Effects of miR-330 restoration on pancreatic cancer cells oncogenesis.

BACKGROUND: Inappropriate expressions of various miRNAs have reported in different human malignancies. Evidence suggested that miR-330 may play as both onco-miR and/or tumor suppressor-miR in different cancers. In the present study, we evaluated effects of miR-330 on proliferation and migration of pancreatic cancer (PC) cells as well as underlying molecular mechanisms. DESIGN: The expression of miR-330 was evaluated in clinical tissue samples of patients with PC. Transfection of the PC cells (PANC-1) by miR-330 was conducted by pCMV vector. The cancer-related genes expression was investigated in mRNA and protein level following transfection of the PC cells. Furthermore, the PC cells viability, invasion, migration, mitochondrial membrane potential, apoptosis, autophagy, and cell cycle profile were investigated after transfection by miR-330. RESULTS: The results indicated that expression of miR-330 downregulated in patients with PC. Stable increase of miR-330 expression after transfection in PC cells reduces viability, mitochondrial membrane potential, invasion, and migration. Further assessments demonstrated that upregulation of miR-330 increases apoptosis and autophagy percentage in the PC cells. Moreover, a cell cycle arrest was observed in G1, Sub-G1, and S phases following transfection of the PC cells. These findings can be explained by modified mRNA and protein expression of apoptosis- and metastasis-related genes. CONCLUSION: Our study suggested that miR-330 acts as a tumor suppressor in PC cells, and revealed that upregulation of miR-330 may provide an effective therapeutic approach for overcoming progression and metastasis in patients with PC.

Expression of Galectin-9-related immune checkpoint receptors in B-cell acute lymphoblastic leukemia.

Objectives: Exhausted CD8+ T-cells over-express immune checkpoint receptors (ICRs), which interact with their ligands on malignant cells. However, some ICRs have been reported to be expressed on both T-cells and tumor cells, including V-domain immunoglobulin suppressor of T cell activation (VISTA), Galectin-9, and T-cell immunoglobulin mucin-3 (TIM-3). We aimed to evaluate the mRNA expression of VISTA, Galectin-9, and TIM-3 on CD8+ T-cells and leukemic cells in B-cell acute lymphoblastic leukemia (B-ALL). Materials and Methods: Samples were obtained from 26 untreated B-ALL patients and 25 control subjects. CD8+ T-cells were isolated using Magnetic Activated Cell Sorting (MACS). Relative gene expression was then evaluated by qRT-PCR with specific primers for VISTA, Galectin-9, and TIM-3. Also, the mRNA expression profile and clinical data of 154 B-ALL patients were obtained from the TARGET. Results: mRNA expression of Galectin-9 on CD8+ T-cells in B-ALL patients was significantly lower than those in the control group (P=0.043), while VISTA expression was not significantly different between the two study groups (P=0.259). Besides, TIM-3 expression was significantly higher in B-ALL patients than in the control group (P<0.001). Also, data obtained from TARGET showed that the relapse incidence was not significantly different between patients with high and low expression of Galectin-9 and TIM-3 in leukemic cells (P=0.360 and P=0.655, respectively). Conclusion: Collectively, gene expression results suggest an important role for TIM-3, but not VISTA and Galectin-9, in B-ALL and it seems that TIM-3 could be a candidate for immune checkpoint therapy.

Analysis of KLF7 and KLF5 transcription factors gene variants in coronary artery disease.

INTRODUCTION AND OBJECTIVE: Genetic susceptibility has a key role in the pathogenesis of coronary artery disease (CAD). KLF5 and KLF7 are transcriptional factors essential to cell development and differentiation. Their genetic variants have been associated with the risk of metabolic disorders. The present study aimed to evaluate the possible correlation of KLF5 (rs3812852) and KLF7 (rs2302870) single nucleotide polymorphisms (SNPs) with the risk of CAD for the first time in the world. METHODS: The clinical trial study comprised 150 patients with CAD and 150 control subjects without CAD from the Iranian population. After blood sampling, deoxyribonucleic acid was extracted and genotyped using the Tetra Primer ARMS-PCR method and confirmed by Sanger sequencing. RESULTS: The KLF7 A/C genotypes and C allele frequency were meaningfully higher in the control group compared to the CAD+ group (p<0.05). No obvious association has been observed between KLF5 variants and CAD risk. However, the distribution of the AG genotype of KLF5 was statistically lower in CAD+ patients with diabetes than in CAD+ patients without diabetes (p<0.05). CONCLUSION: This study identified KLF7 SNP as a causative gene contributing to CAD, which presents novel insight into the molecular pathogenesis of the disease. It is, however, unlikely that KLF5 SNP has an essential role in the risk of CAD in the studied population.

The effects of Abemaciclib on cell cycle and apoptosis regulation in anaplastic thyroid cancer cells.

BACKGROUND: Anaplastic thyroid cancer (ATC) is an aggressive subtype of thyroid cancer, accounting for 1 to 2% of all cases. Deregulations of cell cycle regulatory genes including cyclins, cyclin-dependent kinases (CDKs), and endogenous inhibitors of CDKs (CKIs) are hallmarks of cancer cells and hence, studies indicate the inhibition of CDK4/6 kinases and cell cycle progression as potent therapeutic strategies. In this study, we investigated the anti-tumor activity of Abemaciclib, a CDK4 and CDK6 inhibitor, in ATC cell lines. METHODS AND RESULTS: The ATC cell lines C643 and SW1736 were selected to study the antiproliferative effects of Abemaciclib using a cell proliferation assay and crystal violet staining assay. Annexin V/PI staining and cell cycle analysis by flow cytometry were also performed to examine the effects on apoptosis induction and cell cycle arrest. Wound healing assay and zymography analysis examined the effects of the drug on invasive abilities of ATC cells and Western blot analyses were applied to further study the anti-tumor mechanism of Abemaciclib, in addition to combination treatment with alpelisib. Our data demonstrated that Abemaciclib significantly inhibited cell proliferation and increased cellular apoptosis and cell cycle arrest in ATC cell lines, while considerably reducing cell migration and colony formation. The mechanism seemed to involve the PI3K pathway. CONCLUSION: Our preclinical data highlight CDK4/6 as interesting therapeutic targets in ATC and suggest CDK4/6-blockade therapies as promising strategies in this malignancy.

Inconsistency in the expression pattern of a five-lncRNA signature as a potential diagnostic biomarker for gastric cancer patients in bioinformatics and in vitro.

Objectives: Due to diagnosis of gastric cancer in advanced stages as well as its poor prognosis, finding biomarkers is essential. In this study, using the TCGA RNAseq data of gastric cancer patients, we evaluated the diagnostic value of lncRNAs that had differential expression. Materials and Methods: We evaluated P-value, FDR, and log fold change for whole transcripts. Next, by comparison of the RNAseq gene names with the total known lncRNA names, we identified differential expressed lncRNAs. Following this, specificity and sensitivity for lncRNAs coming from the previous step were calculated. For more confirmation, we predicted target genes and performed GO and KEGG signaling pathway analysis. In the end, we examined reliability and consistency of expression of this signature in three gastric cancer cell lines and one of them in twenty tumors and tumor-adjacent normal tissue samples using qRT-PCR. Results: Five lncRNAs had proper sensitivity and specificity and had target genes involved in cancer-related signaling pathways; however, they showed different expression patterns in TCGA data and in vitro. Conclusion: The results of our study demonstrated that the five-lncRNAs PART1, UCA1, DIRC3, HOTAIR, and HOXA11AS require more investigation to be confirmed as diagnostic biomarkers in gastric cancer.

WITHDRAWN: In silico and Experimental Analysis of miR-125b-5 and miR-485-5p Expression in Serum of Patients with Breast Cancer

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Long non-coding RNA AC087388.1 as a novel biomarker in colorectal cancer.

BACKGROUND: Several investigations have reported diverse roles of long non-coding RNA (lncRNA) in biological processes, tumor development, and progression of colorectal cancer (CRC). In this study, we investigated the lncRNA AC087388.1 tumorigenic role in CRC cells. METHODS: The CRC tissues were collected at the Reza Radiotherapy and Oncology Center, Mashhad, Iran. The human SW-48 and HT-29 CRC cell lines were obtained from the national cell bank of Iran. The cells were cultured according to ATCC (the American Type Culture Collection) recommendations. Quantitative real-time PCR was applied to assess the RNA expression. ShRNA transfection was done to downregulate the target gene. MTT and apoptosis assays were conducted to evaluate cell proliferation and viability, respectively. Colony formation assay, wound healing assay, and invasion assay were applied to determine growth, motility, and invasion of the cells, respectively. ENCORI online tool was used as downstream enrichment analysis. RESULTS: Forty CRC patients were encompassed in this study. The results demonstrated that the lncRNA SLC16A1-AS1, AC087388.1, and ELFN1-AS1 were significantly overexpressed in the CRC tissues in comparison to their normal counterpart margins. All the lncRNAs have shown significant Area Under Curve (AUC) values in the patients. Downregulation of lncRNA AC087388.1 remarkably decreased the cell proliferation and viability of the CRC cells. In addition, the data demonstrated that the downregulation of lncRNA AC087388.1 significantly suppressed cell growth and colony formation capability in the cells. Also, downregulation of lncRNA AC087388.1 attenuated motility and invasion of CRC cells, and significantly decreased the expression of invasion genes. In-silico functional enrichment analysis indicated that the lncRNA AC087388.1 has contributed to crucial signaling pathways in tumorigenesis such as the p53 and Wnt signaling pathways, apoptosis, and cell cycle. CONCLUSIONS: Altogether, we showed that lncRNA AC087388.1 has an oncogenic role in tumorigenesis of CRC, and it can be considered as a novel diagnostic and prognostic biomarker in CRC.

Evaluation of correlation between transcription factors and IL-17 in oral and cutaneous lichen planus lesions and Leukocytes.

BACKGROUND: Lichen planus (LP) is a chronic autoimmune disease with different clinical subtypes including cutaneous LP (CLP) and oral LP (OLP). We aimed to compare mRNA expression of RORγt and IL-17 in paraffin-embedded blocks of OLP and CLP lesions with normal oral mucosa (NOM), and also its correlation with hematologic parameters. MATERIALS & METHODS: This study included 89 paraffin-embedded blocks contain OLP (44 cases), CLP (45 cases) and NOM from the archive of Mashhad University of Medical Sciences, Mashhad, Iran. The expression of RORγt and IL-17 was evaluated by Real-time RT-PCR method. The result was compared to Leukocyte counts and the other hematological parameters of studied patients. RESULTS: The results of our study showed IL-17 and RORγt expression in OLP lesions were significantly higher than CLP and NOM groups (P = 0.001). Although we found high expression of RORγt and IL-17 in erosive OLP in compared to classic OLP lesion, but this increment was not significant for IL-17 (P = 0.26) and RORγt (P = 0.14). Further, Leukocyte and monocyte counts were substantially high in OLP group in compared to the CLP and NOM groups (P < 0.05). CONCLUSIONS: We concluded that increased expression of RORγt and IL-17 in LP lesions could play role in the pathogenesis of LP. As well, higher expression of RORγt and IL-17 in oral LP more than cutaneous LP might be associated with difference in clinical behavior of the two types of disease and role of these factors in premalignant behavior of OLP lesions.

Altered expression of EGFR and miR-34a derived from serum and tumoral tissue was associated with glioblastoma multiform.

OBJECTIVE: Glioblastoma multiform (GBM) is the most prevalent and invasive brain malignancy in adults. There are ongoing researches to introduce novel and non-invasive potential biomarkers for the early detection of GBM. METHODS: Here we compared the expression of EGFR, miR-34a, and miR-19a between tumoral and adjacent non-cancerous tissues (ANCTs) of 50 GBM patients and also compared their expression levels in serum samples of GBM patients with serum samples of 50 control subjects. RESULTS: The expression level of the EGFR gene was elevated in GBM tissues in comparison to the corresponding ANCTs (P < 0.0001) and also was higher in the serum sample of patients compared with control serum (P < 0.0001). The miR-34a was significantly downregulated in serum samples as well as tissues obtained from GBM patients compared with the corresponding controls (expression ratio = 0.57 and 0.4, P = 0.02 and 0.001 respectively). CONCLUSIONS: Dysregulation of the EGFR gene and miR-34a in serum samples of GBM patients compared with the control subjects promises the emergence of non-invasive biomarkers for early detection of GBM which need confirmative studies with a large sample size.

Mechanisms of long non-coding RNA function in colorectal cancer tumorigenesis.

Colorectal cancer (CRC) is one of the most common cancers globally. Although a variety of CRC screening methods have been developed, many patients are diagnosed at advanced stages of CRC with tumor invasion and distance metastasis. Several studies have suggested the long noncoding RNAs (lncRNAs) as one of the main contributors in CRC tumorigenesis, although the exact underlying mechanism of lncRNAs in CRC is still unknown. Numerous studies have indicated aberrant expression of lncRNAs in CRC through different modes of action such as cell proliferation, apoptosis, cell cycle, DNA repair response, drug-resistance, migration, and metastasis. Furthermore, lncRNA polymorphisms can influence the risk of CRC development. Accordingly, lncRNAs can be served as promising diagnostic or prognostic biomarkers and also desired therapeutic targets affecting the outcome of patients with CRC. In this review, we summarized the updated and novel evidence that identifies different roles of lncRNAs in the tumorigenesis of CRC.

Glucocorticoid receptors and their upstream epigenetic regulators in adults with steroid-resistant nephrotic syndrome.

Steroid-resistant nephrotic syndrome (SRNS) is a clinical challenge with variable clinical outcomes. In patients with SRNS, unsuccessful anti-inflammatory and anti-proteinuric effects of steroids lead to end-stage renal disease (ESRD). Our objective was to define the expression pattern of the glucocorticoid receptors (GR) α and ß and their epigenetic regulators (miR-24, miR-30a, and miR-370) in a group of adults with SRNS. In this regard, sixty primary NS patients with focal segmental glomerulosclerosis (FSGS, N = 30) and membranous glomerulonephritis (MGN, N = 30) and also healthy volunteers (N = 24) were enrolled. Real-time PCR was performed to evaluate the expression levels of the aforementioned genes in peripheral blood mononuclear cell (PBMC) samples. Furthermore, an in-silico analysis was performed to understand the signaling pathways and biological procedures that may be targeted by these microRNAs in NS. The decreased and increased levels of GRα and GRß were not significant, respectively. Statistically significant reduced miR-24 levels were observed between control/MGN (p = .022) and MGN/FSGS (p = .032) groups. Additionally, a decrease was detected in miR-30a between MGN and FSGS (p = .049) groups. There was a significant increase in miR-370 expression level between control and NS groups (p = .029), as well as control/MGN (p = .008), and MGN/FSGS (p = .046). Bioinformatics analysis predicted the possible targets of the studied genes including genes involved in TGF-ß, Notch1, and p53 signaling pathways, regulation of gene expression, intracellular signal transduction, negative regulation of response to the stimulus, cell-cell signaling, and cell activation in the pathogenesis of SRNS. Taken all together, dysregulated levels of GRα, GRß were not attributed to SRNS in our patients. It seems that pharmacokinetics and the genetic variations in podocyte-related genes may be associated with the steroid-resistance in our adult patients with NS rather than GR expression.

Clinicopathological Significance of Long Non-Coding RNA GHET1 in Human Cancers: A Meta-Analysis.

BACKGROUND: Cancer is considered as the main public health problem and the second leading cause of morbidity and mortality worldwide. Numerous environmental-lifestyle related risk factors account for around one-third of cancer deaths. Recently, the key role of lncRNAs has been widely investigated in a variety of disorders, including cancer. The lncRNA GHET1 has been considered as an essential oncogenic lncRNA in many types of human cancers. Clinical investigations indicated that expression of lncRNA GHET1 is correlated with clinicopathological characteristics in cancer. This metaanalysis investigated the correlation between the lncRNA GHET1 expression and clinicopathological features in different types of cancers. MATERIALS AND METHODS: Comprehensive literature searches in PubMed, Scopus, and Web of Knowledge were conducted up to April 11, 2019. Sixteen studies were included in this meta-analysis. All statistical analyses were conducted using Stata software, version 12.0. RESULTS: The pooled OR and 95%CIs of the sixteen relevant studies showed that over expression of lncRNA GHET1 was associated with tumor-size ≥5 cm (OR= 2.51, 95% CI: 1.89-3.33, p=0.00, I2=38.30%), positive lymph node metastasis (OR= 2.83, 95% CI: 1.78-4.52, p=0.00, I2=45.60%), advanced tumor stage (OR= 3.92, 95% CI: 2.97-5.19, p=0.00, I2=0.00%), positive distant metastasis (OR= 5.74, 95% CI: 2.58-12.77, p=0.00, I2=0.00%), advanced tumor status (OR= 2.97, 95% CI: 1.40- 6.29, p=0.01, I2=34.70%), and positive vascular invasion (OR= 2.69, 95% CI: 1.61-4.50, p=0.00, I2=29.20%). CONCLUSION: Taken together, the current study demonstrated that overexpression of lncRNA GHET1 is significantly associated with clinicopathological features in human cancers. Our results suggested that lncRNA GHET1 can be utilized as a prognostic biomarker in human cancer.

Integration analysis of long non-coding RNA (lncRNA) role in tumorigenesis of colon adenocarcinoma.

BACKGROUND: Colon adenocarcinoma (COAD) is one of the most common gastrointestinal cancers globally. Molecular aberrations of tumor suppressors and/or oncogenes are the main contributors to tumorigenesis. However, the exact underlying mechanisms of COAD pathogenesis are clearly not known yet. In this regard, there is an urgent need to indicate promising potential diagnostic and prognostic biomarkers in COAD patients. METHODS: In the current study, level 3 RNA-Seq and miR-Seq data and corresponding clinical data of colon adenocarcinoma (COAD) were retrieved from the TCGA database. The "limma" package in R software was utilized to indicate the differentially expressed genes. For in silico functional analysis, GO and KEGG signaling pathways were conducted. PPI network was constructed based on the STRING online database by Cytoscape 3.7.2. A ceRNA network was also constructed by "GDCRNATools" package in R software. Kaplan-Meier survival analysis (log-rank test) and ROC curve analysis were used to indicate the diagnostic and prognostic values of the biomarkers. RESULTS: The differential expression data demonstrated that 2995 mRNAs, 205 lncRNAs, and 345 miRNAs were differentially expressed in COAD. The GO and KEGG pathway analysis indicated that the differentially expressed mRNAs were primarily enriched in canonical processes in cancer. The PPI network showed that the CDKN2A, CCND1, MYC, E2F, CDK4, BRCA2, CDC25B, and CDKN1A proteins were the critical hubs. In addition, the Kaplan-Meier analysis revealed that 215 mRNAs, 14 lncRNAs, and 39 miRNAs were associated with overall survival time in the patients. Also, the ceRNA network data demonstrated that three lncRNAs including MIR17HG, H19, SNHG1, KCNQ1OT1, MALAT1, GAS5, SNHG20, OR2A1-AS1, and MAGI2-AS3 genes were involved in the development of COAD. CONCLUSIONS: Our data suggested several promising lncRNAs in the diagnosis and prognosis of patients with COAD.

EGFR Blockade Reverses Cisplatin Resistance in Human Epithelial Ovarian Cancer Cells.

Background: Epithelial ovarian cancer (EOC) is one of the most lethal gynecological malignancy worldwide. Although the majority of EOC patients achieve clinical remission after induction therapy, over 80% relapse and succumb to the chemoresistant disease. Previous investigations have demonstrated the association of epidermal growth factor receptor (EGFR) with resistance to cytotoxic chemotherapies, hormone therapy, and radiotherapy in the cancers. These studies have highlighted the role of EGFR as an attractive therapeutic target in cisplatin-resistant EOC cells. Methods: The human ovarian cell lines (SKOV3 and OVCAR3) were cultured according to ATCC recommendations. The MTT assay was used to determine the chemosensitivity of the cell lines in exposure to cisplatin and erlotinib. The qRT-PCR was applied to analyze the mRNA expression of the desired genes. Results: Erlotinib in combination with cisplatin reduced the cell proliferation in the chemoresistant EOC cells in comparison to monotherapy of the drugs (p < 0.05). Moreover, erlotinib/cisplatin combination synergistically decreased the expression of anti-apoptotic and also increased pro-apoptotic genes expression (p < 0.05). Cisplatin alone could increase the expression of multi-drug resistant genes. The data suggested that EGFR and cisplatin drive chemoresistance in the EOC cells through MEKK signal transduction as well as through EGFR/MEKK pathways in the cells, respectively. Conclusion: Our findings propose that EGFR is an attractive therapeutic target in chemoresistant EOC to be exploited in translational oncology, and erlotinib/cisplatin combination treatment is a potential anti-cancer approach to overcome chemoresistance and inhibit the proliferation of the EOC cells.

Non-coding RNAs underlying chemoresistance in gastric cancer.

BACKGROUND: Gastric cancer (GC) is a major health issue in the Western world. Current clinical imperatives for this disease include the identification of more effective biomarkers to detect GC at early stages and enhance the prevention and treatment of metastatic and chemoresistant GC. The advent of non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs) and long-non coding RNAs (lncRNAs), has led to a better understanding of the mechanisms by which GC cells acquire features of therapy resistance. ncRNAs play critical roles in normal physiology, but their dysregulation has been detected in a variety of cancers, including GC. A subset of ncRNAs is GC-specific, implying their potential application as biomarkers and/or therapeutic targets. Hence, evaluating the specific functions of ncRNAs will help to expand novel treatment options for GC. CONCLUSIONS: In this review, we summarize some of the well-known ncRNAs that play a role in the development and progression of GC. We also review the application of such ncRNAs in clinical diagnostics and trials as potential biomarkers. Obviously, a deeper understanding of the biology and function of ncRNAs underlying chemoresistance can broaden horizons toward the development of personalized therapy against GC.

SARS-CoV infection crosstalk with human host cell noncoding-RNA machinery: An in-silico approach.

Although 70 % of the genome is transcribed to RNA in humans, only ∼2% of these transcripts are translated into proteins. The rest of the transcripts are defined as noncoding RNAs, including Long noncoding RNAs (LncRNAs) and MicroRNAs (miRNAs) that mostly function post-transcriptionally to regulate the gene expression. The outbreak of a novel coronavirus (SARS-CoV) has caused a major public health concern across the globe. The SARS-CoV is the seventh coronavirus that is known to cause human disease. There are currently no promising antiviral drugs with proven efficacy nor are there vaccines for its prevention. As of August 10, 2020, SARS-CoV has been infected more than 13 million cases in more than 213 countries, with an estimated mortality rate of ∼3 %. Thus, it is of utmost important priority to develop novel therapies for COVID-19. It is not fully investigated whether noncoding RNAs regulate signaling pathways that SARS-CoV involved in. Hence, computational analysis of the noncoding RNA interactions and determining importance of key regulatory noncoding RNAs in antiviral defense mechanisms will likely be helpful in developing new drugs to attack SARS-CoV infection. To elucidate this, we utilized bioinformatic approaches to find the interaction network of SARS-CoV/human proteins, miRNAs, and lncRNAs. We found TGF-beta signaling pathway as one of the potential interactive pathways. Furthermore, potential miRNAs/lncRNAs networks that the virus might engage during infection in human host cells have been shown. Altogether, TGF-beta signaling pathway as well as hub miRNAs, and LncRNAs involve during SARS-CoV pathogenesis can be considered as potential therapeutic targets.

In silico evidence of high frequency of miRNA-related SNPs in Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) is the dominant histological type of esophageal cancer significantly reported in developing nations. There is an increasing evidence suggesting that single nucleotide polymorphisms (SNPs) in the untranslated regions of genes (3'-UTRs) targeted by microRNAs (miRNAs) can change the target gene's expression and thereby affect the individual's cancer risk. Thus, in support of the role of SNPs occurring in miRNA target sites (miR-TS-SNPs) in the cancer, we analyzed the next generation sequencing data of 10 ESCC patients. In each patient, about 3,000 SNPs in 3'-UTRs were obtained in their whole-exome sequencing profiles. We applied two separate methods, manual and computational in silico approaches, to predict the miR-TS-SNPs with more effects on the miRNA-target interactions. dbSNP, 1000G, ExAC, Iranome, miRandb, miRCancer, TargetScan, Human, miRNASNP2 and miRBase databases were used for positive selection of miR-TS-SNPs and DIANA-miRPath v3.0 for pathway analysis. We identified six rare germline miR-TS-SNPs and two other ones with unknown miR-TS-SNPs. We interestingly observed all of these variants in only one patient, which can be evidence of the relationship between miR-TS-SNPs and cancer incidence. The study of cancer genetics including miR-TS-SNPs reveals miRNAs and their related pathways, which will be greatly useful in cancer research from noninvasive biomarkers to new treatments.

Obesity, diabetes and the risk of colorectal adenoma and cancer.

BACKGROUND: Colorectal cancer (CRC) is the fourth most commonly diagnosed gastrointestinal (GI) malignancy and the third leading cause of cancer-related death worldwide. In the current case-control study, an association between diagnosis of CRC, obesity and diabetes was investigated. METHODS: Demographic characteristics, colonoscopy reports, history of drug, smoking, and medical history were collected from patients referred to a colonoscopy unit. The location, size and number of the polyps were recorded during the colonoscopy. Statistically, t-test was conducted for mean comparison for the groups. Pearson's chi-squared test (χ2) was applied to categorize variables. Five classification methods based on the important clinicopathological characteristics such as age, BMI, diabetes, family history of colon cancer was performed to predict the results of colonoscopy. RESULTS: Overall, 693 patients participated in this study. In the present study, 115 and 515 patients were evaluated for adenoma/adenocarcinoma and normal colonoscopy, respectively. The mean age of patients positive for adenoma or adenocarcinoma were significantly higher than the negative groups (p value < 0.001). Incidence of overweight and/or obesity (BMI > 25 kg/m2) were significantly higher in adenoma positive patients as compared to controls (49.9 and 0.9% respectively, p value = 0.04). The results also demonstrated a significant association between suffering from diabetes and having colon adenoma (OR = 1.831, 95%CI = 1.058-3.169, p value = 0.023). The experimental results of 5 classification methods on higher risk factors between colon adenoma and normal colonoscopy data were more than 82% and less than 0.42 for the percentage of classification accuracy and root mean squared error, respectively. CONCLUSIONS: In the current study, the occurrence of obesity measured based on BMI and diabetes in the adenoma positive patient group was significantly higher than the control group although there was no notable association between obesity, diabetes and adenocarcinoma.

Familial combined hyperlipidemia: An overview of the underlying molecular mechanisms and therapeutic strategies.

Among different types of dyslipidemia, familial combined hyperlipidemia (FCHL) is the most common genetic disorder, which is characterized by at least two different forms of lipid abnormalities: hypercholesterolemia and hypertriglyceridemia. FCHL is an important cause of cardiovascular diseases. FCHL is a heterogeneous condition linked with some metabolic defects that are closely associated with FCHL. These metabolic features include dysfunctional adipose tissue, delayed clearance of triglyceride-rich lipoproteins, overproduction of very low-density lipoprotein and hepatic lipids, and defect in the clearance of low-density lipoprotein particles. There are also some genes associated with FCHL such as those affecting the metabolism and clearance of plasma lipoprotein particles. Due to the high prevalence of FCHL especially in cardiovascular patients, targeted treatment is ideal but this necessitates identification of the genetic background of patients. This review describes the metabolic pathways and associated genes that are implicated in FCHL pathogenesis. We also review existing and novel treatment options for FCHL. © 2019 IUBMB Life, 71(9):1221-1229, 2019.

IL-6/IL-6R pathway is a therapeutic target in chemoresistant ovarian cancer.

INTRODUCTION:: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy worldwide and despite an initial response to therapeutic agents, the majority of patients have chemoresistant disease. There is no treatment strategy with proven efficacy against chemoresistant EOC and in this setting, overcoming therapy resistance is the key to successful treatment. METHODS:: This study aimed to investigate expression of interleukin-6 (IL-6) (IL-6) and IL-6 receptor (IL-6R) in a panel of the EOC cell lines. To achieve this, the expression of IL-6 and its receptor were compared in the EOC cells using quantitative reverse transcription polymerase chain reaction. MTT assay was performed to obtain chemosensitivity of the EOC cells. RESULTS:: In this report, we show that expressions of IL6 and IL6R are higher in therapy-resistant EOC cells compared to sensitive ones. Higher expression of IL6 and its receptor correlated with resistance to certain chemotherapeutic agents. Moreover, our findings showed that combination of tocilizumab (Actemra; Roche), an anti-IL-6R monoclonal antibody, with carboplatin synergistically inhibited growth and proliferation of the EOC cells and the most direct axis for IL-6 gene expression was NF-κB pathway. CONCLUSION:: Collectively, our findings suggest that blockade of the IL-6 signaling pathway with anti-IL-6 receptor antibody tocilizumab might resensitize the chemoresistant cells to the current chemotherapeutics.