Browsing by Author "Riazalhosseini, Y."
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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 Modules of correlated genes in a gene expression regulatory network of CDDP-resistant cancer cells(Institute of Electrical and Electronics Engineers, 2018) Vargas, D. J.; Acón, M. S.; Sahin, Özgür; Eyüpoğlu, Erol; Riazalhosseini, Y.; Mora, J. M.; Coto, J. G.; Rodriguez, R. M.Chemotherapeutic drugs have been used as important strategies in cancer treatment. However, chemotherapy-resistant tumors arise especially in relapsing and progressive disease. Understanding of mechanisms underlaying Cisplatin-CDDP chemotherapy resistance may help find new therapeutic targets to revert this phenotype. The aim of this work, through an integrative Systems Biology approach, is to optimize an in silico model of TFs-miRNAs gene expression regulatory network of CDDP-chemoresistant cancer cell lines. By identifying modules of co-expressed genes in this regulatory network we expect further understanding of CDDP-chemoresistant phenotype. A set of deregulated genes was determined for two CDDP-chemoresistant cancer cell lines by considering gene copy number and transcriptomics. These genes were used as input targets for the construction and fitting of a large scale ordinary differential equations (ODE) model using our biocomputational platform previously reported. Model optimization was performed using COPASI and modules of correlated genes were determined using WGCNA. A model of 108 deregulated target genes, 44 transcription factors and 21 miRNAs was successfully constructed and optimized. Eleven modules of correlated genes were determined along with their gene product annotation. This report contributes to the understanding of the complex regulatory networks of CDDP-resistance and the future design of therapeutic strategies to overcome drug resistance.Item Open Access Reactivation of cAMP pathway by PDE4D inhibition represents a novel druggable axis for overcoming tamoxifen resistance in ER-positive breast cancer(American Association for Cancer Research, 2018) Mishra, Rasmi R.; Belder, Nevin; Ansari, Suhail A.; Kayhan, Merve; Bal, Hilal; Raza, Umar; Ersan, Pelin G.; Tokat, Ünal M.; Eyüpoğlu, Erol; Saatçi, Özge; Jandaghi, P.; Wiemann, S.; Üner, A.; Çekiç, Çağlar; Riazalhosseini, Y.; Şahin, ÖzgürPurpose: Tamoxifen remains an important hormonal therapy for ER-positive breast cancer; however, development of resistance is a major obstacle in clinics. Here, we aimed to identify novel mechanisms of tamoxifen resistance and provide actionable drug targets overcoming resistance. Experimental Design: Whole-transcriptome sequencing, downstream pathway analysis, and drug repositioning approaches were used to identify novel modulators [here: phosphodiesterase 4D (PDE4D)] of tamoxifen resistance. Clinical data involving tamoxifen-treated patients with ER-positive breast cancer were used to assess the impact of PDE4D in tamoxifen resistance. Tamoxifen sensitization role of PDE4D was tested in vitro and in vivo. Cytobiology, biochemistry, and functional genomics tools were used to elucidate the mechanisms of PDE4D-mediated tamoxifen resistance. Results: PDE4D, which hydrolyzes cyclic AMP (cAMP), was significantly overexpressed in both MCF-7 and T47D tamoxifen-resistant (TamR) cells. Higher PDE4D expression predicted worse survival in tamoxifen-treated patients with breast cancer (n ¼ 469, P ¼ 0.0036 for DMFS; n ¼ 561, P ¼ 0.0229 for RFS) and remained an independent prognostic factor for RFS in multivariate analysis (n ¼ 132, P ¼ 0.049). Inhibition of PDE4D by either siRNAs or pharmacologic inhibitors (dipyridamole and Gebr-7b) restored tamoxifen sensitivity. Sensitization to tamoxifen is achieved via cAMP-mediated induction of unfolded protein response/ER stress pathway leading to activation of p38/JNK signaling and apoptosis. Remarkably, acetylsalicylic acid (aspirin) was predicted to be a tamoxifen sensitizer using a drug repositioning approach and was shown to reverse resistance by targeting PDE4D/ cAMP/ER stress axis. Finally, combining PDE4D inhibitors and tamoxifen suppressed tumor growth better than individual groups in vivo. Conclusions: PDE4D plays a pivotal role in acquired tamoxifen resistance via blocking cAMP/ER stress/p38-JNK signaling and apoptosis.Item Open Access Targeting HIF1-alpha/miR-326/ITGA5 axis potentiates chemotherapy response in triple-negative breast cancer(Springer New York LLC, 2022-03-25) Tokat, Unal Metin; Tarman, Ibrahim Oguzhan; Ersan, Pelin Gulizar; Raza, Umar; Saatci, O.; Sahin, O.; Ogul, H.; Riazalhosseini, Y.; Can, T.; Assidicky, RidhoPurpose Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer that is frequently treated with chemotherapy. However, many patients exhibit either de novo chemoresistance or ultimately develop resistance to chemotherapy, leading to significantly high mortality rates. Therefore, increasing the efficacy of chemotherapy has potential to improve patient outcomes. Methods Here, we performed whole transcriptome sequencing (both RNA and small RNA-sequencing), coupled with network simulations and patient survival data analyses to build a novel miRNA-mRNA interaction network governing chemoresistance in TNBC. We performed cell proliferation assay, Western blotting, RNAi/miRNA mimic experiments, FN coating, 3D cultures, and ChIP assays to validate the interactions in the network, and their functional roles in chemoresistance. We developed xenograft models to test the therapeutic potential of the identified key miRNA/proteins in potentiating chemoresponse in vivo. We also analyzed several patient datasets to evaluate the clinical relevance of our findings. Results We identified fibronectin (FN1) as a central chemoresistance driver gene. Overexpressing miR-326 reversed FN1-driven chemoresistance by targeting FN1 receptor, ITGA5. miR-326 was downregulated by increased hypoxia/HIF1A and ECM stiffness in chemoresistant tumors, leading to upregulation of ITGA5 and activation of the downstream FAK/Src signaling pathways. Overexpression of miR-326 or inhibition of ITGA5 overcame FN1-driven chemotherapy resistance in vitro by inhibiting FAK/Src pathway and potentiated the efficacy of chemotherapy in vivo. Importantly, lower expression of miR-326 or higher levels of predicted miR-326 target genes was significantly associated with worse overall survival in chemotherapy-treated TNBC patients. Conclusion FN1 is central in chemoresistance. In chemoresistant tumors, hypoxia and resulting ECM stiffness repress the expression of the tumor suppressor miRNA, miR-326. Hence, re-expression of miR-326 or inhibition of its target ITGA5 reverses FN1-driven chemoresistance making them attractive therapeutic approaches to enhance chemotherapy response in TNBCs.Item Open Access Targeting lysyl oxidase (LOX) overcomes chemotherapy resistance in triple negative breast cancer(Nature Research, 2020) Saatçi, Ö.; Kaymak, A.; Raza, Umar; Ersan, Pelin G.; Akbulut, Özge; Banister, C. E.; Sikirzhytski, V.; Tokat, Ünal Metin; Aykut, Gamze; Ansari, Suhail A.; Tatlı-Doğan, H.; Doğan, M.; Jandaghi, P.; Işık, A.; Gündoğdu, F.; Kösemehmetoğlu, K.; Dizdar, Ö.; Aksoy, S.; Akyol, A.; Üner, A.; Buckhaults, P. J.; Riazalhosseini, Y.; Şahin, ÖzgürChemoresistance is a major obstacle in triple negative breast cancer (TNBC), the most aggressive breast cancer subtype. Here we identify hypoxia-induced ECM re-modeler, lysyl oxidase (LOX) as a key inducer of chemoresistance by developing chemoresistant TNBC tumors in vivo and characterizing their transcriptomes by RNA-sequencing. Inhibiting LOX reduces collagen cross-linking and fibronectin assembly, increases drug penetration, and downregulates ITGA5/FN1 expression, resulting in inhibition of FAK/Src signaling, induction of apoptosis and re-sensitization to chemotherapy. Similarly, inhibiting FAK/Src results in chemosensitization. These effects are observed in 3D-cultured cell lines, tumor organoids, chemoresistant xenografts, syngeneic tumors and PDX models. Re-expressing the hypoxia-repressed miR-142-3p, which targets HIF1A, LOX and ITGA5, causes further suppression of the HIF-1α/LOX/ITGA5/FN1 axis. Notably, higher LOX, ITGA5, or FN1, or lower miR-142-3p levels are associated with shorter survival in chemotherapy-treated TNBC patients. These results provide strong pre-clinical rationale for developing and testing LOX inhibitors to overcome chemoresistance in TNBC patients.