CK2 Enzyme Affinity Against c-myc^424-434 Substrate in Human Lung Cancer Tissue

Yaylim, Ilhan,Ozkan, Nazli Ezgi,Isitmangil, Turgut,Isitmangil, Gulbu,Turna, Akif,Isbir, Turgay Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.10

CK2 is a serine threonine kinase that participates in a variety of cellular processes with more than 300 defined substrates. This critical enzyme is known to be upregulated in cancers, but the role of this upregulation in carcinogenesis is not yet fully understood but c-myc, one of the defined CK2 substrates, is a well-known proto-oncogene that is normally essential in developmental process but is also involved in tumor development. We evaluated the optimal enzyme and substrate concentrations for CK2 activity in both neoplastic and non-neoplastic human lung tissues using the c-$myc^{424-434}$ peptide (EQKLISEEDL) as a substrate. The activities measured for the neoplastic tissue were 600-750 U/mg protein while those for the control tissue was in the range of 650-800 U/mg. $K_m$ value for c-myc peptide was determined as $0.33{\mu}M$ in non-neoplastic tissue and $0.18{\mu}M$ in neoplastic tissue. In this study, we did not observe an increased activity in the neoplastic tissue when compared with the non-neoplastic lung tissue, but we recorded two times higher affinity for c-$myc^{424-434}$ in cancer tissue. Considering the metabolic position of c-$myc^{424-434}$, our results suggest that phosphorylation by CK2 may be important in dimerization and thus it might affect the regulation of c-myc in cancer tissues.

Cyclin D1 Gene G870A Variants and Primary Brain Tumors

Zeybek, Umit,Yaylim, Ilhan,Ozkan, Nazli Ezgi,Korkmaz, Gurbet,Turan, Saime,Kafadar, Didem,Cacina, Canan,Kafadar, Ali Metin Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.7

Alterations of cyclin D1, one of the main regulators of the cell cycle, are known to be involved in various cancers. The CCDN1 G870A polymorphism causes production of a truncated variant with a shorter half-life and thus thought to impact the regulatory effect of CCDN1. The aim of the present study was to contribute to existing results to help to determine the prognostic value of this specific gene variant and evaluate the role of CCDN1 G870A polymorphism in brain cancer susceptibility. A Turkish study group including 99 patients with primary brain tumors and 155 healthy controls were examined. Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism analysis. The CCDN1 genotype frequencies in meningioma, glioma and control cases were not significantly different (p>0.05). No significant association was detected according to clinical parameters or tumor characteristics; however, a higher frequency of AG genotype was recorded within patients with astrocytic or oligoastrocytic tumors. A significant association between AG genotype and gliobilastoma multiforme (GBM) was recorded within the patients with glial tumors (p value=0.048 OR: 1.87 CI% 1.010-3.463). According to tumor characteristics, no statistically significant difference was detected within astrocytic, oligoasltrocytic tumors and oligodentrioglias. However, patients with astrocytic astrocytic or oligoastrocytic tumors showed a higher frequency of AG genotype (50%) when compared to those with oligodendrioglial tumors (27.3%). Our results indicate a possible relation between GBM formation and CCDN1 genotype.

TRAIL Mediated Signaling in Pancreatic Cancer

Nogueira, Daniele Rubert,Yaylim, Ilhan,Aamir, Qurratulain,Kahraman, OzlemTimirci,Fayyaz, Sundas,Naqvi, Syed Kamran-Ul-Hassan,Farooqi, Ammad Ahmad Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.15

Research over the years has progressively shown substantial broadening of the tumor necrosis factor alpha-related apoptosis-inducing ligand (TRAIL)-mediated signaling landscape. Increasingly it is being realized that pancreatic cancer is a multifaceted and genomically complex disease. Suppression of tumor suppressors, overexpression of oncogenes, epigenetic silencing, and loss of apoptosis are some of the extensively studied underlying mechanisms. Rapidly accumulating in vitro and in vivo evidence has started to shed light on the resistance mechanisms in pancreatic cancer cells. More interestingly a recent research has opened new horizons of miRNA regulation by DR5 in pancreatic cancer cells. It has been shown that DR5 interacts with the core microprocessor components Drosha and DGCR8, thus impairing processing of primary let-7. Xenografting DR5 silenced pancreatic cancer cells in SCID-mice indicated that there was notable suppression of tumor growth. There is a paradigm shift in our current understanding of TRAIL mediated signaling in pancreatic cancer cells that is now adding new layers of concepts into the existing scientific evidence. In this review we have attempted to provide an overview of recent advances in TRAIL mediated signaling in pancreatic cancer as evidenced by findings of in vitro and in vivo analyses. Furthermore, we discuss nanotechnological advances with emphasis on PEG-TRAIL and four-arm PEG cross-linked hyaluronic acid (HA) hydrogels to improve availability of TRAIL at target sites.

Association of the Cylin D1 G870A Polymorphism with Laryngeal Cancer: Are they Really Related?

Verim, Aysegul,Ozkan, Nazli,Turan, Saime,Korkmaz, Gurbet,Cacina, Canan,Yaylim, Ilhan,Isbir, Turgay Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.12

Background: Cylin D1(CCDN1) is an important regulator of the cell cycle whose alterations are thought to be involved in cancer development. There have been many studies indicating CCDN1 amplification or over-expression in a variety of cancer types. In addition to gene amplification, the G870A polymorphism may be related with altered CCDN1 activity, and therefore with cancer development. This hypothesis has been tested in different cancer types but results have been contradictory. We therefore aimed to investigate any relationship between CCDN1 A870G genotypes and laryngeal squamous cell cancer development and progression. Materials and Methods: A total of 68 Turkish patients with primary laryngeal squamous cell cancer and 133 healthy controls were enrolled. Polymerase chain reaction-restriction fragment length polymorphism analysis was used to determine the CCDN1 genotypes. Results: No significant association was detected between CCDN1 genotypes and laryngeal squamous cell cancer (LxSCCa) development. Similarly CCDN1 genotypes were not related to clinical parameters of Lx SCCa. However, there was a very significant association between CCDN1 G allele and presence of perineural invasion (p=0.003; OR: 1.464; CI% 1.073-1.999). CCDN1 G allele frequency was significantly higher in the individuals with perineural invasion (85.7%) when compared to those without (58.5%). The 2 patients who died of disease were both found to possess the GG genotype. Conclusions: These results pose a controversy in suggesting a protective role of the G allele against LxSCCa development and support the association of CCDN1 gene GG genotype with mortality in patients with LxSCCa.

Identification of a Novel BRCA2 and CHEK2 A-C-G-C Haplotype in Turkish Patients Affected with Breast Cancer

Haytural, Hazal,Yalcinkaya, Nazli,Akan, Gokce,Arikan, Soykan,Ozkok, Elif,Cakmakoglu, Bedia,Yaylim, Ilhan,Aydin, Makbule,Atalar, Fatmahan Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.5

Background: Many breast cancers are caused by certain rare and familial mutations in the high or moderate penetrance genes BRCA1, BRCA2 and CHEK2. The aim of this study was to examine the allele and genotype frequencies of seven mutations in BRCA1, BRCA2 and CHEK2 genes in breast cancer patients and to investigate their isolated and combined associations with breast cancer risk. Methods: We genotyped seven mutations in BRCA1, BRCA2 and CHEK2 genes and then analyzed single variations and haplotype associations in 106 breast cancer patients and 80 healthy controls. Results: We found significant associations in the analyses of CHEK2- 1100delC (p=0.001) and BRCA1-5382insC (p=0.021) mutations in breast cancer patients compared to controls. The highest risk was observed among breast cancer patients carrying both CHEK2-1100delC and BRCA2- Met784Val mutations (OR=0.093; 95%CI 0.021-0.423; p=0.001). We identified one previously undescribed BRCA2 and a CHEK2 four-marker haplotype of A-C-G-C which was overrepresented ($X^2$=7.655; p=0.0057) in the patient group compared to controls. Conclusion: In this study, we identified a previously undescribed BRCA2 and CHEK2 A-C-G-C haplotype in association with the breast cancer in our population. Our results further suggest that the CHEK2-1100delC mutation in combination with BRCA2-Met784Val may lead to an unexpected high risk which needs to be confirmed in larger cohorts in order to better understand their role in the development and prognosis of breast cancer.

Ovarian Cancer: Interplay of Vitamin D Signaling and miRNA Action

Attar, Rukset,Gasparri, Maria Luisa,Di Donato, Violante,Yaylim, Ilhan,Halim, Talha Abdul,Zaman, Farrukh,Farooqi, Ammad Ahmad Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.8

Increasing attention is being devoted to the mechanisms by which cells receive signals and then translate these into decisions for growth, death, or migration. Recent findings have presented significant breakthroughs in developing a deeper understanding of the activation or repression of target genes and proteins in response to various stimuli and of how they are assembled during signal transduction in cancer cells. Detailed mechanistic insights have unveiled new maps of linear and integrated signal transduction cascades, but the multifaceted nature of the pathways remains unclear. Although new layers of information are being added regarding mechanisms underlying ovarian cancer and how polymorphisms in VDR gene influence its development, the findings of this research must be sequentially collected and re-interpreted. We divide this multi-component review into different segments: how vitamin D modulates molecular network in ovarian cancer cells, how ovarian cancer is controlled by tumor suppressors and oncogenic miRNAs and finally how vitamin D signaling regulates miRNA expression. Intra/inter-population variability is insufficiently studied and a better understanding of genetics of population will be helpful in getting a step closer to personalized medicine.

Investigation of ICAM-1 and β3 Integrin Gene Variations in Patients with Brain Tumors

Yilmaz, Umit,Zeybek, Umit,Kahraman, Ozlem Timirci,Kafadar, Ali Metin,Toptas, Bahar,Yamak, Nesibe,Celik, Faruk,Yaylim, Ilhan Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.10

Background: Primary brain tumors constitute a small percent of all malignant cancers, but their etiology remains poorly understood. ${\beta}3$ integrin (ITGB3) has been recognized to play influential roles in angiogenesis, tumor growth and metastasis. Intercellular adhesion molecule-1 (ICAM-1) is a surface glycoprotein important for tumor invasion and angiogenesis. The aim of this study was to investigate whether specific genetic polymorphisms of ICAM-1 and ITGB3 could be associated with brain cancer development and progression in a Turkish population. Our study is the first to our knowledge to investigate the relationship between brain tumor risk and ICAM-1 and ${\beta}3$ integrin gene polymorphisms. Materials and Methods: The study covered 92 patients with primary brain tumors and 92 age-matched healthy control subjects. Evaluation of ${\beta}3$ integrin (Leu33Pro (rs5918)) and ICAM-1 (R241G (rs1799969) and K469E (rs5498)) gene polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: According to results of our research, the A allele of the ICAM-1 R241G gene polymorphism appeared to be a risk factor for primary brain tumors (p<0.001). Similarly, the frequency of the A mutant allele of ICAM-1 R241G was statistically significant in patients with brain tumors classified as glioma (p<0.001). When allele and genotype distributions of ICAM-1 K469E, ICAM-1 R241G and ${\beta}3$ integrin Leu33Pro gene polymorphisms were evaluated with age, sex, and smoking, there were no statistically significant differences. Haplotype analysis revealed that the frequencies of GAC (rs1799969-rs5498-rs5918) and GAT (rs1799969-rs5498-rs5918) haplotypes were significantly lower in patients as compared with controls (p=0.001; p=0.036 respectively). Conclusions: This study provides the first evidence that ICAM-1 R241G SNP significantly contributes to the risk of primary brain tumors in a Turkish population. In addition, our results suggest that ICAM-1 R241G in combination ICAM-1 K469E may have protective effects against the development of brain cancer.

Possible Relation between the NOS3 Gene GLU298ASP Polymorphism and Bladder Cancer in Turkey

Verim, Levent,Toptas, Bahar,Ozkan, Nazli Ezgi,Cacina, Canan,Turan, Saime,Korkmaz, Gurbet,Yaylim, Ilhan Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.2

Endothelial nitric oxide synthase (eNOS), encoded by the NOS3 gene, has been suggested to play an important role in uncontrolled cell growth in several cancer types. The objective of this study was to evaluate the role of the NOS3 Glu298Asp polymorphism in bladder cancer susceptibility in a Turkish population. We determined the genotypes of 66 bladder cancer cases and 88 healthy controls. Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism analysis. A significant association for NOS3 Glu298Asp heterozygotes genotypes and T allele were found between healthy controls and bladder cancer, respectively (p<0.001: p=0.002). There were no significant associations between any genotypes and the stage, grade, and histological type of bladder cancer. Our study suggested an increased risk role of NOS3 GT genotype in bladder cancer susceptibility in our Turkish population.

miR-421, miR-155 and miR-650: Emerging Trends of Regulation of Cancer and Apoptosis

Farooqi, Ammad Ahmad,Qureshi, Muhammad Zahid,Coskunpinar, Ender,Naqvi, Syed Kamran-Ul-Hassan,Yaylim, Ilhan,Ismail, Muhammad Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.5

It is becoming progressively more understandable that between transcription and translation there lies another versatile regulator that quantitatively controls the expression of mRNAs. Identification of miRNAs as key regulators of wide ranging signaling cascades and modulators of different cell-type and context dependent activities attracted basic and clinical scientists to study modes and mechanisms in details. In line with this approach overwhelmingly increasing in vivo and in vitro studies are deepening our understanding regarding miR-421, mir-155 and miR-650 mediated regulation of cellular activities. We also attempt to provide an overview of long non coding RNAs.

Association between Laryngeal Squamous Cell Carcinoma and Polymorphisms in Tumor Necrosis Factor Related Apoptosis Induce Ligand (TRAIL), TRAIL Receptor and sTRAIL Levels

Verim, Aysegul,Turan, Saime,Farooqi, Ammad Ahmad,Kahraman, Ozlem Timirci,Tepe-Karaca, Cigdem,Yildiz, Yemliha,Naiboglu, Baris,Ozkan, Nazli Ezgi,Ergen, Arzu,Isitmangil, Gulbu Aydinoglu,Yaylim, Ilhan Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.24

The laryngeal squamous cell carcinoma (LSCC) is one of the most common malignant tumors occurring in the head and neck. Tumor necrosis factor related apoptosis induce ligand (TRAIL) and TRAIL-receptors (DR4, DR5, DcR1, DcR2) are known as important members of TRAIL-mediated biochemical signaling pathway. Associations between polymorphisms in these genes and clinicopathological characteristics of human laryngeal carcinoma are not well defined. This study therefore aimed to investigate a possible relationship among the TRAIL and TRAIL-DR4 polymorphisms and sTRAIL levels in the risk or progression of LSCC. A total of 99 patients with laryngeal cancer and 120 healthy subjects were enrolled in the study. DR4 C626G and TRAIL 1595 C/T genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis and sTRAIL levels were measured by ELISA. There were significant differences in the distribution of DR4 C626G genotypes and frequencies of the alleles between laryngeal cancer patients and controls (p<0.001) but not in TRAIL 1595 C/T. We found the increased frequency of the DR4 C626G homozygote CC genotype in patients than in controls (p<0.001). Haplotype analysis revealed that there was also a statistically significant relationship between TRAIL and TRAIL-DR4 polymorphisms and laryngeal cancer. Serum sTRAIL levels in the laryngeal patients with CC genotype who had advanced tumour stage were lower than those of patients with early tumor stage (p=0.014). Our findings suggest that DR4 C626G genotypes and sTRAIL levels might be associated with progression of laryngeal cancer in the Turkish population.