Researcher:
Özcan, Gülnihal

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Gülnihal

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Özcan

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Özcan, Gülnihal

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2019 - 201912020 - 20235

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    The hypoxia-inducible factor-1α in stemness and resistance to chemotherapy in gastric cancer: future directions for therapeutic targeting
    (Frontiers Media S.A., 2023) Özcan, Gülnihal; Faculty Member; School of Medicine; 185014
    Hypoxia-inducible factor-1α (HIF-1α) is a crucial mediator of intra-tumoral heterogeneity, tumor progression, and unresponsiveness to therapy in tumors with hypoxia. Gastric tumors, one of the most aggressive tumors in the clinic, are highly enriched in hypoxic niches, and the degree of hypoxia is strongly correlated with poor survival in gastric cancer patients. Stemness and chemoresistance in gastric cancer are the two root causes of poor patient outcomes. Based on the pivotal role of HIF-1α in stemness and chemoresistance in gastric cancer, the interest in identifying critical molecular targets and strategies for surpassing the action of HIF-1α is expanding. Despite that, the understanding of HIF-1α induced signaling in gastric cancer is far from complete, and the development of efficacious HIF-1α inhibitors bears various challenges. Hence, here we review the molecular mechanisms by which HIF-1α signaling stimulates stemness and chemoresistance in gastric cancer, with the clinical efforts and challenges to translate anti-HIF-1α strategies into the clinic.
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    SCUBE2 as a marker of resistance to taxane-based neoadjuvant chemotherapy and a potential therapeutic target in breast cancer
    (Galenos Yayınevi, 2023) N/A; N/A; Özcan, Gülnihal; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 185014
    Objective: Taxane-based neoadjuvant chemotherapy is the most common neoadjuvant approach in breast cancer, especially in human epidermal growth factor receptor 2 (HER2)-positive and triple-negative subtypes. However, chemoresistance is a problem in many patients, and success rates are low in estrogen receptor (ER)-positive breast cancer. The aim of this study was to identify predictive markers for resistance to taxane-based therapy, which may have a potential as therapeutic targets in breast cancer.Materials and Methods: Three comprehensive breast cancer Gene Expression Omnibus datasets were analyzed to identify differentially expressed genes (DEGs) in breast cancer patients resistant to taxane-based neoadjuvant chemotherapy. Functional annotation clustering and enrichment analysis were performed on the DEGs list. A protein-protein interaction network was established with the upregulated genes. The predictive value and the differential expression of the central genes were validated in the extensive ROC Plotter database.Results: Seventeen upregulated genes were found which were associated with resistance to taxane-based neoadjuvant therapy and high connectivity in the network analysis. ESR1, CCND1, and SCUBE2 emerged as the top three key genes associated with resistance. SCUBE2 displayed a high predictive power comparable to ESR1, and better than CCND1, the two commonly accepted markers. The predictive ability of SCUBE2 was higher in ER-positive and HER2-positive breast cancers.Conclusion: These results suggest that SCUBE2 may be used as a predictive marker to guide decisions on neoadjuvant therapy. Emerging evidence about the role of SCUBE2 as a coreceptor involved in tumor progression and angiogenesis also suggests SCUBE2 as a potential therapeutic target. These points should be investigated in further studies.
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    Fourth-year rational pharmacotherapy clerkship at Koc University School of Medicine
    (Springer Heidelberg, 2019) N/A; Gülmez, Sinem Ezgi; Özcan, Gülnihal; Orer, Hakan S.; Faculty Member; Faculty Member; Faculty Member; School of Medicine; School of Medicine; School of Medicine; 281312; 185014; 53477
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    Resorufin enters the photodynamic therapy arena: a monoamine oxidase activatable agent for selective cytotoxicity
    (Amer Chemical Soc, 2020) Atakan, Gizem; Gunbas, Gorkem; Department of Chemistry; N/A; N/A; Department of Chemistry; Almammadov, Toghrul; Leylek, Özen; Özcan, Gülnihal; Kölemen, Safacan; Researcher; PhD Student; Faculty Member; Faculty Member; Department of Chemistry; Koç University Surface Science and Technology Center (KUYTAM) / Koç Üniversitesi Yüzey Teknolojileri Araştırmaları Merkezi (KUYTAM); Koç University Boron and Advanced Materials Application and Research Center (KUBAM) / Koç Üniversitesi Bor ve İleri Malzemeler Uygulama ve Araştırma Merkezi (KUBAM); Koç University Tüpraş Energy Center (KUTEM) / Koç Üniversitesi Tüpraş Enerji Merkezi (KÜTEM); College of Sciences; Graduate School of Health Sciences; School of Medicine; College of Sciences; N/A; N/A; 185014; 272051
    A red-absorbing, water-soluble, and iodinated resorufin derivative (R1) that can be selectively activated with a monoamine oxidase (MAO) enzyme was synthesized, and its potential as a photodynamic therapy (PDT) agent was evaluated. R1 showed high O-1(2) generation yields in aqueous solutions upon addition of MAO isoforms, and it was further tested in cell culture studies. R1 induced photocytotoxicity after being triggered by endogenous MAO enzyme in cancer cells with a much higher efficiency in SH-SYSY neuroblastoma cells with high MAO-A expression. Additionally, R1 displayed differential cytotoxicity between cancer and normal cells, without any considerable dark toxicity. To the best of our knowledge, R1 marks the first example of a resorufin-based photosensitizer (PS) as well as the first anticancer drug that is activated by a MAO enzyme. Remarkably, the target PDT agent was obtained only in three steps as a result of versatile resorufin chemistry.
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    PublicationOpen Access
    Comprehensive bioinformatic analysis reveals a cancer-associated fibroblast gene signature as a poor prognostic factor and potential therapeutic target in gastric cancer
    (BioMed Central, 2022) Metin, Cemre Uçaryılmaz; Özcan, Gülnihal; Faculty Member; Graduate School of Health Sciences; School of Medicine; N/A; 185014
    Background: gastric cancer is one of the deadliest cancers, currently available therapies have limited success. Cancer-associated fibroblasts (CAFs) are pivotal cells in the stroma of gastric tumors posing a great risk for progression and chemoresistance. The poor prognostic signature for CAFs is not clear in gastric cancer, and drugs that target CAFs are lacking in the clinic. In this study, we aim to identify a poor prognostic gene signature for CAFs, targeting which may increase the therapeutic success in gastric cancer. Methods: we analyzed four GEO datasets with a network-based approach and validated key CAF markers in The Cancer Genome Atlas (TCGA) and The Asian Cancer Research Group (ACRG) cohorts. We implemented stepwise multivariate Cox regression guided by a pan-cancer analysis in TCGA to identify a poor prognostic gene signature for CAF infiltration in gastric cancer. Lastly, we conducted a database search for drugs targeting the signature genes. Results: our study revealed the COL1A1, COL1A2, COL3A1, COL5A1, FN1, and SPARC as the key CAF markers in gastric cancer. Analysis of the TCGA and ACRG cohorts validated their upregulation and poor prognostic significance. The stepwise multivariate Cox regression elucidated COL1A1 and COL5A1, together with ITGA4, Emilin1, and TSPAN9 as poor prognostic signature genes for CAF infiltration. The search on drug databases revealed collagenase clostridium histolyticum, ocriplasmin, halofuginone, natalizumab, firategrast, and BIO-1211 as the potential drugs for further investigation. Conclusions: our study demonstrated the central role of extracellular matrix components secreted and remodeled by CAFs in gastric cancer. The gene signature we identified in this study carries high potential as a predictive tool for poor prognosis in gastric cancer patients. Elucidating the mechanisms by which the signature genes contribute to poor patient outcomes can lead to the discovery of more potent molecular-targeted agents and increase the therapeutic success in gastric cancer.
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    PublicationOpen Access
    The HIF-1 alpha as a potent inducer of the hallmarks in gastric cancer
    (Multidisciplinary Digital Publishing Institute (MDPI), 2022) Metin, Cemre Uçaryılmaz; Özcan, Gülnihal; Faculty Member; Graduate School of Health Sciences; School of Medicine; N/A; 185014
    Hypoxia is the principal architect of the topographic heterogeneity in tumors. Hypoxiainducible factor-1 alpha (HIF-1 alpha) reinforces all hallmarks of cancer and donates cancer cells with more aggressive characteristics at hypoxic niches. HIF-1 alpha potently induces sustained growth factor signaling, angiogenesis, epithelial-mesenchymal transition, and replicative immortality. Hypoxia leads to the selection of cancer cells that evade growth suppressors or apoptotic triggers and deregulates cellular energetics. HIF-1 alpha is also associated with genetic instability, tumor-promoting inflammation, and escape from immunity. Therefore, HIF-1 alpha may be an important therapeutic target in cancer. Despite that, the drug market lacks safe and efficacious anti-HIF-1 alpha molecules, raising the quest for fully unveiling the complex interactome of HIF-1 alpha in cancer to discover more effective strategies. The knowledge gap is even wider in gastric cancer, where the number of studies on hypoxia is relatively low compared to other well-dissected cancers. A comprehensive review of the molecular mechanisms by which HIF-1 alpha induces gastric cancer hallmarks could provide a broad perspective to the investigators and reveal missing links to explore in future studies. Thus, here we review the impact of HIF-1 alpha on the cancer hallmarks with a specific focus on gastric cancer.