Browsing by Author "Zhang, J. D."
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Item Open Access Combined DNA methylation and gene expression profiling in gastrointestinal stromal tumors reveals hypomethylation of SPP1 as an independent prognostic factor(IJC, 2014) Haller, R.; Zhang, J. D.; Moskalev, E. A.; Braun, A.; Otto, C.; Geddert, H.; Riazalhosseini, Y.; Ward, A.; Balwierz, A.; Sahin, Ö.; Schaefer, I. M.; Cameron, S.; Ghadimi, B. M.; Agaimy, A.; Fletcher, J. A.; Hoheisel, J.; Hartmann, A.; Werner, M.; Wiemann, S.Gastrointestinal stromal tumors (GISTs) have distinct gene expression patterns according to localization, genotype and aggressiveness. DNA methylation at CpG dinucleotides is an important mechanism for regulation of gene expression. We performed targeted DNA methylation analysis of 1.505 CpG loci in 807 cancer-related genes in a cohort of 76 GISTs, combined with genome-wide mRNA expression analysis in 22 GISTs, to identify signatures associated with clinicopathological parameters and prognosis. Principal component analysis revealed distinct DNA methylation patterns associated with anatomical localization, genotype, mitotic counts and clinical follow-up. Methylation of a single CpG dinucleotide in the non-CpG island promoter of SPP1 was significantly correlated with shorter disease-free survival. Hypomethylation of this CpG was an independent prognostic parameter in a multivariate analysis compared to anatomical localization, genotype, tumor size and mitotic counts in a cohort of 141 GISTs with clinical follow-up. The epigenetic regulation of SPP1 was confirmed in vitro, and the functional impact of SPP1 protein on tumorigenesis-related signaling pathways was demonstrated. In summary, SPP1 promoter methylation is a novel and independent prognostic parameter in GISTs, and might be helpful in estimating the aggressiveness of GISTs from the intermediate-risk category. © 2014 UICC.Item Open Access MicroRNas: master regulators of drug resistance, stemness and metastasis(Springer Berlin Heidelberg, 2014-04) Raza, U.; Zhang, J. D.; Şahin, Ö.MicroRNAs (miRNAs) are 20-22 nucleotides long small non-coding RNAs that regulate gene expression post-transcriptionally. Last decade has witnessed emerging evidences of active roles of miRNAs in tumor development, progression, metastasis, and drug resistance. Many factors contribute to their dysregulation in cancer, such as chromosomal aberrations, differential methylation of their own or host genes' promoters and alterations in miRNA biogenesis pathways. miRNAs have been shown to act as tumor suppressors or oncogenes depending on the targets they regulate and the tissue where they are expressed. Because miRNAs can regulate dozens of genes simultaneously and they can function as tumor suppressors or oncogenes, they have been proposed as promising targets for cancer therapy. In this review, we focus on the role of miRNAs in driving drug resistance and metastasis which are associated with stem cell properties of cancer cells. Furthermore, we discuss systems biology approaches to combine experimental and computational methods to study effects of miRNAs on gene or protein networks regulating these processes. Finally, we describe methods to target oncogenic or replace tumor suppressor miRNAs and current delivery strategies to sensitize refractory cells and to prevent metastasis. A holistic understanding of miRNAs' functions in drug resistance and metastasis, which are major causes of cancer-related deaths, and the development of novel strategies to target them efficiently will pave the way towards better translation of miRNAs into clinics and management of cancer therapy. © 2014 Springer-Verlag Berlin Heidelberg.Item Open Access The miR-644a/CTBP1/p53 axis suppresses drug resistance by simultaneous inhibition of cell survival and epithelialmesenchymal transition in breast cancer(Impact Journals LLC, 2016) Raza, U.; Saatci, O.; Uhlmann, S.; Ansari, S. A.; Eyüpoglu, E.; Yurdusev, E.; Mutlu, M.; Ersan, P. G.; Altundağ, M. K.; Zhang, J. D.; Dogan, H. T.; Güler, G.; Şahin, Ö.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.