Publications by authors named "Milad Bastami"

54 Publications

Perturbation of miR-146b and relevant inflammatory elements in esophageal carcinoma patients supports an immune downregulatory mechanism.

Pathol Res Pract 2021 Sep 20;225:153560. Epub 2021 Jul 20.

Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

Background: Esophageal Cancer is known as one of the deadliest cancers worldwide with the squamous cell carcinoma (ESCC) being the predominant subtype. There is a growing body of evidence linking the dysregulated microRNA (miRNA) pathway of immune cells to the progression of several tumors. In a previous study, we investigated molecular alterations pertaining to miR-146a and some components of NF-kB signaling pathway and proposed a possible immune downregulatory mechanism in peripheral blood mononuclear cells (PBMCs) of ESCC patients. Here, we further scrutinized other components of this pathway by evaluating PBMC levels of miR-146b, TLR4, IL10, and TNFA.

Methods: Gene expressions were quantified using RT-qPCR assays. To prevent the vulnerability of results to the expression instability of reference genes, nine additional transcripts were quantified, and stable reference genes for normalizing qPCR data were identified using the NormFinder and the geNorm algorithms. The efficiency-corrected normalized relative quantity values were used to compare gene expressions among study groups.

Results: The PBMC expression of miR-146b and TNFA was downregulated in ESCC patients as compared to healthy subjects. While the level of TLR4 was not different among the study groups, the PBMC level of IL10 was upregulated in ESCC patients. Logistic regression analyses coupled with the ROC curve and cross-validation analysis suggested that PBMC expression may serve as potential candidate biomarker for discriminating ESCC patients from healthy subjects.

Conclusion: The present findings, in line with our previous report, propose a particular gene expression pattern in PBMCs of ESCC patients, providing evidence in support of an immune downregulatory mechanism.
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http://dx.doi.org/10.1016/j.prp.2021.153560DOI Listing
September 2021

The expression of miR-513c and miR-3163 was downregulated in tumor tissues compared with normal adjacent tissue of patients with breast cancer.

BMC Med Genomics 2021 Jul 7;14(1):180. Epub 2021 Jul 7.

Molecular Genetics, Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.

Background: Breast cancer (BC) is the most invasive cancer with different subtypes that its metabolism is unique compared with normal cells. Glutamine is considered critical nutrition that many cancer cells, particularly BC cells, are dependent on it for growth and proliferation. Therefore, targeting glutamine metabolism, especially enzymes that are related to this pathway, can be beneficial to design anti-cancer agents. Recent evidence has shown that microRNAs (miRNAs), with a short length and single-strand properties, play a prominent role in regulating the genes related to glutamine metabolism, which may control the development of cancer.

Methods: In silico analysis confirmed that miR-513c and miR-3163 might be involved in glutamine metabolism. The expression level of these two miRNAs was evaluated in eighty BC tissues and normal adjacent tissues. Furthermore, GSE38167, GSE38867, GSE42128, GSE45666, and GSE53179 were employed from gene expression omnibus (GEO). The Limma package was utilized to identify differentially expressed miRNAs (DEMs) of mentioned datasets to evaluate miR-513c and miR-3163 expression. Further, in silico analysis was utilized to predict the potential biological processes and molecular pathways of miR-513c and miR-3163, based on their target genes.

Results: In silico studies revealed top categories of biological processes and cellular pathways that might play a critical role in metabolism reprogramming and cancer development and were target genes for miR-513c and miR-3163. The current study showed that miR-513c (p value = 0.02062 and FC =  - 2.3801) and miR-3163 (p value = 0.02034 and FC =  - 2.3792) were downregulated in tumor tissues compared to normal adjacent tissues. The analysis of GEO microarray datasets showed that miR-513c was downregulated in GSE38167, GSE38867, GSE42128, GSE45666 and GSE53179, whereas there was a significant downregulation of miR-3163 in only two studies, including GSE38867 and GSE42128 that they were in accordance with our experimental results. Furthermore, the subgroup analysis did not show any substantial relationship between expression levels of these two miRNAs and factors such as age, family history of cancer, and abortion history.

Conclusion: MiR-513c and miR-3163 were downregulated in BC tissues, which might serve as tumor suppressors. They are suggested as potential therapeutic targets for patients with BC.
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http://dx.doi.org/10.1186/s12920-021-01029-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265124PMC
July 2021

Critical roles of microRNA-196 in normal physiology and non-malignant diseases: Diagnostic and therapeutic implications.

Exp Mol Pathol 2021 Jun 21;122:104664. Epub 2021 Jun 21.

Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

MicroRNAs (miRNAs) have emerged as a critical component of regulatory networks that modulate and fine-tune gene expression in a post-transcriptional manner. The microRNA-196 family is encoded by three loci in the human genome, namely hsa-mir-196a-1, hsa-mir-196a-2, and hsa-mir-196b. Increasing evidence supports the roles of different components of this miRNA family in regulating key cellular processes during differentiation and development, ranging from inflammation and differentiation of stem cells to limb development and remodeling and structure of adipose tissue. This review first discusses about the genomic context and regulation of this miRNA family and then take a bird's eye view on the updated list of its target genes and their biological processes to obtain insights about various functions played by members of the microRNA-196 family. We then describe evidence supporting the involvement of the human microRNA-196 family in regulating critical cellular processes both in physiological and non-malignant inflammatory conditions, highlighting recent seminal findings that carry implications for developing novel therapeutic or diagnostic strategies.
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http://dx.doi.org/10.1016/j.yexmp.2021.104664DOI Listing
June 2021

The expression of miRNA-152-3p and miRNA-185 in tumor tissues versus margin tissues of patients with chemo-treated breast cancer.

BMC Res Notes 2021 Jun 16;14(1):234. Epub 2021 Jun 16.

Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.

Objective: Breast cancer (BC) is the most significant and lethal type of cancer in women. Although there are many newly develop chemotherapy drugs for patients with BC treating at various stages, drug resistance is the most important obstacle in their effectiveness for BC treatment. On the other hand, microRNAs are considered key regulators of genes involved in carcinogenesis and chemoresistance in cancers. The purpose of this study was to evaluate the role of miR-152-3p and miR-185 in intrinsic chemoresistance and proliferation of BC. In addition, the potential role of these miRNAs during chemoresistance was evaluated through possible signaling pathways.

Results: Here, miR-152-3p was significantly downregulated in tumor tissues compared to the corresponding margin tissues in patients with BC (p-value ≥ 0.04407 and fold change = - 2.0552). In contrast, no statistically significant difference was observed in the miR-185 expression between the two groups. Furthermore, no significant correlation was found between the expression of these two miRNAs and subfactors, including cancer family history, abortion, and age. Downregulation of miR-152-3p could be considered a promising regulator of BC chemoresistance.
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http://dx.doi.org/10.1186/s13104-021-05647-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207775PMC
June 2021

The pathways related to glutamine metabolism, glutamine inhibitors and their implication for improving the efficiency of chemotherapy in triple-negative breast cancer.

Mutat Res Rev Mutat Res 2021 Jan-Jun;787:108366. Epub 2021 Jan 18.

Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

Breast cancer (BC) is a heterogeneous cancer with multiple subtypes affecting women worldwide. Triple-negative breast cancer (TNBC) is a prominent subtype of BC with poor prognosis and an aggressive phenotype. Recent understanding of metabolic reprogramming supports its role in the growth of cancer cells and their adaptation to their microenvironment. The Warburg effect is characterized by the shift from oxidative to reductive metabolism and external secretion of lactate. The Warburg effect prevents the use of the required pyruvate in the tricarboxylic acid (TCA) cycle progressing through pyruvate dehydrogenase inactivation. Therefore, it is a major regulatory mechanism to promote glycolysis and disrupt the TCA cycle. Glutamine (Gln) can supply the complementary energy for cancer cells. Additionally, it is the main substrate to support bioenergetics and biosynthetic activities in cancer cells and plays a vital role in a wide array of other processes such as ferroptosis. Thus, the switching of glucose to Gln in the TCA cycle toward reductive Gln metabolism is carried out by hypoxia-inducible factors (HIFs) conducted through the Warburg effect. The literature suggests that the addiction of TNBC to Gln could facilitate the proliferation and invasiveness of these cancers. Thus, Gln metabolism inhibitors, such as CB-839, could be applied to manage the carcinogenic properties of TNBC. Such inhibitors, along with conventional chemotherapy agents, can potentially improve the efficiency and efficacy of TNBC treatment. In this review, we discuss the associations between glucose and Gln metabolism and control of cancer cell growth from the perspective that Gln metabolism inhibitors could improve the current chemotherapy drug effects.
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http://dx.doi.org/10.1016/j.mrrev.2021.108366DOI Listing
July 2021

A methylation signature at the CpG island promoter of estrogen receptor beta (ER-β) in breasts of women may be an early footmark of lack of breastfeeding and nulliparity.

Pathol Res Pract 2021 Feb 28;218:153328. Epub 2020 Dec 28.

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Although little is known regarding the mechanisms behind the onset of breast cancer (BC) through reproductive risk factors, new researches have highlighted some early tumor-related methylation footmarks in the breast tissue of apparently clinically healthy women as their potential epigenetic mechanism. Previous evidence supports that the estrogen receptor beta (ER-β), whose anti-cancer roles had already been revealed in BC, is downregulated in the breasts of healthy nulliparous women. Nevertheless, data on such a link about its methylation alterations have not been reported. The goal of current study was to determine possible methylation alterations at CpG island promoter of the ER-β gene, including promoter 0 N and exon 0 N, in relation to aspects of reproductive history in the healthy breasts. The DNA was extracted from the breasts of 120 subjects undergoing cosmetic mammoplasty. Thereafter, the methylation levels of targeted regions in ER-β gene were determined by using MeDIP-qPCR assay. The results revealed that ER-β exon 0 N had no methylation in 84.2 % of the women, whereas the rest, comprising 2.5 % and 13.3 % of the samples, showed a lower and higher of its methylation, respectively. Interestingly, nulliparous women were found to have an elevated methylation level of the ER-β exon 0 N than parous women (P = 0.036). Moreover, we observed a high methylation of the ER-β exon 0 N in the breasts of non-breastfeeding women compared to breastfeeding subgroup (P = 0.048). Likewise, the non-breastfeeding subgroup showed exon 0N high methylation in comparison to women with breastfeeding >24 months (P = 0.023). Finally, although we found that 6.67 % of the samples had a high methylation level at the promoter 0N, no any relationship was found between its methylation and reproductive history. These results may provide key clues to revealing the epigenetic mechanism through which the nulliparity and lack of breastfeeding influencing the risk factor of BC as well as introducing the potential new early prediction and prevention strategies. Although further investigations need to be done in order to gain a better understanding the roles of these epigenetic signatures.
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http://dx.doi.org/10.1016/j.prp.2020.153328DOI Listing
February 2021

Dysregulated levels of glycogen synthase kinase-3β (GSK-3β) and miR-135 in peripheral blood samples of cases with nephrotic syndrome.

PeerJ 2020 16;8:e10377. Epub 2020 Dec 16.

Center of Experimental Orthopaedics, Universität des Saarlandes, Homburg/Saar, Germany.

Background: Glycogen synthase kinase-3 (GSK-3β) is a serine/threonine kinase with multifunctions in various physiological procedures. Aberrant level of GSK-3β in kidney cells has a harmful role in podocyte injury.

Methods: In this article, the expression levels of GSK-3β and one of its upstream regulators, miR-135a-5p, were measured in peripheral blood mononuclear cells (PBMCs) of cases with the most common types of nephrotic syndrome (NS); focal segmental glomerulosclerosis (FSGS) and membranous glomerulonephritis (MGN). In so doing, fifty-two cases along with twenty-four healthy controls were included based on the strict criteria.

Results: Levels of GSK-3β mRNA and miR-135 were measured with quantitative real-time PCR. There were statistically significant increases in GSK-3β expression level in NS ( = 0.001), MGN ( = 0.002), and FSGS ( = 0.015) groups compared to the control group. Dysregulated levels of miR-135a-5p in PBMCs was not significant between the studied groups. Moreover, a significant decrease was observed in the expression level of miR-135a-5p in the plasma of patients with NS ( = 0.020), MGN ( = 0.040), and FSGS ( = 0.046) compared to the control group. ROC curve analysis approved a diagnostic power of GSK-3β in discriminating patients from healthy controls (AUC: 0.72,  = 0.002) with high sensitivity and specificity.

Conclusions: Dysregulated levels of GSK-3β and its regulator miR-135a may participate in the pathogenesis of NS with different etiology. Therefore, more research is needed for understanding the relationship between them.
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http://dx.doi.org/10.7717/peerj.10377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749650PMC
December 2020

An in silico approach to identify and prioritize miRNAs target sites polymorphisms in colorectal cancer and obesity.

Cancer Med 2020 12 18;9(24):9511-9528. Epub 2020 Oct 18.

Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.

Colorectal cancer (CRC) and obesity are linked clinical entities with a series of complex processes being engaged in their development. MicroRNAs (miRNAs) participate in these processes through regulating CRC and obesity-related genes. This study aimed to develop an in silico approach to systematically identify and prioritize miRNAs target sites polymorphisms in obesity and CRC. Data from genome-wide association studies (GWASs) were used to retrieve CRC and obesity-associated variants. The polymorphisms that were resided in experimentally verified or computationally predicted miRNA target sites were retrieved and prioritized using a range of bioinformatics analyses. We found 6284 CRC and 38931 obesity unique variants. For CRC 33 haplotypes variants in 134 interactions were in miRNA targetome, while for obesity we found more than 935 unique interactions. Functionally prioritized SNPs revealed that, SNPs in 153 obesity and 50 CRC unique interactions were have disruptive effects on miRNA:mRNA integration by changing on target RNA secondary structure. Structural accessibility of target sites were decreased in 418 and 103 unique interactions and increased in 516 and 79 interactions, for obesity and CRC, respectively. The miRNA:mRNA hybrid stability was increased in 127 and 17 unique interactions and decreased in 33 and 24 interactions for the effect of obesity and CRC SNPs, respectively. In this study, seven SNPs with 15 interactions and three SNPs with four interactions were prioritized for obesity and CRC, respectively. These SNPs could be used for future studies for finding potential biomarkers for diagnoses, prognosis, or treatment of CRC and obesity.
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http://dx.doi.org/10.1002/cam4.3546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774712PMC
December 2020

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

Biofactors 2020 Nov 8;46(6):995-1005. Epub 2020 Oct 8.

Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

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 β 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 GRβ 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-β, 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, GRβ 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.
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http://dx.doi.org/10.1002/biof.1680DOI Listing
November 2020

Dysregulated Expression of miR-146a and Its Associated Immune Effectors in Peripheral Blood Mononuclear Cells of Esophageal Carcinoma Patients.

Immunol Invest 2020 Oct 2:1-11. Epub 2020 Oct 2.

Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Esophageal cancer is one of the least studied aggressive tumors, with the squamous cell carcinoma (ESCC) being the most frequent histological type around the world. Growing evidence has shown that the abnormal expression of microRNAs (miRNAs) in peripheral blood mononuclear cells (PBMCs) is closely related to the pathogenesis of cancers. MiR-146a is a crucial regulator of inflammatory cascades. There is currently no data available regarding the possible role of miR-146a in PBMCs of ESCC patients. We evaluated the expression of miR-146a, as well as its target genes (IRAK1 and TRAF6) and its associated immune effectors (NF-κB1, IL1B, and IL6) in PBMCs of 40 ESCC patients and 50 control subjects. The geometric mean expression of five transcripts was used for normalizing expressions. The PBMC level of miR-146a, as measured by RT-qPCR, was upregulated, whereas levels of its target genes, IRAK1 and TRAF6, were downregulated in ESCC patients. NF-κB1 and IL6 was downregulated in PBMCs of ESCC patients. There was no difference in terms of the IL1B level between patients and the control group. Logistic regression and receiver operating characteristic curve analysis suggested that a model with PBMC levels of either NF-κB1+ IL6 or NF-κB1+ miR-146a as predictors may discriminate ESCC patients from subjects of the control group. Our findings, in the context of the current literature, may suggest a possible downregulatory mechanism of immune responses in PBMCs of ESCC patients.
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http://dx.doi.org/10.1080/08820139.2020.1828454DOI Listing
October 2020

Clinical and Outcomes of the Expression of miR-130a-5p and miR-615-3p in Tumor Compared with Non-Tumor Adjacent Tissues of Patients with BC.

Anticancer Agents Med Chem 2021 ;21(7):927-935

Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.

Background: Breast Cancer (BC) is the most common malignancy among women with a high mortality rate. The blockade of asparagine-related pathways may be an effective measure to control the progression and reduction of BC metastasis potential. Recently, it has been shown that various miRNAs, as part of small non-coding RNAs, have a great role in cancer development, especially asparagine-related pathways, to modulate the invasiveness.

Objective: This study aimed to evaluate the expression of miR-130a-5p and miR-615-3p in tumoral and nontumoral adjacent tissues of patients with BC.

Methods: There is a chance that asparagine metabolism is influenced by miR-130a-5p and miR-615-3p as confirmed by bioinformatics analysis. Hence, real-time PCR was conducted on eighty BC tumoral and non-tumoral adjacent tissues to evaluate the expression level of the two miRNAs. To predict the potential biological process and molecular pathways of miR-130a-5p, an in silico analysis was performed.

Results: This study indicated that miR-130a was downregulated in tumoral tissues compared to non-tumoral adjacent tissues (P-value= 0.01443 and fold change= -2.5137), while miR-615-3p did not show a significant difference between the two groups. Furthermore, the subgroup studies did not reveal any significant correlation between the expression of these two miRNAs and subfactors. Furthermore, in silico studies unraveled several biological processes related to amino-acid metabolism, as well as pathways related to tumor development such as Phosphatase and Tensin Homolog (PTEN) and JAK-STAT pathways among miR-130a-5p target genes.

Conclusion: Our findings indicate that miRNA-130a-5p is downregulated in BC tissues and may play a tumor suppressor role in patients with BC. Therefore, it may be suggested as a potential diagnostic and therapeutic target for BC.
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http://dx.doi.org/10.2174/1871520620666200924105352DOI Listing
January 2021

The Engaged Role of Tumor Microenvironment in Cancer Metabolism: Focusing on Cancer-Associated Fibroblast and Exosome Mediators.

Anticancer Agents Med Chem 2021 ;21(2):254-266

Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.

Metabolic reprogramming is a significant property of various cancer cells, which most commonly arises from the Tumor Microenvironment (TME). The events of metabolic pathways include the Warburg effect, shifting in Krebs cycle metabolites, and the rate of oxidative phosphorylation, potentially providing energy and structural requirements for the development and invasiveness of cancer cells. TME and tumor metabolism shifting have a close relationship through bidirectional signaling pathways between stromal and tumor cells. Cancer- Associated Fibroblasts (CAFs), as the most dominant cells of TME, play a crucial role in the aberrant metabolism of cancer. Furthermore, the stated relationship can affect survival, progression, and metastasis in cancer development. Recently, exosomes are considered one of the most prominent factors in cellular communications considering effective content and bidirectional mediatory effect between tumor and stromal cells. In this regard, CAF-Derived Exosomes (CDE) exhibit an efficient obligation to induce metabolic reprogramming for promoting growth and metastasis of cancer cells. The understanding of cancer metabolism, including factors related to TME, could lead to the discovery of a potential biomarker for diagnostic and therapeutic approaches in cancer management. This review focuses on the association between metabolic reprogramming and engaged microenvironmental, factors such as CAFs, and the associated derived exosomes.
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http://dx.doi.org/10.2174/1871520620666200910123428DOI Listing
June 2021

miRNAs Modulate the Dichotomy of Cisplatin Resistance or Sensitivity in Breast Cancer: An Update of Therapeutic Implications.

Anticancer Agents Med Chem 2021 ;21(9):1069-1081

Clinical Research Development Unit, Shohada Hospital, Tabriz University of Medical Sciences, Tabriz, Iran.

Cisplatin has a broad-spectrum antitumor activity and is widely used for the treatment of various malignant tumors. However, acquired or intrinsic resistance of cisplatin is a major problem for patients during the therapy. Recently, it has been reported Cancer Stem Cell (CSC)-derived drug resistance is a great challenge of tumor development and recurrence; therefore, the sensitivity of Breast Cancer Stem Cells (BCSCs) to cisplatin is of particular importance. Increasing evidence has shown that there is a relationship between cisplatin resistance/sensitivity genes and related miRNAs. It is known that dysregulation of relevant miRNAs plays a critical role in regulating target genes of cisplatin resistance/sensitivity in various pathways such as cellular uptake/efflux, Epithelial-Mesenchymal Transition (EMT), hypoxia, and apoptosis. Furthermore, the efficacy of the current chemotherapeutic drugs, including cisplatin, for providing personalized medicine, can be improved by controlling the expression of miRNAs. Thus, potential targeting of miRNAs can lead to miRNA-based therapies, which will help overcome drug resistance and develop more effective personalized anti-cancer and cotreatment strategies in breast cancer. In this review, we summarized the general understandings of miRNAregulated biological processes in breast cancer, particularly focused on the role of miRNA in cisplatin resistance/ sensitivity.
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http://dx.doi.org/10.2174/1871520620666200903145939DOI Listing
January 2021

Reverse expression pattern of sirtuin-1 and histone deacetylase-9 in coronary artery disease.

Arch Physiol Biochem 2020 Aug 6:1-8. Epub 2020 Aug 6.

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Background: and 9 genes are related to inflammation and may contribute to the pathogenesis of coronary artery disease (CAD). We aimed to evaluate the expression level, methylation profile and polymorphisms of these genes in CAD patients.

Methods: In this study, 50 CAD patients and 50 healthy individuals were recruited. The expression level change was evaluated using the TaqMan Real-Time PCR method. The methylation of genes promoter and genotyping of polymorphisms were evaluated by the HRM.

Results: The expression level of was reduced while the expression level showed a significant elevation ( < .001). The gene promoter was hypomethylated and the gene promoter was hypermethylated in CAD patients. Also, CG + GG genotype in and both genotypes in the gene were associated with expression change.

Conclusions: and genes, expression changes can be suggested as a potential biomarker for CAD detection.
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http://dx.doi.org/10.1080/13813455.2020.1797100DOI Listing
August 2020

Proteomic Applications in Antimicrobial Resistance and Clinical Microbiology Studies.

Infect Drug Resist 2020 16;13:1785-1806. Epub 2020 Jun 16.

Drug Applied Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.

Sequences of the genomes of all-important bacterial pathogens of man, plants, and animals have been completed. Still, it is not enough to achieve complete information of all the mechanisms controlling the biological processes of an organism. Along with all advances in different proteomics technologies, proteomics has completed our knowledge of biological processes all around the world. Proteomics is a valuable technique to explain the complement of proteins in any organism. One of the fields that has been notably benefited from other systems approaches is bacterial pathogenesis. An emerging field is to use proteomics to examine the infectious agents in terms of, among many, the response the host and pathogen to the infection process, which leads to a deeper knowledge of the mechanisms of bacterial virulence. This trend also enables us to identify quantitative measurements for proteins extracted from microorganisms. The present review study is an attempt to summarize a variety of different proteomic techniques and advances. The significant applications in bacterial pathogenesis studies are also covered. Moreover, the areas where proteomics may lead the future studies are introduced.
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http://dx.doi.org/10.2147/IDR.S238446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305820PMC
June 2020

Pre-Eclampsia: Microbiota possibly playing a role.

Pharmacol Res 2020 05 15;155:104692. Epub 2020 Feb 15.

Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

Pre-eclampsia (PE) is a complication of pregnancy that is associated with mortality and morbidity in mothers and fetuses worldwide. Oxygen dysregulation in the placenta, abnormal remodeling of the spiral artery, defective placentation, oxidative stress at the fetal-maternal border, inflammation and angiogenic impairment in the maternal circulation are the main causes of this syndrome. These events result in a systemic and diffuse endothelial cell dysfunction, an essential pathophysiological feature of PE. The impact of bacteria on the multifactorial pathway of PE is the recent focus of scientific inquiry since microbes may cause each of the aforementioned features. Microbes and their derivatives by producing antigens and other inflammatory factors may trigger infection and inflammatory responses. A mother's bacterial communities in the oral cavity, gut, vagina, cervix and uterine along with the placenta and amniotic fluid microbiota may be involved in the development of PE. Here, we review the mechanistic and pathogenic role of bacteria in the development of PE. Then, we highlight the impact of alterations in a set of maternal microbiota (dysbiosis) on the pathogenesis of PE.
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http://dx.doi.org/10.1016/j.phrs.2020.104692DOI Listing
May 2020

Critical roles of long noncoding RNAs in breast cancer.

J Cell Physiol 2020 06 17;235(6):5059-5071. Epub 2020 Jan 17.

Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Breast cancer is a major clinical challenge that affects a wide range of the female population and heavily burdens the health system. In the past few decades, attempts have been made to understand the etiology of breast cancer, possible environmental risk factors, and the genetic predispositions, pathogenesis, and molecular aberrations involved in the process. Studies have shown that breast cancer is a heterogeneous entity; each subtype has its specific set of aberrations in different cell signaling pathways, such as Notch, Wnt/β-catenin, transforming growth factor-β, and mitogen-activated protein kinase pathways. One novel group of molecules that have been shown to be inducted in the regulation of multiple cell signaling pathways is the long noncoding RNAs (lncRNAs). These molecules have important implications in the regulation of multiple signaling pathways by interacting with various genes, affecting the transcription process, and finally, playing roles in posttranslational control of these genes. There is growing evidence that lncRNAs are involved in the process of breast cancer formation by effecting the aforementioned signaling pathways, and that this involvement can have significant diagnostic and prognostic values in clinical contexts. The present review aims to elicit the significance of lncRNAs in the regulation of cell signaling pathways, and the resulting changes in cell survival, proliferation, and invasion, which are the hallmarks of breast cancer.
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http://dx.doi.org/10.1002/jcp.29442DOI Listing
June 2020

Inflammation related miRNAs as an important player between obesity and cancers.

J Diabetes Metab Disord 2019 Dec 26;18(2):675-692. Epub 2019 Nov 26.

5Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, 5th floor, Shariati Hospital, North Kargar Ave, Tehran, Iran.

The growing trend in addition to their burden, prevalence, and death has made obesity and cancer two of the most concerning diseases worldwide. Obesity is an important risk factor for common types of cancers where the risk of some cancers is directly related to the obesity. Various inflammatory mechanisms and increased level of pro-inflammatory cytokines have been investigated in many previous studies, which play key roles in the pathophysiology and development of both of these conditions. On the other hand, in the recent years, many studies have individually focused on the biomarker's role and therapeutic targeting of microRNAs (miRNAs) in different types of cancers and obesity including newly discovered small noncoding RNAs (sncRNAs) which regulate gene expression and RNA silencing. This study is a comprehensive review of the main inflammation related miRNAs in obesity/obesity related traits. For the first time, the main roles of miRNAs in obesity related cancers have been discussed in response to the question raised in the following hypothesis; do the main inflammatory miRNAs link obesity with obesity-related cancers regarding their role as biomarkers? Graphical abstractConceptual design of inflammatory miRNAs which provide link between obesity and cancers.
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http://dx.doi.org/10.1007/s40200-019-00459-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915181PMC
December 2019

Steroid-resistant nephrotic syndrome: pharmacogenetics and epigenetic points and views.

Expert Rev Clin Pharmacol 2020 Feb 6;13(2):147-156. Epub 2020 Jan 6.

Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

: Glucocorticoids (GCs) are the first-line therapy for patients with nephrotic syndrome (NS), a common glomerular disease, that cause complete remission in most of the cases. In response to the treatment, NS patients are divided into glucocorticoid-sensitive and -resistant. This variation is due to the differences in pharmacokinetics and pharmacodynamics of GCs in each patient that affect the response to the treatment modality. Since the genetic variations in drug-metabolizing enzymes and transporter proteins significantly impact the pharmacokinetics, efficacy and safety of the applied medications, this review highlights the basic mechanisms of genetic variations involved in GCs metabolism in drug-resistant NS patients.: This review explains the pharmacogenetic variations that influence the profile of GCs responses and their pharmacokinetics in NS patients. Moreover, the epigenetic variations including histone modifications and miRNA gene regulation that have an influence on GCs responses will review. A comprehensive literature search was performed using different keywords to the reviewed topics.: The accumulative data suggest the importance of pharmacogenetic studies to develop personalized therapies and increase the GCs responsiveness in these patients. It is imperative to know that genetic testing does not give absolute answers to all existing questions in steroid resistance.
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http://dx.doi.org/10.1080/17512433.2020.1702877DOI Listing
February 2020

MicroRNAs in breast cancer: Roles, functions, and mechanism of actions.

J Cell Physiol 2020 06 14;235(6):5008-5029. Epub 2019 Nov 14.

Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Breast cancer is one of the most lethal malignancies in women in the world. Various factors are involved in the development and promotion of the malignancy; most of them involve changes in the expression of certain genes, such as microRNAs (miRNAs). MiRNAs can regulate signaling pathways negatively or positively, thereby affecting tumorigenesis and various aspects of cancer progression, particularly breast cancer. Besides, accumulating data demonstrated that miRNAs are a novel tool for prognosis and diagnosis of breast cancer patients. Herein, we will review the roles of these RNA molecules in several important signaling pathways, such as transforming growth factor, Wnt, Notch, nuclear factor-κ B, phosphoinositide-3-kinase/Akt, and extracellular-signal-regulated kinase/mitogen activated protein kinase signaling pathways in breast cancer.
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http://dx.doi.org/10.1002/jcp.29396DOI Listing
June 2020

AdeB efflux pump gene knockdown by mRNA mediated peptide nucleic acid in multidrug resistance Acinetobacter baumannii.

Microb Pathog 2020 Feb 6;139:103825. Epub 2019 Nov 6.

Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

Multidrug-resistant Acinetobacter baumannii isolates cause critical problems in health-care environments. AdeABC is a resistance-nodulation-cell division (RND)-type multidrug efflux pump conferring resistance to clinically essential antibiotics in A. baumannii, such as ciprofloxacin. This study aimed to target adeB gene with antisense peptide nucleic acid (PNA) and investigate its effect on resistance to antibiotics. NCBI database was used to design appropriate PNA to target adeB gene, by connecting PNA to mRNA, the translation of mRNA can be prevented. Three clinical isolates and A. baumannii ATCC 17978 were treated with the designed PNA by electroporation and competence procedure. Minimum Inhibitory concentration (MIC) of ciprofloxacin, colistin, and tetracycline were determined by microbroth dilution method. In addition, the expression level of adeB gene was measured by quantitative real-time PCR (qRT-PCR). Isolates used in this study had mutations in gyrA and parC genes corresponding to resistance to ciprofloxacin. MIC of resistance to ciprofloxacin after treatment with PNA was reduced from 32 μg/ml to16 μg/ml in A. baumannii ATCC 17978 isolate. Susceptibility level of tetracycline, in the 2 clinical isolates was decreased from 64 μg/ml to 32 μg/ml and in the other isolate was reduced from 128 μg/ml to 64 μg/ml. The expression level of adeB gene was decreased in A. baumannii ATCC 17978 (P > 0.01) but not in clinical isolate (P = 0.107). Findings of the present study indicate overexpression of adeB efflux pump has extra effect on resistance to antibiotics in isolates with a defined mechanism of resistance. Antisense technology is a feasible technique to suppress the function of these genes, which may be further exploited to control multidrug-resistant isolates.
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http://dx.doi.org/10.1016/j.micpath.2019.103825DOI Listing
February 2020

MicroRNA-binding site polymorphisms and risk of colorectal cancer: A systematic review and meta-analysis.

Cancer Med 2019 12 21;8(17):7477-7499. Epub 2019 Oct 21.

Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.

Genetic variations in miRNAs binding site might participate in cancer risk. This study aimed to systematically review the association between miRNA-binding site polymorphisms and colorectal cancer (CRC). Electronic literature search was carried out on PubMed, Web of Science (WOS), Scopus, and Embase. All types of observational studies till 30 November 2018 were included. Overall 85 studies (21 SNPs) from two systematic searches were included analysis. The results showed that in the Middle East population, the minor allele of rs731236 was associated with decreased risk of CRC (heterozygote model: 0.76 [0.61-0.95]). The minor allele of rs3025039 was related to increased risk of CRC in East Asian population (allelic model: 1.25 [1.01-1.54]). Results for rs3212986 were significant in overall and subgroup analysis (P < .05). For rs1801157 in subgroup analysis the association was significant in Asian populations (including allelic model: 2.28 [1.11-4.69]). For rs712, subgroup analysis revealed a significant (allelic model: 1.41 [1.23-1.61]) and borderline (allelic model: 0.92 [0.84-1.00]) association in Chinese and Czech populations, respectively. The minor allele of rs17281995 increased risk of CRC in different genetic models (P < .05). Finally, rs5275, rs4648298, and rs61764370 did not show significant associations. In conclusion, minor allele of rs3025039, rs3212986, and rs712 polymorphisms increases the risk of CRC in the East Asian population, and heterozygote model of rs731236 polymorphism shows protective effect in the Middle East population. In Europeans, the minor allele of rs17281995 may increase the risk of CRC, while rs712 may have a protective effect. Further analysis based on population stratifications should be considered in future studies.
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http://dx.doi.org/10.1002/cam4.2600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885874PMC
December 2019

Evidences from a Systematic Review and Meta-Analysis Unveil the Role of MiRNA Polymorphisms in the Predisposition to Female Neoplasms.

Int J Mol Sci 2019 Oct 14;20(20). Epub 2019 Oct 14.

Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz 5138663134, Iran.

Breast (BCa) and gynecological (GCa) cancers constitute a group of female neoplasms that has a worldwide significant contribution to cancer morbidity and mortality. Evidence suggests that polymorphisms influencing miRNA function can provide useful information towards predicting the risk of female neoplasms. Inconsistent findings in the literature should be detected and resolved to facilitate the genetic screening of miRNA polymorphisms, even during childhood or adolescence, and their use as predictors of future malignancies. This study represents a comprehensive systematic review and meta-analysis of the association between miRNA polymorphisms and the risk of female neoplasms. Meta-analysis was performed by pooling odds-ratios (ORs) and generalized ORs while using a random-effects model for 15 miRNA polymorphisms. The results suggest that miR-146a rs2910164 is implicated in the susceptibility to GCa. Moreover, miR-196a2 rs11614913-T had a moderate protective effect against female neoplasms, especially GCa, in Asians but not in Caucasians. MiR-27a rs895819-G might pose a protective effect against BCa among Caucasians. MiR-499 rs3746444-C may slightly increase the risk of female neoplasms, especially BCa. MiR-124 rs531564-G may be associated with a lower risk of female neoplasms. The current evidences do not support the association of the remaining polymorphisms and the risk of female neoplasms.
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http://dx.doi.org/10.3390/ijms20205088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834313PMC
October 2019

Peptide nucleic acid-mediated re-sensitization of colistin resistance Escherichia coli KP81 harboring mcr-1 plasmid.

Microb Pathog 2019 Oct 22;135:103646. Epub 2019 Jul 22.

Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

Escherichia coli is a gram-negative bacterium and it causes a variety of diseases in humans. It causes a wide range of clinical infections in humans; urinary tract infections is the most prevalent infection caused by uropathogenic Escherichia coli. In recent years, the observation of antibiotic-resistant genes such as resistance to colistin, makes the Escherichia coli resistant to antibiotics like colistin (polymyxin E), because of that the use of new therapies like peptide nucleic acid (PNA) has attracted the consideration of scientists. The aim of this study is the assessment of the inhibitory role of PNA against mcr-1 gene and reduction of mcr-1 gene expression and MIC in colistin resistant E. coli by PNA. NCBI database was used to design PNA. Our study was carried out on E. coli KP81 bacteria containing the mcr-1 gene. Microbroth dilution (MIC) method was used to survey phenotypic sensitivity and determine the sensitivity of the bacteria to the colistin antibiotic. E. coli KP81 isolates were further investigated by polymerase chain reaction to assess the presence of mcr-1 genes and target genes were quantified by real-time PCR assay using specific primers. The MIC result after treatment with specific PNA showed that the resistance to colistin reduced about three fold and the resistance level dropped from 32 μg/ml to 4 μg/ml. The expression analysis of mcr-1 gene in E. coli KP81 isolate indicates the PNA, 95% reduced the expression of the mcr-1 gene. Our observations showed that by inhibiting the expression of mcr-1, sensitivity to colistin can be defeated. Using higher concentrations of PNA and an in vivo study can reveal more clinical application of this method.
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http://dx.doi.org/10.1016/j.micpath.2019.103646DOI Listing
October 2019

Dysregulated expression of STAT1, miR-150, and miR-223 in peripheral blood mononuclear cells of coronary artery disease patients with significant or insignificant stenosis.

J Cell Biochem 2019 12 18;120(12):19810-19824. Epub 2019 Jul 18.

Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Coronary artery disease (CAD) is a multicellular disease characterized by chronic inflammation. Peripheral blood-mononuclear cells (PBMCs), as a critical component of immune system, actively cross-talk with pathophysiological conditions induced by endothelial cell injury, reflecting in perturbed PBMC expression. STAT1 is believed to be relevant to CAD pathogenesis through regulating key inflammatory processes and modulating STAT1 expression play key roles in fine-tuning CAD-related inflammatory processes. This study evaluated PBMC expressions of STAT1, and its regulators (miR-150 and miR-223) in a cohort including 72 patients with CAD with significant ( ≥ 50%) stenosis, 30 patients with insignificant ( < 50%) coronary stenosis (ICAD), and 74 healthy controls, and assessed potential of PBMC expressions to discriminate between patients and controls. We designed quantitative real-time polymerase chain reaction (RT-qPCR) assays and identified stable reference genes for normalizing PBMC quantities of miR-150, miR-223, and STAT1 applying geNorm algorithm to six small RNAs and five mRNAs. There was no significant difference between CAD and ICAD patients regarding STAT1 expression. However, both groups of patients had higher levels of STAT1 than healthy controls. miR-150 and miR-223 were differently expressed across three groups of subjects and were downregulated in patients compared with healthy controls, with the lowest expression levels being observed in patients with ICAD. ROC curves suggested that PBMC expressions may separate between different groups of study subjects. PBMC expressions also discriminated different clinical manifestations of CAD from ICADs or healthy controls. In conclusion, the present study reported PBMC dysregulations of STAT1, miR-150, and miR-223, in patients with significant or insignificant coronary stenosis and suggested that these changes may have diagnostic implications.
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http://dx.doi.org/10.1002/jcb.29286DOI Listing
December 2019

Needle-shaped amphoteric calix[4]arene as a magnetic nanocarrier for simultaneous delivery of anticancer drugs to the breast cancer cells.

Int J Nanomedicine 2019 15;14:2619-2636. Epub 2019 Apr 15.

Drug Applied Research Center, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran,

Background: Chemotherapy as an important tool for cancer treatment faces many obstacles such as multidrug resistance and adverse toxic effects on healthy tissues. Drug delivery systems has opened a new window to overcome these problems. There has been a strong interest development of new platform and system for delivof chemotherapeutic agents.

Purpose: In the present study, a green synthesis method was chosen and performed for preparation of a novel amphoteric calix[4]arene (Calix) macrocycle with low toxicity to the human body.

Materials And Methods: The amphoteric Calix was coated on the surface of FeO magnetic nanoparticles and used as a magnetic nanocarrier for simultaneous delivery of two anticancer agents, doxorubicin and methotrexate, against MCF7 cancer cells. Several chemical characterizations were done for validation of prepared nanocarrier, and in vitro loading and release studies of drugs were performed with good encapsulation efficiency.

Results: In vitro biological studies including hemolysis assay, erythrocytes sedimentation rate, red blood cells aggregation, cyto cellular internalization, and apoptosis evaluations were performed. Based on results, the developed nanocarrier has many advantages and capability for an efficient codelivery of DOX and MTX, which has a highly potent ability to kill cancer cells.

Conclusion: All these results persuade us, this nanocarrier could be effectively used for cancer therapy of MCF7 breast cancer cells and is suitable for use in further animal studies in future investigations.
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http://dx.doi.org/10.2147/IJN.S194596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6472283PMC
May 2019

Synergistic Antiproliferative Effects of Co-nanoencapsulated Curcumin and Chrysin on MDA-MB-231 Breast Cancer Cells Through Upregulating miR-132 and miR-502c.

Nutr Cancer 2019 7;71(7):1201-1213. Epub 2019 Apr 7.

Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences , Tabriz , Iran.

In this study, we explored whether co-nanoencapsulated Curcumin (Cur) and Chrysin (Chr), natural herbal compounds with antitumor activities, regulate miR-132 and miR-502c and their downstream targets, leading to the synergistic growth inhibition in MDA-MB-231 breast cancer cells. For this purpose, Cur and Chr were co-encapsulated into PLGA-PEG nanoparticles (NPs) and characterized through DLS, FTIR and FE-SEM. MTT assay and cell cycle arrest analysis revealed that CurChr-loaded NPs had a considerable synergistic cytotoxicity against MDA-MB-231 cells with more cell accumulation in G2/M phase compared to the other groups. In addition, highest percentage of cell apoptosis was acquired in cells treated with CurChr-loaded NPs according to apoptosis analysis. Real-time PCR findings revealed that co-encapsulated form of Cur and Chr than free combination could further upregulate miR-132 and miR-502c expression ( < 0.001). Also, the strong reduction was detected in the protein levels of HN1 and P65 at the cells co-nanodelivered with Cur and Chr. These findings demonstrated that the co-nanodelivery of Cur and Chr through targeting miR-132 and miR-205c might be a novel strategy for the treatment of breast cancer.
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http://dx.doi.org/10.1080/01635581.2019.1599968DOI Listing
June 2020

Association of mir-196a-2 rs11614913 and mir-149 rs2292832 Polymorphisms With Risk of Cancer: An Updated Meta-Analysis.

Front Genet 2019 15;10:186. Epub 2019 Mar 15.

Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Accumulating evidence suggests that functional dysregulations of miRNAs, especially miR-196a-2 and miR-149, in cancers could be attributed to polymorphisms in miRNA sequences. This study was aimed at clarifying the association of mir-196a-2 rs11614913 and mir-149 rs2292832 with cancer risk by performing an updated meta-analysis of genetic association studies. PubMed, Embase, Scopus, and ScienceDirect databases were searched until 9 April 2018 to identify eligible studies. Studies should meet the following criteria to be included in the meta-analysis: evaluation of genetic association between rs11614913 and/or rs2292832 and susceptibility to cancer; A case-control design; Written in English; Availability of sufficient data for estimating odds ratio (OR) and its 95% confidence interval (95%CI). Studies that met the following criteria were excluded: review articles, meta-analysis, abstracts or conference papers; duplicate publications; studies on animals or cell-lines; studies without a case-control design; studies that did not report genotype frequencies. Pooled ORs and 95% CIs were estimated using a total of 111 studies (41,673 cases and 49,570 controls) for mir-196a rs11614913 and 44 studies (15,954 cases and 19,594 controls) for mir-149 rs2292832. Stratified analysis according to quality scores, genotyping method, ethnicity, broad cancer category and cancer type was also performed. Mir-196a-2 rs11614913 T allele was associated with decreased cancer risk in overall population. The association was only significant in Asians but not Caucasians. In subgroup analysis, significant associations were found in high quality studies, gynecological cancers, ovarian, breast, and hepatocellular cancer. Mir-149 rs2292832 was not associated with cancer risk in overall population and there were no differences between Asians and Caucasians. However, the T allele was associated with a decrease risk of gastrointestinal tract cancers under the heterozygote model and an increased risk of colorectal cancer under the recessive model. The present meta-analysis suggests that mir-196a-2 rs11614913 may contribute to the risk of cancer especially in Asians. Mir-149 rs2292832 may modulate the risk of gastrointestinal tract cancers especially colorectal cancer. This study had some limitations such as significant heterogeneity in most contrasts, limited number of studies enrolling Africans or Caucasians ancestry and lack of adjustment for covariates and environmental interactions.
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http://dx.doi.org/10.3389/fgene.2019.00186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429108PMC
March 2019

Expression pattern of miR-21, miR-25 and PTEN in peripheral blood mononuclear cells of patients with significant or insignificant coronary stenosis.

Gene 2019 May 6;698:170-178. Epub 2019 Mar 6.

Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran. Electronic address:

Coronary artery disease (CAD) is primarily caused by atherosclerosis, which is a series of chronic inflammatory processes leading to the initiation and progression of vascular endothelial cell injury enhancing plaque formation. As critical components of the immune system, peripheral blood mononuclear cells (PBMCs) actively cross-talk with pathophysiological conditions induced by endothelial cell injury, reflecting in altered PBMC expression pattern. This study explored PBMC expression levels of miR-21, miR-25 and PTEN in patients with angiographically proven significant coronary stenosis (the CAD group), patients with insignificant coronary stenosis (the ICAD group) and healthy subjects, and assessed potentials of PBMC expressions in discriminating groups of study subjects. In-silico analysis was also performed to obtain insights into CAD-related pathways and biological processes that may be influenced by altered miRNA expressions. A reduced level of PBMC miR-21 was observed in the ICAD group compared to the CAD group (P: 0.004) or healthy controls (P: 0.0001). PBMC miR-21 level was negatively correlated with the PTEN expression (Spearman r: -0.43, P: 3.9e-09). The PTEN expression was increased in the CAD or ICAD group compared to the control group (CAD vs. controls P: 0.0003, ICAD vs. controls P: 0.03). A stepwise increase in PBMC miR-25 levels was observed from healthy controls to ICADs and CAD patients (Kruskal-Wallis P: 7.68e-12). PBMC gene expressions had reasonable power to discriminate between pairs of study groups. PBMC miR-21 levels were able to discriminate ICADs from both CADs and controls and miR-25 levels had potentials to differentiate among all pairs of study groups (i.e. CADs-ICADs, CADs-controls, CADs-all other subjects, ICADs-controls). PBMC PTEN expression was able to discriminate patients with CAD or ICAD from control subjects. Overrepresentation enrichment analysis of experimentally validated targets of miR-21 and miR-25 highlighted key biological processes and pathways, such as "angiogenesis" and "leukocyte cell-cell adhesion", that may be influenced by dysregulation of PBMC miR-21 and miR-25. In conclusion, these findings suggest that patients with insignificant coronary stenosis may have a distinct PBMC miRNA expression profile than those with significant stenosis or healthy controls.
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http://dx.doi.org/10.1016/j.gene.2019.02.074DOI Listing
May 2019

Methylation of progesterone receptor isoform A promoter in normal breast tissue: An epigenetic link between early age at menarche and risk of breast cancer?

J Cell Biochem 2019 08 28;120(8):12393-12401. Epub 2019 Feb 28.

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Emerging evidence indicates that some altered patterns of methylation that occur in breast tumors may also be found in breast tissue of healthy women in relation to the breast cancer (BC) risk factors. Progesterone receptor (PR) isoform α is a crucial regulator of breast hormone responsiveness and its hypermethylation plays an important role in the initiation and development of breast tumors. However, such a methylation change in healthy women and its link with the different risk factors has not yet been investigated. In the present study, we aimed to examine the relationship of possible methylation changes within a critical region in the promoter CpG island of PGR-α (progesterone receptor α) gene in the healthy women with a set of reproductive and nonreproductive BC risk factors. The breast tissues were collected from 120 cancer-free women who had undergone cosmetic mammoplasty. The genomic DNA was extracted from the breast tissues and the methylation level of PGR-α promoter CpG island was determined by using MeDIP-qPCR assay. Using regression analysis, we found that increasing menarche age is inversely associated with the high methylation of PGR-α promoter ( β = -0.790, SE = 0.362; P = 0.031). Although lactating women had more methylation than nonlactating women (P = 0.026, the t test), this result was not confirmed by regression models. Such an observation may be helpful in better understanding of the underlying mechanisms by which early age at menarche increases the risk of BC. However, this perspective requires further validations in larger studies of more subjects as well as the inclusion of other related genes.
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http://dx.doi.org/10.1002/jcb.28505DOI Listing
August 2019
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