Regulation of Nrf2/Keap1 signaling pathway in cancer drug resistance by galectin-1: cellular and molecular implications.

Oxidative stress is characterized by the deregulation of the redox state in the cells, which plays a role in the initiation of various types of cancers. The activity of galectin-1 (Gal-1) depends on the cell redox state and the redox state of the microenvironment. Gal-1 expression has been related to many different tumor types, as it plays important roles in several processes involved in cancer progression, such as apoptosis, cell migration, adhesion, and immune response. The erythroid-2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) signaling pathway is a crucial mechanism involved in both cell survival and cell defense against oxidative stress. In this review, we delve into the cellular and molecular roles played by Gal-1 in the context of oxidative stress onset in cancer cells, particularly focusing on its involvement in activating the Nrf2/Keap1 signaling pathway. The emerging evidence concerning the anti-apoptotic effect of Gal-1, together with its ability to sustain the activation of the Nrf2 pathway in counteracting oxidative stress, supports the role of Gal-1 in the promotion of tumor cells proliferation, immuno-suppression, and anti-tumor drug resistance, thus highlighting that the inhibition of Gal-1 emerges as a potential strategy for the restraint and regression of tumor progression. Overall, a deeper understanding of the multi-functionality and disease-specific expression profiling of Gal-1 will be crucial for the design and development of novel Gal-1 inhibitors as anticancer agents. Excitingly, although it is still understudied, the ever-growing knowledge of the sophisticated interplay between Gal-1 and Nrf2/Keap1 will enable researchers to gain valuable insights into the underlying causes of carcinogenesis and metastasis.

Genetic Investigation of the Trail Mechanism in Diabetic and Non-diabetic Obese Patients.

Obesity is an important healthcare issue caused by abnormally increased adipose tissue because of energy-intake overcoming energy expenditure. Disturbances in the physiological function of adipose tissue mediate the development of diabetes. It is a metabolic disease that results from decreased insulin-levels and/or changes in the insulin action mechanism. Tumor Necrosis Factor-Associated Apoptosis-Inducing Ligand(TRAIL), which is a member of the Tumor Necrosis Factor(TNF)-family with an important role in adipose tissue biology, is included in many studies with its ability to induce apoptosis in cancer cells, but the number of human-studies conducted on the gene related to its protective-role against diabetes and obesity at this level is insufficient. Our study was carried out as a case and control and included three groups (80 diabetic obese, 80 non-diabetic obese, and 80 healthy individuals as the control group). The Real-Time-PZR(RT-qPZR), and DNA Sanger-Sequencing Methods were used for gene expression and gene squences. As a result of the analyses, TRAIL gene expression level was found to be higher in the controls than in the diabetic-obese and non-diabetic-obese group. This change in TRAIL gene expression suggests that TRAIL maybe a protective factor against diabetes. The presence of rs781673405, rs143353036, rs1244378045, rs767450259, rs759369504, rs750556128, and rs369143448 mutations, which was determined with the Sequencing-Method, was shown for the first time in the present study. In addition, it is the first study in which human TRAIL gene-expression and sequencing were performed together. We believe that these data will make an important contribution to the literature.

Investigation of the effects of oxidative stress, inflammation on the pathway of tryptophan/kynurenine in OCD.

OBJECTIVES: Recent studies have shown that the distribution of the tryptophan/kynurenine pathway (KP) plays a role in the development of obsessive-compulsive disorder (OCD). We aimed to reveal the relationship between CYP1A1 rs464903 and aryl hydrocarbon receptor (AhR) rs10249788 associated with the KP and interferon gamma (IFN γ) and oxidative stress in OCD. METHODS: In our study, the serum and DNAs of 150 samples, including 100 OCD patients and 50 controls, were used. The activity of glutathione peroxidase (GSH-Px), and the levels of IFN γ, thiobarbituric acid reactive substances (TBARS), tryptophan, and kynurenine were determined by biochemical methods. AhR rs10249788 and cytochrome P450 family CYP1A1 rs4646903, which interact directly with the KP, were analysed by polymerase chain reaction followed by restriction fragment length polymorphism. P < 0.05 was considered statistically significant. RESULT: There were no significant differences between groups in CYP1A1 rs4646903 and AhR rs10249788 while tryptophan and IFN γ were found to be higher in controls (p < 0.001, for both), and TBARS and indolamine-2,3-dioxygenase were found to be higher in OCD (p < 0.001, for both). There were significant correlations between IFN γ and TBARS and GSH-Px (p = 0.028, p = 0.020, respectively) in the OCD group. CONCLUSIONS: For the first time studied in OCD, it has been shown that IFN γ, tryptophan, oxidative stress parameters, and gene variants of CYP1A1 rs4646903 anAhR rs10249788 are shown effective on the KP.

Investigation of miR221 and miR222 as Biomarkers in Non-small Cell Lung Cancer.

BACKGROUND/AIM: MicroRNAs (miRNA) are a class of small non-coding RNAs of 18-25 nucleotides, which regulate gene expression at the post-transcriptional level by disrupting or blocking translation of messenger RNA targets. Non-small cell lung cancer (NSCLC) represents approximately 85% of all lung cancers. Early and accurate diagnosis of the disease affects the probability of success of treatment. The purpose of this study was to investigate the expression levels of serum specific miRNA221 and miRNA222 as a biomarker in NSCLC. MATERIALS AND METHODS: Thirty-two NSCLC cases and 30 healthy control cases that were diagnosed at Istanbul Yedikule Chest Diseases and Thoracic Surgery Training Hospital were included in this study. miRNAs were detected using miRNA-specific quantitative real-time-PCR. The relative expression of miRNAs was calculated using the 2-ΔΔCt method. RESULTS: miR221 and miR222 showed 1.46 and 1.63-fold higher expression in the samples from patients with NSCLC compared to controls, and the difference of expression was statistically significant for miR221 (p=0.000095) but not for miR222 (p=0.084470). In the presence of metastasis in NSCLC patients, miR221 levels were 2.33-fold higher compared to non-metastatic cases (p=0.014), and those of miR221 and miR222 were expressed 1.44 and 1.52-fold higher, respectively, in advanced stage compared to early stage (p=0.000387, p=0.000302). CONCLUSION: The levels of miR221 and miR222 in the serum of patients could be used as biomarkers for the diagnosis, treatment, and prognosis of NSCLC.

Plasma Levels of Kynurenine, Soluble OX40 and Mir-138-5p Are Associated With Tumor-infiltrating Lymphocytes in Colorectal Cancer: An Exploratory Study.

BACKGROUND/AIM: Colorectal cancer (CRC) is one of leading cancers in terms of incidence and mortality. Interaction of tumor cells with the surrounding microenvironment plays a crucial role in the development and progression of CRC. Many pathways such as the kynurenine pathway, OX40/OX40L-mediated signaling and microRNAs targeting PD-L1 may be involved in CRC development by affecting T cell activation, thus creating an immune-deficient microenvironment. Herein, our goal was to assess the association between plasma levels of tryptophan (TRP), kynurenine (KYN), KYN/TRP ratio, soluble OX40 (sOX40) and PD-L1-targeting miR-138-5p and CRC risk. PATIENTS AND METHODS: Plasma concentrations of TRP and KYN were determined by HPLC; sOX40 was measured by ELISA whereas circulating miR-138-5p was measured by quantitative PCR in pathologically confirmed CRC patients and colonoscopy-verified CRC-free controls without polyps (control group 1) and with polyps (control group 2). RESULTS: We found significantly lower plasma levels of TRP in CRC patients compared to control groups which resulted in significantly higher KYN/TRP ratio in CRC patients than in the controls (p=0.007). Plasma levels of sOX40 did not significantly differ between groups. The levels of circulating miR-138-5p were significantly lower in CRC patients (relative median value 0.02) than in the control groups (relative median values 0.2 and 4.29, respectively) (p=0.03). Plasma levels of KYN and sOX40 were considerably higher in patients with no tumor-infiltrating lymphocytes (TILs) than those with TILs whereas circulating miR-138-5p had opposite expression pattern in plasma. CONCLUSION: The kynurenine pathway and miR-138-5p are associated with CRC risk and plasma levels of KYN, sOX40 and miR-138-5p are related to TILs, making them possible target molecules in possible immunotherapeutic targets for CRC.

The analysis of Survivin promoter (-31G/C) gene variation in oral squamous cell carcinoma risk and prognosis.

BACKGROUND/AIM: Oral squamous cell carcinoma (OSCC) is a malign tumor that associated with smoking and alcohol consumption, eating habits, environmental factors, and genetic susceptibility of the individuals. The Survivin gene, also known as BIRC5, plays important roles in the regulation of the cell cycle and apoptosis. The aim of the present study is to investigate Survivin -31G/C polymorphism in OSCC development and prognosis. MATERIALS AND METHODS: A total of 61 patients with oral squamous cell carcinoma and 133 healthy individuals were genotyped by using the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism method (PCR-RFLP) to evaluate the role of the Survivin gene promoter region (-31) variation. RESULTS: There were no statistically significant differences in the distribution of Survivin promoter -31 polymorphism genotype and allele frequencies between the cases and controls but we analyzed the clinicopathological characteristics of patients and noticed a significant correlation between the C allele and advanced tumor stage in the patients (p = 0.022). CONCLUSION: The Survivin (-31) gene polymorphism might be associated with advanced tumor stage in oral squamous cell carcinoma but further studies in a larger population are needed most effective evaluation of the Survivin (-31) gene variation in the OSCC risk and prognosis.

lncRNA NORAD, soluble ICAM1 and their correlations may be related to the regulation of the tumor immune microenvironment in laryngeal squamous cell carcinoma (LSCC).

NORAD, non-coding RNA activated by DNA damage, is a Long non-coding RNA (lncRNA) transcript that modulates genome stability and has been reported to be dysregulated in different cancers. Although it has been reported to be upregulated in tumor cells mostly for solid organ cancers, it has also been reported to be downregulated in some cancers. Although the pathophysiological mechanism is not fully understood, a negative correlation between NORAD and intercellular cell adhesion molecule-1 (ICAM-1) has been shown in experimental models, but this situation has not been evaluated in terms of cancer. We aimed to evaluate the potential roles of these two biomarker candidates together and separately in the clinicopathological axis in Laryngeal squamous cell carcinoma (LSCC) in a case-control study setting. The interactions of NORAD and ICAM1 at the RNA level were evaluated interactively by the RIblast program. sICAM1 (soluble intercellular cell adhesion molecule-1) levels were determined by ELISA in one hundred and five individuals (forty-four LSCC, sixty-one control) and lncRNA NORAD expression in eighty-eight tissues (forty-four LSCC tumors, forty-four tumor-free surrounding tissues) was determined by Real-time PCR. While the energy treesholud was - 16 kcal/mol between NORAD and ICAM1, the total energy was 176.33 kcal/mol, and 9 base pair pairings from 4 critical points were detected. NORAD expression level was found to be higher in tumor surrounding tissue compared to tumor tissue, and sICAM1 was higher in the control group compared to LSCC (p = 0.004; p = 0.02). NORAD discreminte tumor surrounding tissue from tumor (AUC: 0.674; optimal sensitivity:87.50%; optimal specificity 54.55%; cut-off point as >1.58 fold change; P = 0.034). The sICAM1 level was found to be higher in the control (494,814 ± 93.64 ng/L) than LSCC (432.95 ± 93.64 ng/L) (p = 0.02). sICAM1 discreminte control group from LSCC (AUC: 0.624; optimal sensitivity 68,85%; optimal specificity 61,36%; cut-off point ≤115,0 ng/L; (p = 0.033). A very strong negative correlation was found between NORAD expression and patients' sICAM1 levels (r = -.967; n = 44; p = 0.033). sICAM1 levels were found to be 1.63 times higher in NORAD downregulated subjects compared to upregulated ones (p = 0.031). NORAD was 3.63 times higher in those with alcohol use, and sICAM 1 was 5.77 times higher in those without distant organ metastasis (p = 0.043; 0.004). The increased NORAD expression in the tumor microenvironment in LSCC, the activation of T cells via TCR signaling, and the decrease of sICAM in the control group in correlation with NORAD suggests that ICAM1 may be needed as a membrane protein in the tumor microenvironment. NORAD and ICAM1 may be functionally related to tumor microenvironment and immune control in LSCC.

An application of raman spectroscopy in combination with machine learning to determine gastric cancer spectroscopy marker.

BACKGROUND AND OBJECTIVE: Globally, gastric carcinoma (Gca) ranks fifth in terms of incidence and third in terms of mortality. Higher serum tumor markers (TMs) than those from healthy individuals, led to TMs clinical application as diagnostic biomarkers for Gca. Actually, there is no accurate blood test to diagnose Gca. METHODS: Raman spectroscopy is applied as an efficient, credible, minimally invasive technique to evaluate the serum TMs levels in blood samples. After curative gastrectomy, serum TMs levels are important in predicting the recurrence of gastric cancer, which must be detected early. The experimentally assesed TMs levels using Raman measurements and ELISA test were used to develop a prediction model based on machine learning techniques. A total of 70 participants diagnosed with gastric cancer after surgery (n = 26) and healthy (n = 44) were comrpised in this study. RESULTS: In the Raman spectra of gastric cancer patients, an additional peak at 1182 cm-1 was observed and, the Raman intensity of amide III, II, I, and CH2 proteins as well as lipids functional group was higher. Furthermore, Principal Component Analysis (PCA) showed, that it is possible to distinguish between the control and Gca groups using the Raman range between 800 and 1800 cm-1, as well as between 2700 and 3000 cm-1. The analysis of Raman spectra dynamics in gastric cancer and healthy patients showed, that the vibrations at 1302 and 1306 cm-1 were characteristic for cancer patients. In addition, the selected machine learning methods showed classification accuracy of more than 95%, while obtaining an AUROC of 0.98. Such results were obtained using Deep Neural Networks and the XGBoost algorithm. CONCLUSIONS: The obtained results suggest, that Raman shifts at 1302 and 1306 cm-1 could be spectroscopic markers of gastric cancer.

The Investigation of MAPK7 Gene Variations in Colorectal Cancer Risk.

BACKGROUND/AIM: Mitogen-activated protein kinases (MAPKs) are important regulatory molecules, which have essential roles in physiology and pathology. In the present study, we examined the possible correlation between the MAPK7 gene and colorectal cancer risk in the Turkish population. MATERIALS AND METHODS: A total of 100 human DNA samples (50 colorectal cancer patients and 50 healthy individuals) were sequenced using next-generation sequencing to define the potential genetic variations in the MAPK7 gene. RESULTS: Five genetic variations (MAPK7; rs2233072, rs2233076, rs181138364, rs34984998, rs148989290) were detected in our study group. The G (variant) allele of the MAPK7; rs2233072 (T>G) gene polymorphism was found in 76% of colorectal cancer cases, and 66% of controls. The prevalence of rs2233076, rs181138364, rs34984998, and rs148989290 gene variations was quite rare in the subjects and no significant association in terms of genotype and allele frequencies was observed between the cases and controls. CONCLUSION: No statistically significant correlation between the MAP7 kinase gene variations and colorectal cancer risk was observed. This is the first investigation in the Turkish population that may initiate additional studies in larger populations to analyze the effect of MAPK7 gene on the colorectal cancer risk.

Correlation between human colon cancer specific antigens and Raman spectra. Attempting to use Raman spectroscopy in the determination of tumor markers for colon cancer.

Colorectal cancer is the second most common cause of cancer-related deaths worldwide. To follow up on the progression of the disease, tumor markers are commonly used. Here, we report serum analysis based on Raman spectroscopy to provide a rapid cancer diagnosis with tumor markers and two new cell adhesion molecules measured using the ELISA method. Raman spectra showed higher Raman intensities at 1447 cm-1 1560 cm-1, 1665 cm-1, and 1769 cm-1, which originated from CH2 proteins and lipids, amide II and amide I, and CO lipids vibrations. Furthermore, the correlation test showed, that only the CEA colon cancer marker correlated with the Raman spectra. Importantly, machine learning methods showed, that the accuracy of the Raman method in the detection of colon cancer was around 95 %. Obtained results suggest, that Raman shifts at 1302 cm-1 and 1306 cm-1 can be used as spectroscopy markers of colon cancer.

Interplay between Non-Coding RNAs and NRF2 in Different Cancers: Spotlight on MicroRNAs and Long Non-Coding RNAs.

Cancer is a multifactorial disease, and a wealth of information has enabled basic and clinical researchers to develop a better conceptual knowledge of the highly heterogeneous nature of cancer. Deregulations of spatio-temporally controlled transduction pathways play a central role in cancer progression. NRF2-driven signaling has engrossed significant attention because of its fundamentally unique features to dualistically regulate cancer progression. Context-dependent diametrically opposed roles of NRF2-induced signaling are exciting. More importantly, non-coding RNA (ncRNA) mediated regulation of NRF2 and interplay between NRF2 and ncRNAs have added new layers of complexity to already intricate nature of NRF2 signaling. There is a gradual enrichment in the existing pool of knowledge related to interplay between microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in different cancers. However, surprisingly, there are no clues about interplay between circular RNAs and NRF2 in various cancers. Therefore, future studies must converge on the functional characterization of additional important lncRNAs and circular RNAs, which regulated NRF2-driven signaling or, conversely, NRF2 transcriptionally controlled their expression to regulate various stages of cancer. SIGNIFICANCE STATEMENT: Recently, many researchers have focused on the NRF2-driven signaling in cancer progression. Excitingly, discovery of non-coding RNAs has added new layers of intricacy to the already complicated nature of KEAP1/NRF2 signaling in different cancers. These interactions are shaping the NRF2-driven signaling landscape, and better knowledge of these pathways will be advantageous in pharmacological modulation of non-coding RNA-mediated NRF2 signaling in various cancers.

Predicting the predisposition to colorectal cancer based on SNP profiles of immune phenotypes using supervised learning models.

This study explores the machine learning-based assessment of predisposition to colorectal cancer based on single nucleotide polymorphisms (SNP). Such a computational approach may be used as a risk indicator and an auxiliary diagnosis method that complements the traditional methods such as biopsy and CT scan. Moreover, it may be used to develop a low-cost screening test for the early detection of colorectal cancers to improve public health. We employ several supervised classification algorithms. Besides, we apply data imputation to fill in the missing genotype values. The employed dataset includes SNPs observed in particular colorectal cancer-associated genomic loci that are located within DNA regions of 11 selected genes obtained from 115 individuals. We make the following observations: (i) random forest-based classifier using one-hot encoding and K-nearest neighbor (KNN)-based imputation performs the best among the studied classifiers with an F1 score of 89% and area under the curve (AUC) score of 0.96. (ii) One-hot encoding together with K-nearest neighbor-based data imputation increases the F1 scores by around 26% in comparison to the baseline approach which does not employ them. (iii) The proposed model outperforms a commonly employed state-of-the-art approach, ColonFlag, under all evaluated settings by up to 24% in terms of the AUC score. Based on the high accuracy of the constructed predictive models, the studied 11 genes may be considered a gene panel candidate for colon cancer risk screening.

Vitamin D increases the efficacy of cisplatin on bladder cancer cell lines.

BACKGROUND: 1,25(OH)2D3(Calcitriol), which is a broad regulatory molecule, plays a role in changing the efficacy of chemotherapeutic drugs. Cisplatin is one of a current standard chemotherapy regimen for bladder cancer. Increasing the effectiveness of the treatment and reducing the side effects to chemotherapeutics are of great importance in bladder cancer. We aimed to investigate the effect of the combination of cisplatin and calcitriol in order to create a possible advantage in treatment of bladder cancer. METHODS: T24, ECV-304 and HUVEC cell lines were treated with calcitriol and cisplatin individually and in combination. Dose determination and combination treatments of calcitriol and cisplatin were evaluated using the MTT assay for cytotoxicity analysis on the cells. Annexin V-PI staining method was used for apoptosis determination by flow cytometry. Also the P-gp expression levels were determined by flow cytometry. RESULTS: The combination treatment increased the anti-proliferative efficacy compared to the efficacy in cisplatin alone in T24 cells and reduced the cytotoxicity in the HUVEC healthy cells compared to cisplatin alone. Combination treatment achieved significantly higher apoptosis rate in T24 cells compared with the rates in treatment of cisplatin alone. However apoptosis decreased in HUVEC cell line. P-gp ratios were increased in HUVEC and decreased in T24 cells with combination treatment compared to the numbers in the control cells. The rate of apoptosis and P-gp levels showed no significant change in ECV-304 cells. CONCLUSION: Our study revealed that the combination of calcitriol and cisplatin allows the use of cisplatin at lower doses in T24 bladder cancer cell line.

Significance of Intercellular adhesion molecule-1 Lys496Glu gene polimorphism on plasma redox status regulation in laryngeal carcinoma.

BACKGROUND: Intercellular adhesion molecule-1 (ICAM-1) is a surface glycoprotein important for tumor invasion and angiogenesis. The present research is conducted to investigate whether specific gene polymorphism of ICAM-1 K469E (rs5498) and plasma redox status could be associated with laryngeal cancer (LC) development. Since there is no clear evidence which investigates the relationship between ICAM-1 polymorphism and ROS-mediated plasma protein oxidation in LC, our study is the first significant contribution for investigating the relationship. METHODS: The study covered patients with primary LC and their age-matched healthy control subjects. Evaluation of ICAM-1 K469E (rs5498) gene polymorphism was performed by polymerase chain reaction-restriction fragment length polymorphism. Plasma redox status was assessed with spectrophotometric methods. RESULTS: In the current paper, we found that LC patients with GG genotype had a decreasing trend for the plasma oxidative damage biomarker levels when compared with all allele genotypes (AA and AG). CONCLUSION: We concluded that G allele of the ICAM-1 K469E gene plays a significant role in the optimal regulation of plasma redox homeostasis in patients with LC.

Six potential biomarkers for bladder cancer: key proteins in cell-cycle division and apoptosis pathways.

BACKGROUND: The bladder cancer (BC) pathology is caused by both exogenous environmental and endogenous molecular factors. Several genes have been implicated, but the molecular pathogenesis of BC and its subtypes remains debatable. The bioinformatic analysis evaluates high numbers of proteins in a single study, increasing the opportunity to identify possible biomarkers for disorders. METHODS: The aim of this study is to identify biomarkers for the identification of BC using several bioinformatic analytical tools and methods. BC and normal samples were compared for each probeset with T test in GSE13507 and GSE37817 datasets, and statistical probesets were verified with GSE52519 and E-MTAB-1940 datasets. Differential gene expression, hierarchical clustering, gene ontology enrichment analysis, and heuristic online phenotype prediction algorithm methods were utilized. Statistically significant proteins were assessed in the Human Protein Atlas database. GSE13507 (6271 probesets) and GSE37817 (3267 probesets) data were significant after the extraction of probesets without gene annotation information. Common probesets in both datasets (2888) were further narrowed by analyzing the first 100 upregulated and downregulated probesets in BC samples. RESULTS: Among the total 400 probesets, 68 were significant for both datasets with similar fold-change values (Pearson r: 0.995). Protein-protein interaction networks demonstrated strong interactions between CCNB1, BUB1B, and AURKB. The HPA database revealed similar protein expression levels for CKAP2L, AURKB, APIP, and LGALS3 both for BC and control samples. CONCLUSION: This study disclosed six candidate biomarkers for the early diagnosis of BC. It is suggested that these candidate proteins be investigated in a wet lab to identify their functions in BC pathology and possible treatment approaches.

The role of cytokeratin 19 levels in the determination of endometriosis stages.

OBJECTIVE/AIM: Endometrisosis, one of the most common gynecological disease, is characterized by the presence of endometriotic tissue outside of uterine cavity. The development and the validation of a simple blood biomarker specific and sensitive for endometriosis may facilitate the rapid and the accurate diagnosis of the disease and thus early treatment. Cytokeratin expression changes during epithelial differentiation and this expression is important for the modulation and the control of cell cycle regulation, tumor cell motility and apoptosis. Cytokeratin 19 (CK-19) is expressed in most simple epithelial cells and their malignant counterparts. The aim of this study is to investigate serum CK-19 expression levels in patients with endometriosis and to determine the diagnostic role of CK-19 levels in differentiating various stage of endometriosis. METHODS: Ctytokeratin-19 expression and level were studied in 70 endometriosis patients and 50 volunteers by ELISA and RT-PCR. ROC analysis was performed by comparing all stages with each other and with the control group. RESULTS: The CK-19 levels were significantly higher in the endometriosis groups than that of the control group by ELISA and RT-PCR. A significant (p < .05) difference was observed in endometriosis patients according to the stages. CONCLUSION: Based on our data, it suggests that Cytokeratin-19 may have a potential role in the development of endometriosis.

Ribosome-Directed Therapies in Cancer.

The human ribosomes are the cellular machines that participate in protein synthesis, which is deeply affected during cancer transformation by different oncoproteins and is shown to provide cancer cell proliferation and therefore biomass. Cancer diseases are associated with an increase in ribosome biogenesis and mutation of ribosomal proteins. The ribosome represents an attractive anti-cancer therapy target and several strategies are used to identify specific drugs. Here we review the role of different drugs that may decrease ribosome biogenesis and cancer cell proliferation.

Cell-free methylation of RASSF1 and CDKN2AIP genes in the diagnosis of hepatocellular carcinoma associated with hepatitis B virus cirrhosis.

Background and Aim: Chronic hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC). Circulating cell-free DNA (cfDNA) methylation of tumor suppressor genes are emerging potential biomarkers in HCC. We aimed to evaluate the cfDNA methylation status of RASSF1 and CDKN2AIP genes in patients with liver cirrhosis (LC) with or without HCC caused by HBV. Materials and Methods: A total of 47 patients with HBV cirrhosis were included in the study. Patients were divided into two groups: HCC and LC (HCC+LC, n=22) and HBV cirrhosis only (LC, n=25). cfDNA was isolated from the plasma samples of the patients. Methylation analysis was performed for RASSF1 and CDKN2AIP genes. Results: Mean methylation percentage of CDKN2AIP gene was 0.001±0.004% in the HCC+LC group and 0.008±0.004 % in the LC only group. The mean methylation percentage of RASSF1 gene was 5.1±16.1% in the HCC+LC group and 9.7±25.9% in the LC only group. The methylation rate of CDKN2AIP was significantly lower in the HCC+LC group (p=0.027). A positive correlation was found with the absence of cfDNA methylation of CDKN2AIP gene in the presence of HCC (R=0.667, p=0.018). Conclusion: cfDNA methylation of CDKN2AIP and RASSF1 genes may provide important diagnostic information regarding the development of HCC in the setting of HBV cirrhosis.

Investigation of possible associations between tryptophan/kynurenine status and FOXP3 expression in colorectal cancer.

Tryptophan metabolism in the tumor microenvironment exerts immunosuppressive effects by affecting the anti-tumor functions of immune cells. The immunosuppressive roles of tryptophan and tryptophan metabolites and their effects on the FOXP3 gene, highly expressed in regulatory T cells (Tregs), are remarkable. Our study aimed to investigate the relation between tryptophan metabolism and the transcription factor FOXP3 gene in colorectal cancer (CRC). Patients with CRC (n = 159) and controls (n = 112) were included in the study. The FOXP3 rs3761548 variant genotyping from the isolated genomic DNA was performed by PCR-RFLP. FOXP3 gene expression was determined by Q-PCR in RNAs isolated from resected tissues at the same time. Serum tryptophan, kynurenine, kynurenic acid levels of the cases were determined by HPLC. In serum samples with CRC, tryptophan level was 14.32 ± 1.09 µmol/L, kynurenine level was 1.33 ± 0.02 µmol/L, and the kynurenic acid level was 0.01 ± 0.001 µmol/L. The level of tryptophan was found to be low in CRC compared to control (p < .001). In cases with CRC, CC genotype (p = .048) and C allele (p = .012) frequency for FOXP3 rs3761548 were higher than the control group. It was found that the expression level of the FOXP3 gene was approximately 44 times higher in the advanced tumor stage (T3 + T4) than in the early tumor stage (T1 + T2) (p = .021).We suggest that there may be a possible relationship among serum TRP, TRP metabolites (KYN, KYNA) levels, FOXP3 gene expression, and FOXP3 gene variants in CRC pathogenesis.

Anti-Mullerian Hormone Levels Increase After Bariatric Surgery in Obese Female Patients With and Without Polycystic Ovary Syndrome.

This study was aimed to investigate the effect of weight loss by bariatric surgery on the level of anti-Mullerian hormone (AMH) in morbidly obese female patients with or without polycystic ovary syndrome (PCOS). This prospective study includes 70 females, obese, and fertile patients of reproductive age. All patients were evaluated to determine the changes in weight, body mass index (BMI), serum AMH, and other biochemical parameters at the end of six months. The mean levels of the preop and postop AMH were 1.66±0.87 ng/ml and 5.99±1.39 ng/ml in the PCOS group; 1.35±0.76 ng/ml and 6.23±1.47 ng/ml in the non-PCOS group, respectively. The postop AMH levels were significantly higher than the preop levels for both groups (p<0.001). There were significant differences in the level of glucose, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride, total cholesterol, hemoglobin A1c, HOMA-IR, insulin between preop and postop 6th month. A negative correlation was found between postop AMH and body weight in all patients (r=-0.337, p=0.031). Postop AMH levels were negatively correlated with postop BMI levels in the non-PCOS patient group (r=-0.408, p=0.043). No significant difference was observed between the PCOS and non-PCOS groups in terms of all the parameters examined. In conclusion, our study suggests that the significantly increased AMH levels by losing weight with bariatric surgery in patients with morbid obesity with and without PCOS may indicate the improvement of fertilization potential. It could be considered when evaluating fertility in patients with morbid obesity.