Browsing by Author "Konu, Ozlen"
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Item Open Access Aging alters the molecular dynamics of synapses in a sexually dimorphic pattern in zebrafish (Danio rerio)(Elsevier, 2017-06) Karoglu, Elif Tugce; Halim, Dilara Ozge; Erkaya, Bahriye; Altaytas, Ferda; Arslan-Ergul, Ayca; Konu, Ozlen; Adams, Michelle M.The zebrafish has become a popular model for studying normal brain aging due to its large fecundity, conserved genome, and available genetic tools; but little data exists about neurobiological age-related alterations. The current study tested the hypothesis of an association between brain aging and synaptic protein loss across males and females. Western blot analysis of synaptophysin (SYP), a presynaptic vesicle protein, and postsynaptic density-95 (PSD-95) and gephyrin (GEP), excitatory and inhibitory postsynaptic receptor-clustering proteins, respectively, was performed in young, middle-aged, and old male and female zebrafish (Danio rerio) brains. Univariate and multivariate analyses demonstrated that PSD-95 significantly increased in aged females and SYP significantly decreased in males, but GEP was stable. Thus, these key synaptic proteins vary across age in a sexually dimorphic manner, which has been observed in other species, and these consequences may represent selective vulnerabilities for aged males and females. These data expand our knowledge of normal aging in zebrafish, as well as further establish this model as an appropriate one for examining human brain aging.Item Open Access Cholinergic receptor nicotinic alpha 5 (CHRNA5) RNAi is associated with cell cycle inhibition, apoptosis, DNA damage response and drug sensitivity in Breast cancer(Public Library of Science, 2018) Koker, Sahika Cingir; Jahja, Ermira; Shehwana, Huma; Keskus, Ayse Gokce; Konu, OzlenCholinergic Receptor Nicotinic Alpha 5 (CHRNA5) is an important susceptibility locus for nicotine addiction and lung cancer. Depletion of CHRNA5 has been associated with reduced cell viability, increased apoptosis and alterations in cellular motility in different cancers yet not in Breast cancer. Herein we first showed the expression of CHRNA5 was variable and positively correlated with the fraction of total genomic alterations in Breast cancer cell lines and tumors indicating its potential role in DNA damage response (DDR). Next, we demonstrated that silencing of CHRNA5 expression in MCF7 Breast cancer cell line by RNAi affected expression of genes involved in cytoskeleton, TP53 signaling, DNA synthesis and repair, cell cycle, and apoptosis. The transcription profile of CHRNA5 depleted MCF7 cells showed a significant positive correlation with that of A549 lung cancer cell line while exhibiting a negative association with the CHRNA5 co-expression profile obtained from Cancer Cell Line Encylopedia (CCLE). Moreover, it exhibited high similarities with published MCF7 expression profiles obtained from exposure to TP53 inducer nutlin-3a and topoisomerase inhibitors. We then demonstrated that CHRNA5 siRNA treatment reduced cell viability and DNA synthesis indicating G1 arrest while it significantly increased apoptotic sub-G1 cell population. Accordingly, we observed lower levels of phosphorylated RB (Ser807/811) and an increased BAX/BCL2 ratio in RNAi treated MCF7 cells. We also showed that CHRNA5 RNAi transcriptome correlated negatively with DDR relevant gene expression profile in Breast cancer gene expression datasets while the coexposure to topoisomerase inhibitors in the presence of CHRNA5 RNAi enhanced chemosensitivity potentially due to reduced DDR. CHRNA5 RNAi consistently lowered total CHEK1 mRNA and protein levels as well as phosphorylated CHEK1 (Ser345) in MCF7 cells. We also detected a significant positive correlation between the expression levels of CHRNA5 and CHEK1 in CCLE, TCGA and METABRIC Breast cancer datasets. Our study suggests CHRNA5 RNAi is associated with cell cycle inhibition, apoptosis as well as reduced DDR and increased drug sensitivity in Breast cancer yet future studies are warranted since dose- and cell line-specific differences exist in response to CHRNA5 depletion. Gene expression microarray data can be accessed from GEO database under the accession number GSE89333.Item Open Access CHRNA5 belongs to the secondary estrogen signaling network exhibiting prognostic significance in breast cancer(Springer, 2021-04) Shehwana, Huma; Keskus, Ayse Gokce; Ozdemir, E. Sila; Acikgöz, Azer Aylin; Biyik-Sit, Rumeysa; Cagnan, I.; Gunes, Damla; Jahja, Ermira; Cingir-Koker, Sahika; Olmezer, Gizem; Sucularli, Ceren; Konu, OzlenCholinergic signals can be important modulators of cellular signaling in cancer. We recently have shown that knockdown of nicotinic acetylcholine receptor subunit alpha 5, CHRNA5, diminishes the proliferative potential of breast cancer cells. However, modulation of CHRNA5 expression in the context of estrogen signaling and its prognostic implications in breast cancer remained unexplored.Item Open Access Global miRNA expression of bone marrow mesenchymal stem/stromal cells derived from Fanconi anemia patients(Springer, 2021-11-18) Cagnan, I.; Keles, M.; Keskus, Ayse Gokce; Tombaz, Melike; Sahan, O. B.; Aerts-Kaya, F.; Uckan-Cetinkaya, D.; Konu, Ozlen; Gunel-Ozcan, A.Fanconi anemia (FA) is a rare genetic disorder characterized by genomic instability, developmental defects, and bone marrow (BM) failure. Hematopoietic stem cells (HSCs) in BM interact with the mesenchymal stem/stromal cells (MSCs); and this partly sustains the tissue homeostasis. MicroRNAs (miRNAs) can play a critical role during these interactions possibly via paracrine mechanisms. This is the first study addressing the miRNA profile of FA BM–MSCs obtained before and after BM transplantation (preBMT and postBMT, respectively). Non-coding RNA expression profiling and quality control analyses were performed in Donors (n = 13), FA preBMT (n = 11), and FA postBMT (n = 6) BM–MSCs using GeneChip miRNA 2.0 Array. Six Donor-FA preBMT pairs were used to identify a differentially expressed miRNA expression signature containing 50 miRNAs, which exhibited a strong correlation with the signature obtained from unpaired samples. Five miRNAs (hsa-miR-146a-5p, hsa-miR-148b-3p, hsa-miR-187-3p, hsa-miR-196b-5p, and hsa-miR-25-3p) significantly downregulated in both the paired and unpaired analyses were used to generate the BM–MSCs’ miRNA—BM mononuclear mRNA networks upon integration of a public dataset (GSE16334; studying Donor versus FA samples). Functionally enriched KEGG pathways included cellular senescence, miRNAs, and pathways in cancer. Here, we showed that hsa-miR-146a-5p and hsa-miR-874-3p were rescued upon BMT (n = 3 triplets). The decrease in miR-146a-5p was also validated using RT-qPCR and emerged as a strong candidate as a modulator of BM mRNAs in FA patients.Item Open Access Zebrafish xenotransplantation models for studying gene function and drug treatment in hepatocellular carcinoma(2022-01-15) Konu, Ozlen; Targen, SeniyeIntroduction Zebrafish is a promising model organism for human disease including hepatocellular cancer (HCC). Recently, zebrafish has emerged also as a host for xenograft studies of liver cancer cell lines and patient derived tumors of HCC. Zebrafish embryos enable drug screening and gene function studies of xenografted cells via ease of microinjection and visualization of tumor growth and metastasis. Objectives In this review, we aimed to overview zebrafish HCC and liver cancer xenotransplantation studies focusing on ‘gene functional analysis’ and ‘drug/chemical screening’. Methods Herein, a comprehensive literature search was performed for liver and HCC xenografts in zebrafish on PubMed using different key words and filters for molecular modifications or drug exposure. Results Our literature search revealed around 250 studies which were filtered and summarized in a table (Table 1) revealing comprehensive collection of experimental and technical details on microinjection, injected cell lines, molecular modifications of injected cells, types and doses of drug treatments as well as biological assessments. Conclusion This review provides a platform for HCC and liver xenografts and highlights studies performed to understand gene functionality and drug efficacy in vivo in zebrafish.