Browsing by Subject "Cancer"

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Afşin-Elbistan Termik Santralinin insan sağlığına ve doğaya olan etkileri
(Bilkent University, 2020) Baltacı, Berk; Er, Erhan; Eraslan, Nur; Gezay, Mina; Turunç, Furkan
Afşin-Elbistan A Termik Santrali 1984 yılında Çoğulhan mahallesinde kurulmuştur. 2006 yılında ise termik santralin B ünitesinin yapım aşaması tamamlanmıştır. Bugün her iki ünite de çalışmaya devam etmektedir. Araştırmada A santralinin çevre ve insan sağlığı üzerindeki etkileri incelenmiştir. Santral bacalarından NO2 ve SO2 gazlarının salınımının çevreye ve insan sağlığına etkileri mevcuttur. Kurulduğu günden bu yana termik santral Çoğulhan bölgesinde yaşayan insanlarda görülen çeşitli sağlık sorunlarıyla ilişkilendirilmiştir. Araştırmada ise bu sağlık sorunları istatistiklere dayanarak ortaya konulmuştur ve alınan önlemler ele alınmıştır.
Open Access
Cancer cell Cytotoxicities of 1-(4-substitutedbenzoyl)-4-(4-chlorobenzhydryl) piperazine derivatives
(M D P I AG, 2012) Yarim, M.; Koksal, M.; Durmaz, I.; Atalay, R.
A series of novel 1-(4-substitutedbenzoyl)-4-(4-chlorobenzhydryl)piperazine derivatives 5a-g was designed by a nucleophilic substitution reaction of 1-(4-chlorobenzhydryl)piperazine with various benzoyl chlorides and characterized by elemental analyses, IR and 1H nuclear magnetic resonance spectra. Cytotoxicity of the compounds was demonstrated on cancer cell lines from liver (HUH7, FOCUS, MAHLAVU, HEPG2, HEP3B), breast (MCF7, BT20, T47D, CAMA-1), colon (HCT-116), gastric (KATO-3) and endometrial (MFE-296) cancer cell lines. Time-dependent cytotoxicity analysis of compound 5a indicated the long-term in situ stability of this compound. All compounds showed significant cell growth inhibitory activity on the selected cancer cell lines. © 2012 by the authors; licensee MDPI, Basel, Switzerland.
Open Access
CAP-RNAseq: an online platform for RNA-seq data clustering, annotation and prioritization based on gene essentiality and congruence between mRNA and protein levels
(2024-04) Özdeniz, Merve Vural
In recent years, there has been a remarkable growth in the application of RNA-seq in both clinical and molecular biology research contexts. The analysis and interpretation of these RNA-seq data demands a good knowledge of bioinformatics. Many different applications are available to perform the analysis, but more comprehensive applications are needed, especially for researchers without coding experience. Therefore, I developed an all-in-one novel RNA-seq analysis tool, CAP-RNAseq (http://konulabapps.bilkent.edu.tr:3838/CAPRNAseq/), which provide valuable analysis for co-expression cluster prioritization and annotation. CAP-RNAseq in particular performs clustering of the genes based on their expression patterns, annotates mirror clusters that display inverse patterns with a network-based visualizations before prioritization of clusters and/or genes based on "gene essentiality", protein levels and the degree of congruence between mRNA and protein levels of genes. Furthermore, for illustration of the use of CAP-RNAseq in this thesis, I reanalyzed a number of published RNA-seq datasets and identified novel pathways modulated by NTRK2 overexpression (GSE136868) in neural stem cells and also showed significance of the essential genes/pathways in senescent cell clearance focusing on NTRK2 (fibroblast; GSE190998) and THBD (Huh7, GSE228941) siRNA models. In addition, I analyzed our lab’s novel RNA-seq data obtained from breast cancer cell lines in CAP-RNAseq; and the findings revealed a) the complex associations between steroid hormones; Drospirenone, Aldosterone, and Estrogen in hormone positive T47D and mineralocorticoid receptor-overexpressing MCF-7 cells; and b) significant differences in essential and non-essential gene expression of the isogenic MCF7 cells overexpressing wildtype or mutant TP53. I also studied a public breast cancer dataset (GSE201085) demonstrating CAP-RNAseq’s ability to identify novel breast cancer markers exhibiting high mRNA-protein level correlations. In conclusion, this thesis not only demonstrates the use and power of CAP-RNAseq as a tool to identify essential genes and pathways by analyzing RNA-seq data, but also provides new insights into the roles of essential genes in glioma, senescence and breast cancer.
Open Access
Causal interactions from proteomic profiles: Molecular data meet pathway knowledge
(Cell Press, 2021-06) Babur, Ö.; Luna, A.; Korkut, A.; Durupınar, F.; Siper, M. C.; Doğrusöz, Uğur; Jacome, A. S. V.; Peckner, R.; Christiansen, K. E.; Jaffe, J.D; Spellman, P.T.; Aslan, J. E.; Sander, C.; Demir, E.
We present a computational method to infer causal mechanisms in cell biology by analyzing changes in high-throughput proteomic profiles on the background of prior knowledge captured in biochemical reaction knowledge bases. The method mimics a biologist's traditional approach of explaining changes in data using prior knowledge but does this at the scale of hundreds of thousands of reactions. This is a specific example of how to automate scientific reasoning processes and illustrates the power of mapping from experimental data to prior knowledge via logic programming. The identified mechanisms can explain how experimental and physiological perturbations, propagating in a network of reactions, affect cellular responses and their phenotypic consequences. Causal pathway analysis is a powerful and flexible discovery tool for a wide range of cellular profiling data types and biological questions. The automated causation inference tool, as well as the source code, are freely available at http://causalpath.org.
Open Access
Cell penetrating peptide amphiphile integrated liposomal systems for enhanced delivery of cargo to tumor cells
(2013) Kılınç, Murat
Liposomes have been extensively utilized as effective nanocarriers due to their enhanced solubility, higher stability and greater ability to facilitate the slow release of encapsulated drugs compared to free drug administrations. Liposomes are also preferred as drug vectors due to their non-toxic nature, biodegradability and structural resemblance to the cell membrane. However, their low internalization efficiencies pose an important challenge for their use in drug delivery applications. Internalization issues inherent in many liposomal systems can be circumvented by the use of cell penetrating peptides, which non-covalently attach on the liposome surface and greatly enhance liposomal uptake in a receptor- and charge-dependent manner. In this study, we examined the liposomal dynamics effected through the integration of an amphiphilic cell penetrating peptide into a simple liposome system. Peptide amphiphiles with a cell penetrating arginine-rich domain were incorporated into liposomal membranes formed by negatively charged dioleoylphosphoglycerol (DOPG) phospholipids in the presence of cholesterol. Throughout the present study, we sought to analyze the effect of peptide incorporation on (a) the physical characteristics, such as size, surface potential and membrane polarity, of the liposomal membrane, (b) the alterations in the encapsulation and delivery mechanisms of hydrophilic (Rhodamine B) and hydrophobic (Nile Red) drug models and (c) the enhancement of therapeutic capability in liposomes loaded with the drugs Doxorubicin-HCl and Paclitaxel. Our results revealed that the modification of liposomes by cell penetrating peptide amphiphiles results in the improvement of cargo delivery and the enhancement of the therapeutic effects of the anticancer drugs Doxurubicin and Paclitaxel.
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Çernobil faciasının Doğu Karadeniz’deki çay üretimi ve tüketimi üzerine olan etkisi
(Bilkent University, 2021) Uzun, Ahmet Cihan; Aslan, Ahmet Arif; Ayartepe, Cem; Özcan, Ege Hamdi; Yenal, Mehmet Kağan; Gülcüoğlu, Utku
Bu araştırmanın amacı Çernobil faciası sonrası Türkiye’de çay üretiminin ve çay üretiminin etkilediği diğer alanların bu felaketten nasıl etkilendiği hakkında bilgi toplamaktır. Bu yolda öncelikle Çernobil faciasının çayda ve çay üretimi olan bölgelerde bıraktığı fiziksel etkiler yani radyoaktif birikim incelenmiştir. Ardından bu olayın Türkiye’nin çay ticaretine etkisi ve bu çay ticaretindeki etkinin ekonomiye etkileri araştırılmıştır. Araştırmanın devamında Çernobil felaketinden etkilenmiş çayların tüketiminin Türkiye’de yarattığı sağlık sorunları incelenmiştir, sonrasında ise Çernobil felaketinin bahsedilen etkilerinin Türkiye medya ve politikasında nasıl yer bulduğu ve buralara nasıl etki ettiği incelenmiştir. Tüm bu araştırmaların sonucunda, Çernobil felaketinin Türkiye’de uzun ve kısa vadeli olumsuz sonuçlar doğurduğu anlaşılmıştır.
Open Access
Characterization of differential expression patterns of the extracellular purinergic enzymes in colorectal cancer
(Trakya University, 2022-10-15) Göktuna, Serkan
The aim of this study is to characterize tumor cell specific expression of purinergic ecto-enzymes CD39 and CD73, and to associate prognostic significance of these expression patterns in colorectal cancer (CRC) patients. Protein and gene expression of the target genes in various CRC cell lines were assessed via Western Blot (WB) analysis and Real Time PCR (RT-PCR). Additionally, tumor vs stromal cell expression of the target genes was analyzed from publicly available patient expression datasets. Finally, the correlation between CD39 and CD73 expression with patient prognosis was analyzed via The Cancer Genome Atlas (TCGA) datasets. In CRC cell lines, CD39 was found to be not expressed at all while CD73 was expressed extensively in most cell lines via WB and RT-PCR analyses. Patient microarray expression data confirmed the results from CRC cell lines that CD39 expression was very low in epithelial/tumor cells relative to other stromal cell types yet CD73 was expressed abundantly in every cell type within patient tumor samples. Interestingly, CD39 expression in patient tumors was correlated with favorable prognosis while CD73 expression was associated with worse prognosis. Although CD39 and CD73 are related enzymes involved in extracellular purinergic signaling, their expression patterns in tumor cells and prognostic effects in patients show opposing outcomes. Therefore, better insights in understanding the functional involvement of purinergic ecto-enzymes in colorectal tumor development is needed via further mechanistic studies.
Open Access
Color graphs for automated cancer diagnosis and grading
(Institute of Electrical and Electronics Engineers, 2010-03) Altunbay, D.; Cigir, C.; Sokmensuer, C.; Gunduz Demir, C.
This paper reports a new structural method to mathematically represent and quantify a tissue for the purpose of automated and objective cancer diagnosis and grading. Unlike the previous structural methods, which quantify a tissue considering the spatial distributions of its cell nuclei, the proposed method relies on the use of distributions of multiple tissue components for the representation. To this end, it constructs a graph on multiple tissue components and colors its edges depending on the component types of their endpoints. Subsequently, it extracts a new set of structural features from these color graphs and uses these features in the classification of tissues. Working with the images of colon tissues, our experiments demonstrate that the color-graph approach leads to 82.65% test accuracy and that it significantly improves the performance of its counterparts. © 2006 IEEE.
Open Access
Design of a novel MRI compatible manipulator for image guided prostate interventions
(IEEE, 2005-02) Krieger, A.; Susil, R. C.; Ménard, C.; Coleman, J. A.; Fichtinger, G.; Atalar, Ergin; Whitcomb, L. L.
This paper reports a novel remotely actuated manipulator for access to prostate tissue under magnetic resonance imaging guidance (APT-MRI) device, designed for use in a standard high-field MRI scanner. The device provides three-dimensional MRI guided needle placement with millimeter accuracy under physician control. Procedures enabled by this device include MRI guided needle biopsy, fiducial marker placements, and therapy delivery. Its compact size allows for use in both standard cylindrical and open configuration MRI scanners. Preliminary in vivo canine experiments and first clinical trials are reported.
Open Access
Design of synthetic biological devices for detection and targeting human diseases
(Elsevier, 2022-01-01) Hacıosmanoğlu, Nedim; Köse, Sıla; Ostaku, Julian; Köksaldi, İlkay Çisil; Saltepe, Behide; Şeker, Urartu Özgür Şafak; Singh, V.
Interpreting signals coming from the surrounding environment and responding to these stimuli by adjusting physical or metabolic state is the most fundamental ability of living organisms. Repurposing these natural abilities for the detection and responding to different molecules is one of the key focuses of synthetic biology because the overall strategy could provide advanced solutions for different diseases. Also by being naturally suitable to the design-build-test-learn manner of synthetic biology, biosensors are great examples of what engineering and biology could achieve when they come together. Literature has many examples of intellectually designed biosensor systems, which may overachieve and outperform existing technologies with a completely biocompatible structure. In this chapter, design and application of these biosensor systems will be investigated.
Open Access
Detection of phosphorylation signatures specific to cancer-related PI3-Kinase isoforms p110α and p110β
(2023-01) Sulaiman, Mahnoor
The PI3K signaling pathway is required for many physiological activities, but it is commonly disrupted during cancer formation. The PI3K p110α and βisoforms, encoded by the PIK3CA and PIK3CB genes, are lipid kinases that phosphorylate PIP2 to PIP3 to activate the PI3K pathway. However, the distinct molecular targets of these isoforms have yet to be discovered, making targeted treatment problematic. According to cancer genomics research, the PIK3CA gene is commonly altered in cancers, but the PIK3CB gene is frequently amplified. The clinical usage of Pan-PI3K inhibitors has resulted in significant side effects, prompting the development of isoform-specific inhibitors. However, it has been shown that these drugs trigger alternate signaling systems downstream, leading in resistance to single-agent treatment. Our research intends to uncover distinctive protein-protein interactions of PI3K isoforms, as well as the consequent different phospho-proteomic signatures, which might be crucial determinants of specific cellular activities. This will be accomplished by using isogenic MEF cells that are only dependent on the p110α or p110β isoforms, isoform-specific pharmacological inhibitors BYL-719 and KIN 193, and a high-resolution mass spectrometry-based method to determine the phosphorylation levels of these protein samples. The predictive biomarkers discovered in this study can be utilized to identify patients who will benefit from PI3K-targeted drugs and to better understand the resistance mechanisms that may arise in response to pathway inhibition.
Open Access
Discovery of cancer-specific and independent prognostic gene subsets of the slit-robo family using TCGA-PANCAN datasets
(Mary Ann Liebert, 2021-12-08) Özhan, Ayşe; Tombaz, Melike; Konu, Özlen
The Slit-Robo family of axon guidance molecules works in concert, playing important roles in organ devel opment and cancer. Expressions of individual Slit-Robo genes have been used in calculating univariable hazard ratios (HRuni) for predicting cancer prognosis in the literature. However, Slit-Robo members do not act in dependently; hence, hazard ratios from multivariable Cox regression (HRmulti) on the whole gene set can further lead to identification of cancer-specific, novel, and independent prognostic gene pairs or modules. Herein, we obtained mRNA expressions of the Slit-Robo family consisting of four Robos (ROBO1/2/3/4) and three Slits (SLIT1/2/3), along with four types of survival outcome across cancers found in the Cancer Genome Atlas (TCGA). We used cluster heat maps to visualize closely associated pairs/modules of prognostic genes across 33 different cancers. We found a smaller number of significant genes in HRmulti than in HRuni, suggesting that the former analysis was less redundant. High ROBO4 expression emerged as relatively protective within the family, in both types of HR analyses. Multivariable Cox regression, on the other hand, revealed significantly more HR signatures containing Slit-Robo pairs acting in opposing directions than those containing Slit-Slit or Robo-Robo pairs for disease-specific survival. Furthermore, we discovered, through the online app SmulTCan’s lasso regression, Slit-Robo gene subsets that significantly differentiated between high- versus low-risk prog nosis patient groups, particularly for renal cancers and low-grade glioma. The statistical pipeline reported herein can help test independent and significant pairs/modules within a codependent gene family for cancer prog nostication, and thus should also prove useful in personalized/precision medicine research.
Open Access
Drug repurposing and investigation of novel combinations for glioblastoma therapeutics using in vitro and zebrafish in vivo models
(2024-01) Tok, Güneş
Glioblastoma is the most common and aggressive brain cancer type with the survival rate less than 2 years after diagnosis. Yet, potent drug treatments used in patients are limited and the field is in need of development of new potential drugs. In this study, repurposing of approved drugs alone or in combination and novel drugs are investigated in terms of inhibition of cell viability, glial fluorescent signals and their effects on behavior in zebrafish larval models. The main aim of this study was to test whether phenothiazines, trifluoperazine and a novel molecule 10, could be repurposed for glioblastoma treatment with lower dosages and more potency when combined with Sorafenib, an approved drug, in glioblastoma cell lines and zebrafish larvae. Those drug combinations were not found as toxic in the dosages studied while acted on glia cells in zebrafish transgenic larval models. Last but not least, behavior and stress response of the wild type and heterozygous mutant ache larvae in comparison with homozygous siblings were tested upon drug administration to assess genotype by drug interactions. Combination treatments exhibited higher efficacies suggesting phenothiazines with sorafenib could have potential in glioblastoma treatment. Genotype specific effects of individual and combination treatments on larval light-dark behavior, stress response and recovery exhibited potential for passage of blood brain barrier by the tested drugs. The established protocols for genotype and drug interactions could be applied to other kinases in combination with phenothiazines.
Open Access
Enhancer cooperativity as a novel mechanism underlying the transcriptional regulation of E-cadherin during mesenchymal to epithelial transition
(Elsevier, 2015) Alotaibi, H.; Basilicata, M. F.; Shehwana, H.; Kosowan, T.; Schreck, I.; Braeutigam, C.; Konu, O.; Brabletz, T.; Stemmler, M. P.
Epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) highlight crucial steps during embryogenesis and tumorigenesis. Induction of dramatic changes in gene expression and cell features is reflected by modulation of Cdh1 (E-cadherin) expression. We show that Cdh1 activity during MET is governed by two enhancers at +. 7.8. kb and at +. 11.5. kb within intron 2 that are activated by binding of Grhl3 and Hnf4α, respectively. Recruitment of Grhl3 and Hnf4α to the enhancers is crucial for activating Cdh1 and accomplishing MET in non-tumorigenic mouse mammary gland cells (NMuMG). Moreover, the two enhancers cooperate via Grhl3 and Hnf4α binding, induction of DNA-looping and clustering at the promoter to orchestrate E-cadherin re-expression. Our results provide novel insights into the cellular mechanisms whereby cells respond to MET signals and re-establish an epithelial phenotype by enhancer cooperativity. A general importance of our findings including MET-mediated colonization of metastasizing tumor cells is suggested.
Open Access
Epithelial Wnt secretion drives the progression of inflammation-induced colon carcinoma in murine model
(Elsevier Inc., 2021-12-17) Değirmenci Uzun, Bahar; Dincer, C.; Demirel, H. C.; Berkova, L.; Moor, A. E.; Kahraman, A.; Hausmann, G.; Aguet, M.; Tuncbag, N.; Valenta, T.; Basler, K.
Colon cancer is initiated by stem cells that escape the strict control. This process is often driven through aberrant activation of Wnt signaling by mutations in components acting downstream of the receptor complex that unfetter tumor cells from the need for Wnts. Here we describe a class of colon cancer that does not depend on mutated core components of the Wnt pathway. Genetically blocking Wnt secretion from epithelial cells of such tumors results in apoptosis, reduced expression of colon cancer markers, followed by enhanced tumor differentiation. In contrast to the normal colonic epithelium, such tumor cells autosecrete Wnts to maintain their uncontrolled proliferative behavior. In humans, we determined certain cases of colon cancers in which the Wnt pathway is hyperactive, but not through mutations in its core components. Our findings illuminate the path in therapy to find further subtypes of Wnt-dependent colon cancer that might be responsive to Wnt secretion inhibitors.
Open Access
Epithelial-to-mesenchymal transition is not a major modulating factor in the cytotoxic response to natural products in cancer cell lines
(MDPI AG, 2021-09-27) Küçükkaraduman, Barş; Çiçek, Ekin Gökçe; Akbar, Muhammad Waqas; Demirkol Canlı, Seçil; Vural, Burçak; Gure, Ali Osmay
Numerous natural products exhibit antiproliferative activity against cancer cells by modulating various biological pathways. In this study, we investigated the potential use of eight natural compounds (apigenin, curcumin, epigallocatechin gallate, fisetin, forskolin, procyanidin B2, resveratrol, urolithin A) and two repurposed agents (fulvestrant and metformin) as chemotherapy enhancers and mesenchymal-to-epithelial (MET) inducers of cancer cells. Screening of these compounds in various colon, breast, and pancreatic cancer cell lines revealed anti-cancer activity for all compounds, with curcumin being the most effective among these in all cell lines. Although some of the natural products were able to induce MET in some cancer cell lines, the MET induction was not related to increased synergy with either 5-FU, irinotecan, gemcitabine, or gefitinib. When synergy was observed, for example with curcumin and irinotecan, this was unrelated to MET induction, as assessed by changes in E-cadherin and vimentin expression. Our results show that MET induction is compound and cell line specific, and that MET is not necessarily related to enhanced chemosensitivity.
Open Access
Exosomes: Natural nanovesicle candidates used in the diagnosis and treatment
(Turkish Society of Immunology, 2013) Kahraman, T.; Gíiçlíiler G.; Gürsel I.
Exosomes are nano-vesicles released by all known cells. Although they were called as residual cells acting as a cleaner of undesired molecules out of cell during the first discovery in 1980s, recent studies have revealed critical physiological tasks of these vesicles over the past 20 years. These vesicles which can be produced by all body fluids play an important role in many biological activities including intracellular communication, signal conduction, genetic material transfer, and regulation of immune response. Due to their several tasks, exosomes play a crucial role in the disease pathogenesis. Considering all these tasks, exosomes can be considered in both diagnosis and treatment. Exosomes originating from distinct cells have immunosuppressive and immunostimulatory features and, thereby, therapeutic attempts which regulate immune function in case of autoimmune and immunosuppression. In addition, thanks to being natural nano-carriers, exosomes may pave the way for the development of new-generation vaccines containing both adjuvant and antigen. Besides therapeutic applications, there are evidences indicating that exosomes can be used in the diagnosis of several cancer forms including prostate cancer, glioblastoma, squamous-cell lung carcinoma and hepatocellular carcinoma, as they play a role in the disease pathogenesis. © 2014 Turkish Journal of Immunology.
Open Access
Extraction and prioritization of a gene-cancer-by-survival network involved in homeostasis of intracellular calcium concentrations using TCGA PANCAN data
(Mary Ann Liebert, Inc. Publishers, 2022-05-26) Tombaz, Melike; Yanyatan, Çağdaş; Keşküş, Ayşe Gökçe; Konu, Özlen
Regulation of intracellular calcium concentrations, [Ca++]i is important in maintaining the viability of normal as well as cancer cells and can be mediated by tumor microenvironment. Calcium release-activated calcium channel protein (ORAI) calcium channels on the plasma membrane (PM) become physically connected by stromal interaction molecules (STIMs) to the endoplasmic reticulum (ER), on which paralogous receptors of inositol phosphate and of ryanodine are also present along with ATP2A/SERCA (sarco/endoplasmic reticulum calcium ATPases) subunits (also known as PM-ER geneset). Proper expression of this functionally and physically interconnected geneset is essential for the maintenance of [Ca++]i, yet has not been interrogated as a whole for its role in cancer prognosis using multivariable Cox regression. In the present study, we examined whether the expression profile of the PM-ER geneset exhibited prognostic significance across different cancers found in The Cancer Genome Atlas (TCGA) by generating gene-cancer-by-survival networks, in which the nodes represented either genes or cancers and the edges, the logarithmically transformed hazard ratios for overall survival (OS). We then applied network clustering to identify the gene-cancer subnetworks with high connectivity, among which uveal melanoma (UVM) emerged exhibiting the highest degree of genes (k = 10). BAP1, a well-known [Ca++]i regulator and a tumor suppressor, was not found to be significant in predicting OS by PM-ER geneset for UVM, yet it was for several others, including mesothelioma (MESO). Moreover, the best subset of the PM-ER geneset obtained by lasso predicted OS in the TCGA UVM cohort with an area under the receiver operating characteristics (AUC) of 91.4%, comparable to or better than previous prognostic signatures in the literature. Our findings indicate that homeostasis of [Ca++]i is an essential determinant of prognosis in multiple cancers and particularly in UVM. The proposed gene-cancer-by-survival network approach can be extended with other gene sets as well as different survival types.
Open Access
Genome-Wide Transcriptional Reorganization Associated with Senescence-to-Immortality Switch during Human Hepatocellular Carcinogenesis
(PLOS ONE, 2013) Yildiz, G.; Arslan Ergul, A.; Bagislar, S.; Konu, O.; Yuzugullu, H.; Gursoy Yuzugullu, O.; Ozturk, N.; Ozen, C.; Ozdag, H.; Erdal, E.; Karademir, S.; Sagol, O.; Mizrak, D.; Bozkaya, H.; Ilk, H. G.; Ilk, O.; Bilen, B.; Cetin Atalay, R.; Akar, N.; Ozturk, M.
Senescence is a permanent proliferation arrest in response to cell stress such as DNA damage. It contributes strongly to tissue aging and serves as a major barrier against tumor development. Most tumor cells are believed to bypass the senescence barrier (become "immortal") by inactivating growth control genes such as TP53 and CDKN2A. They also reactivate telomerase reverse transcriptase. Senescence-to-immortality transition is accompanied by major phenotypic and biochemical changes mediated by genome-wide transcriptional modifications. This appears to happen during hepatocellular carcinoma (HCC) development in patients with liver cirrhosis, however, the accompanying transcriptional changes are virtually unknown. We investigated genome-wide transcriptional changes related to the senescence-to-immortality switch during hepatocellular carcinogenesis. Initially, we performed transcriptome analysis of senescent and immortal clones of Huh7 HCC cell line, and identified genes with significant differential expression to establish a senescence-related gene list. Through the analysis of senescence-related gene expression in different liver tissues we showed that cirrhosis and HCC display expression patterns compatible with senescent and immortal phenotypes, respectively; dysplasia being a transitional state. Gene set enrichment analysis revealed that cirrhosis/senescence-associated genes were preferentially expressed in non-tumor tissues, less malignant tumors, and differentiated or senescent cells. In contrast, HCC/immortality genes were up-regulated in tumor tissues, or more malignant tumors and progenitor cells. In HCC tumors and immortal cells genes involved in DNA repair, cell cycle, telomere extension and branched chain amino acid metabolism were up-regulated, whereas genes involved in cell signaling, as well as in drug, lipid, retinoid and glycolytic metabolism were down-regulated. Based on these distinctive gene expression features we developed a 15-gene hepatocellular immortality signature test that discriminated HCC from cirrhosis with high accuracy. Our findings demonstrate that senescence bypass plays a central role in hepatocellular carcinogenesis engendering systematic changes in the transcription of genes regulating DNA repair, proliferation, differentiation and metabolism.
Open Access
Graph embeddings on protein interaction networks
(2019-02) Kuru, Halil İbrahim
Protein-protein interaction (PPI) networks represent the possible set of interactions among proteins and thereby the genes that code for them. By integrating isolated signals on single genes such as mutations or differential expression patterns, PPI networks have enabled various biological discoveries so far. Furthermore, even the connectivity patterns of proteins in such networks have been proven to be highly informative for various prediction tasks involving proteins or genes. These tasks; however, require task specific feature engineering. Graph embedding techniques that learn a deep representation of the nodes on the network, provides a powerful alternative and obviate the need for this extensive feature engineering on the network. In this study we use graph embedding techniques on PPI networks in two independent machine learning tasks. The first part of the present work focuses on predicting gene essentiality. Using two different node embedding techniques, node2vec and DeepWalk, we present a classifier which only uses node embeddings as input and show that it can achieve up to 88 % AUC score in predicting human gene essentiality. The second part of the thesis proposes a novel representation of patients based on pairwise rank order of patient protein expression values and protein interactions, which we abbreviate as PRER. Specifically, we use the protein expression values of proteins, and generate a patient specific gene embedding to represent relative expression of a protein with other proteins in the neighborhood of that protein. The neighborhood is derived using a biased random-walk strategy. We first check whether a given protein is less or more expressed compared to the other proteins in their neighborhood for a specific tumor. Based on this we generate a representation that not only captures the dysregulation patterns among the proteins but also accounts for the molecular interactions. To test the effectiveness of this representation, we use PRER for the problem of patient survival prediction. When compared against the representation of patients with their individual protein expression features, PRER representation demonstrates significantly superior predictive performance in 8 out of 10 cancer types. Proteins that emerge as important in the PRER as opposed to individual expression values provide a valuable set of biomarkers with high prognostic value. Additionally, they highlight other proteins that should be further investigated for the dysregulation patterns.