CXXC5 as an unmethylated CpG dinucleotide binding protein contributes to estrogen-mediated cellular proliferation.

Evidence suggests that the CXXC type zinc finger (ZF-CXXC) protein 5 (CXXC5) is a critical regulator/integrator of various signaling pathways that include the estrogen (E2)-estrogen receptor α (ERα). Due to its ZF-CXXC domain, CXXC5 is considered to be a member of the ZF-CXXC family, which binds to unmethylated CpG dinucleotides of DNA and through enzymatic activities for DNA methylation and/or chromatin modifications generates a chromatin state critical for gene expressions. Structural/functional features of CXXC5 remain largely unknown. CXXC5, suggested as transcription and/or epigenetic factor, participates in cellular proliferation, differentiation, and death. To explore the role of CXXC5 in E2-ERα mediated cellular events, we verified by generating a recombinant protein that CXXC5 is indeed an unmethylated CpG binder. We uncovered that CXXC5, although lacks a transcription activation/repression function, participates in E2-driven cellular proliferation by modulating the expression of distinct and mutual genes also regulated by E2. Furthermore, we found that the overexpression of CXXC5, which correlates with mRNA and protein levels of ERα, associates with poor prognosis in ER-positive breast cancer patients. Thus, CXXC5 as an unmethylated CpG binder contributes to E2-mediated gene expressions that result in the regulation of cellular proliferation and may contribute to ER-positive breast cancer progression

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

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

Budd-Chiari syndrome in a 25-year-old woman with Behçet's disease: a case report and review of the literature

<p>Abstract</p> <p>Introduction</p> <p>The risk that patients with Behçet's disease will develop thrombotic complications has been previously described. Although it is distributed worldwide, Behçet's disease is rare in the Americas and Europe. Even though the pathogenic mechanisms of vascular complications of Budd-Chiari syndrome in patients with Behçet's disease are unknown, severe vascular complications of Budd-Chiari syndrome associated with Behçet's disease seem to affect mainly young men.</p> <p>Case presentation</p> <p>We report a case of Budd-Chiari syndrome, a severe vascular complication that developed in a 25-year-old Afro-Brazilian woman with Behçet's disease.</p> <p>Conclusion</p> <p>Severe vascular complications of Budd-Chiari syndrome in patients with Behçet's disease are much more common in young adult male patients; we present a rare case of Budd-Chiari syndrome in a young Afro-Brazilian woman with Behçet's disease.</p

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