blocks epithelial-mesenchymal transition (EMT) and reduces migration and invasion of aggressive breast cancer cells. Mechanistically, miR-564 directly targets a network of genes comprising AKT2, GNA12, GYS1 and SRF, thereby facilitating simultaneous repression of PI3K and MAPK pathways. Notably, combinatorial knockdown of these target genes using a cocktail of siRNAs mimics the phenotypes exerted upon miR-564 expression. Importantly, high miR-564 expression or low expression of target genes in combination is significantly correlated with better distant relapse-free survival of patients. Overall, miR-564 is a potential dual inhibitor of PI3K and MAPK pathways, and may be an attractive target and prognostic marker for breast cancer. © The Author(s) 2016

The miR-644a/CTBP1/p53 axis suppresses drug resistance by simultaneous inhibition of cell survival and epithelialmesenchymal transition in breast cancer

Tumor cells develop drug resistance which leads to recurrence and distant metastasis. MicroRNAs are key regulators of tumor pathogenesis; however, little is known whether they can sensitize cells and block metastasis simultaneously. Here, we report miR-644a as a novel inhibitor of both cell survival and EMT whereby acting as pleiotropic therapy-sensitizer in breast cancer. We showed that both miR-644a expression and its gene signature are associated with tumor progression and distant metastasis-free survival. Mechanistically, miR-644a directly targets the transcriptional co-repressor C-Terminal Binding Protein 1 (CTBP1) whose knock-outs by the CRISPRCas9 system inhibit tumor growth, metastasis, and drug resistance, mimicking the phenotypes induced by miR-644a. Furthermore, downregulation of CTBP1 by miR-644a upregulates wild type- or mutant-p53 which acts as a 'molecular switch' between G1-arrest and apoptosis by inducing cyclin-dependent kinase inhibitor 1 (p21, CDKN1A, CIP1) or pro-apoptotic phorbol-12-myristate-13-acetate-induced protein 1 (Noxa, PMAIP1), respectively. Interestingly, an increase in mutant-p53 by either overexpression of miR-644a or downregulation of CTBP1 was enough to shift this balance in favor of apoptosis through upregulation of Noxa. Notably, p53- mutant patients, but not p53-wild type ones, with high CTBP1 have a shorter survival suggesting that CTBP1 could be a potential prognostic factor for breast cancer patients with p53 mutations. Overall, re-activation of the miR-644a/CTBP1/p53 axis may represent a new strategy for overcoming both therapy resistance and metastasis

Investigation of scaffolding accident in a construction site: A case study analysis

WOS:000604258200004The construction sector is one of the few high-risk businesses due to occupational accidents, their rate of frequencies, and related serious consequences, sometimes even resulting in the death of individuals. Therefore, it is a vital necessity and priority for employers and employees during the course of a project to comply with occupational safety rules under any circumstances. Nothing should deter or compromise the safety of any individual working in a potential risk environment. Within the scope of this study, the analysis addresses a scaffolding accident that occurred on a construction site. Once the information about how the accident possibly happened was received, the scaffolding in question identified at the construction was kept for an investigation to carry out the corrective and renovation works. In this paper the suspended scaffoldings are firstly categorized. Then how the accident happened was examined and theorized. The examination and analysis were supported by the results. This study is intended to prevent similar accidents and establish necessary precautions as a matter of procedure. © 2020 Elsevier Lt

Imagining the Middle East:The state, nationalism and regional international society

The Middle East is commonly perceived as a zone of cultural and political differences within the global international society. Imagining the Middle East as a ‘unique’ region is not a new idea, but relocating this conception within the English School (ES) of International Relations (IR) is. This article challenges the perceived ‘exceptionalism’ of the Middle East, which claims that the European concepts of state, sovereignty and nationalism are alien to Islam, therefore preventing the emergence of a regional international society. The first part highlights the correlation between Eurocentrism in IR and the lack of interest in regional – area – studies through the critique of Orientalism and the ES. The second part moves to demonstrate why the ES is more explanatory than other IR theories in the context of the Ottoman–European relations. The third part explores the ‘institutional distinctiveness’ of the Middle East, disproving the notion of regional ‘exceptionalism’ and IR’s foundational Eurocentric assumptions. This article concludes by arguing that there is a strong case for calling the Middle East a ‘regional interstate society’, which remains to be a litmus test of whether or not a truly global international society is possible