Comprehensive analysis of DRAIC and TP53TG1 in breast cancer luminal subtypes through the construction of lncRNAs regulatory model.

BACKGROUND: Deciphering new molecules related to the breast cancer subtypes is crucial for prognosis and determining a better strategy for targeted therapy. In this study, we aimed to model ceRNAs networks in luminal A and luminal B subtypes of breast cancer and then delve deeper into the role of two candidate lncRNAs in breast tumors. METHODS: We constructed two networks as a regulatory model based on our previously identified transcription factors (TFs) and miRNAs with associated lncRNAs. Then, we highlighted the role of some lncRNAs in luminal subtypes of breast cancer using available online databases. Furthermore, we empirically quantified the expression levels of two candidate lncRNAs (DRAIC and TP53TG1) in breast tumors and normal tissues. RESULTS: Here, we proposed a regulatory model for TFs-miRNAs-lncRNAs in luminal subtypes of breast cancer. We found 18 and 17 differentially expressed lncRNAs in luminal A and luminal B subtypes, respectively. Of these lncRNAs, 16 were associated with breast cancer patients' RFS and/or OS rates. Well-known lncRNAs like HOTAIR and MALAT1 were identified as central factors associated with patients' survival rates in both networks. Based on the results acquired from our comprehensive in-silico data analysis, we carried out clinical experiments on two less-known lncRNAs, DRAIC and TP53TG1, and found a significant association between them with luminal subtypes of breast cancer. Interestingly, we discovered a significant association between DRAIC and TP53TG1 lncRNAs with ER- and PR-positive samples and lymph-node invasion in breast cancer patients. CONCLUSION: According to the results, DRAIC and TP53TG1 lncRNAs are overexpressed in breast tumors and may play an oncogenic role with a moderate value of prognosis for luminal subtypes of breast cancer.

Transcription factors linked to the molecular signatures in the development of hepatocellular carcinoma on a cirrhotic background.

Mechanisms underlying the regulation of gene expression in cancer have been surveyed for decades to find novel prognostic factors and new targets for molecular targeted therapies in cancer. Because most cases of liver cancer are associated with liver cirrhosis, we aimed to analyze the gene expression signatures and the gene regulatory mechanism in hepatocellular carcinoma (HCC) on a cirrhotic background using high-throughput data analysis. In the present study, three valid array-based datasets containing HCC and liver cirrhosis samples were obtained to identify common differentially expressed genes (DEGs). Moreover, a comprehensive data analysis was conducted based on RNA-Seq data and using Kaplan-Meier curve analysis to find molecular signatures that reduce patients' survival rate. Furthermore, we proposed a gene regulatory network (GRN) to explore the possible regulatory mechanism of these molecular signatures by transcription factors in HCC progression from cirrhosis. Besides, we analyzed protein-protein interactions, gene ontology (GO), and pathway enrichment to elucidate the cellular and molecular function of the GRN elements in HCC. In this way, we found a list of 231 molecular signatures in HCC derived from cirrhosis. We also found the importance of TCF4, RUNX1, HINFP, KDM2B, MAF, JUN, NR5A2, NFYA, and AR as key differentially expressed transcription factors (DETFs) in the progression of HCC from cirrhosis. In conclusion, the identified molecular signatures and their transcription factors propose candidate prognostic markers and possible molecular targets in the progression of HCC.

Transcriptomics-based screening of molecular signatures associated with patients overall survival and their key regulators in subtypes of breast cancer.

Molecular subtypes of breast cancer are associated with differences in prognosis and strategies of molecular targeted therapies. Gene regulatory mechanisms as one of the reasons might modulate these differences. In the present study, we proposed a comprehensive data analysis and systems biology approach to explore molecular signatures which reduce the chance of patients overall survival and the possible mechanisms of their regulation by transcription factors (TFs) and microRNAs (miRNAs) in the main subtypes of breast tumor consist of Basal like, Her2 enriched, Luminal A and Luminal B breast cancer. In this regards, we used available microarray datasets to assess common differentially expressed genes (DEGs) in breast cancer subtypes. Using Kaplan-Meier curve analysis we identified common DEGs which are associated with decreasing in the overall survival of breast cancer patients. Furthermore, gene regulatory networks (GRNs) were depicted based on TFs and miRNAs with interest target genes. Then GRNs were analyzed and using five algorithms (Control centrality, Betweenness, Degree, Classification, and MCDS) the key regulators were identified for each subtype. In this study, we highlighted mechanisms underlying the regulation of breast cancer molecular signatures by TFs and miRNAs which their alteration reduce the chance of survival rate in each subtype of breast cancer. Our current study in a holistic insight revealed the importance of some genes and their regulators as potential prognostic markers and/or therapeutic targets in breast cancer patients.

Association of Elevated Peripheral Blood Micronucleus Frequency and Bmi-1 mRNA Expression with Metastasis in Iranian Breast Cancer Patients

Background: In order to find cytogenetic and molecular metastasis biomarkers detectable in peripheral blood the spontaneous genomic instability expressed as micronuclei and Bmi-1 expression in peripheral blood of breast cancer (BC) patients were studied in different stages of the disease compared with unaffected first-degree relatives (FDRs) and normal control. Methods: The Cytokinesis Block Micronuclei Cytome (CBMN cyt) and nested real-time Reverse Transcription-Polymerase Chain Reaction (RT-PCR) assays, were respectively used to measure genomic instability and Bmi-1 gene expression in 160 Iranian individuals comprised of BC patients in different stages of the disease, unaffected FDRs and normal control groups. Result: The frequency of micronuclei and Bmi-1 expression were dramatically higher in distant metastasis compared with non-metastatic BC. In spite of micronucleus frequency with no association with lymph node (LN) involvement and hormone receptor status, the Bmi-1 expression level was higher in LN positive and triple negative patients. Conclusion: Our results indicate that increased genomic instability expressed as micronuclei and higher Bmi-1 expression in peripheral blood are associated with metastasis in breast cancer. Therefore implementation of micronucleus assay and Bmi-1 expression analysis in blood as possible cytogenetic and molecular biomarkers in clinical level may potentially enhance the quality of management of patients with breast cancer.

An integrated study on TFs and miRNAs in colorectal cancer metastasis and evaluation of three co-regulated candidate genes as prognostic markers.

Molecular alterations that occur in cancer have the potential to be considered as either cancer biomarkers or targeted therapies or even both. In the presented study, we aimed to elucidate the gene regulatory network of metastatic colorectal cancer using data acquired from microarrays to reach the most common DEGs in colorectal cancer metastasis and find their possible regulatory mechanism by DETFs and DEmiRs. In this regards, seven microarray datasets were employed to assess the most important DEGs, DETFs and DEmiRs in colorectal cancer metastasis. Afterward, GRN based on DETFs and DEmiRs were constructed. Also ARACNE algorithm was used to construct an accurate GRN. GRN was analyzed structurally and then, two DETFs (LEF1 and ETV4) and a less-well known DEG (FABP6) by real time qRT-PCR in 50 patients with colorectal cancer were quantified. The constructed GRN highlighted the importance of some DETFs and DEmiRs in colorectal cancer metastasis. Interestingly the gene expression analysis by qRT-PCR on three candidate genes (LEF1, ETV4 and FABP6) indicated that the three genes were co-expressed in tumor samples, and were significantly associated with metastasis in colorectal cancer. Therefore, our experimental results proved a part of our comprehensive data analysis and system biology results. In summary, according to our empirical study we found the importance of three candidate genes as the potent prognostic factors in colorectal cancer metastasis. Also our study in a holistic insight on gene regulatory mechanism revealed the importance of some gene regulatory factors (DETFs and DEmiRs) and their potential as prognostic factors and/or targets in molecular targeted therapies in colorectal cancer.

Evaluating the effects of ellagic acid on pSTAT3, pAKT, and pERK1/2 signaling pathways in prostate cancer PC3 cells.

OBJECTIVE: One of the most common malignancies among men is prostate cancer. Ellagic acid (EA), a polyphenol antioxidant, has many pharmacological actions, especially anticancer effects. The purpose of this study was to evaluate the effect of EA treatment on interleukin-6 (IL-6) gene expression, cell viability, IL-6 secretion, phosphorylated STAT3, ERK, and AKT cellular signaling proteins in human prostate cancer cells (PC3). MATERIALS AND METHODS: The cytotoxic effects of the EA (0-100 µM) on PC3 cells were determined by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay. IL-6 gene expression was down, using real-time quantitative polymerase chain reaction. The cellular concentration of phosphorylated ERK1/2, AKT, and STAT3 signaling pathways was assessed by Western blotting technic. RESULTS: EA treatment of PC3 cells resulted in a reduction of cell viability and phosphorylated STAT3, ERK, and AKT signaling proteins after 72 h in a dose-dependent manner. IL-6 gene expression and IL-6 levels significantly increased (P < 0.05) in a dose-dependent pattern in treated PC3 with EA. Thus, these data suggested the essential role of signaling proteins in EA-mediated anti-proliferation of PC3 cells. CONCLUSIONS: Our finding shows that EA can be considered as a potent agent that decreases cell proliferation through a reduction of phosphorylated STAT3, ERK, and AKT cellular signaling proteins.

Diagnostic value of carcinoembryonic antigen in malignancy-related ascites: systematic review and meta-analysis.

BACKGROUND AND STUDY AIMS: There is a common misconception that malignant ascites is equivalent to peritoneal carcinomatosis. It seems that malignancy-related ascites is a more appropriate description of malignant ascites, which is difficult to confirm. Carcinoembryonic antigen, a glycoprotein tumor marker shed by malignant cells, increases in a wide range of gastrointestinal malignancies. We carried out the current meta-analysis to determine carcinoembryonic antigen accuracy in the diagnosis of malignancy-related ascites. PATIENTS AND METHODS: Pubmed/Medline and SCOPUS were searched using these search terms: malignan* AND ascites AND (CEA OR carcinoembryonic). The outcome of interest was carcino-embryonic antigen accuracy in the differentiation of malignancy-related ascites and nonmalignant ascites. RESULTS: Seven studies were included in this systematic review. Pooled diagnostic indices using random-effects model were as follows: sensitivity 43.1% [381-48.3]; specificity 95.5% [93-97.3]; LR+ (positive likelihood ratio) 7.33 [4.58-11.73]; LR- (negative likelihood ratio) 0.6 [0.54-0.68]; and DOR (diagnostic odds ratio) 12.93 [7.58-22]. CONCLUSIONS: Carcinoembryonic antigen of the ascitic fluid does not seem to be sensitive enough to diagnose malignancy-related ascites. However, due to high specificity, the positive predictive value of this marker is high and the higher the level of carcino-embryonic antigen, the more likely it is to be malignancy-related. Nevertheless, a negative test result cannot definitely rule out the malignancy.