Cancer stem cell-mediated drug resistance: A comprehensive gene expression profile analysis in breast cancer.

Breast cancer is the most frequently diagnosed malignancy in women and a major public health concern. In the current report, differential expression of the breast cancer resistance promoting genes with a focus on breast cancer stem cell related elements as well as the correlation of their mRNAs with various clinicopathologic characteristics, including molecular subtypes, tumor grade/stage, and methylation status, have been investigated using METABRIC and TCGA datasets. To achieve this goal, we downloaded gene expression data of breast cancer patients from TCGA and METABRIC. Then, statistical analyses were used to assess the correlation between the expression levels of stem cell related drug resistant genes and methylation status, tumor grades, various molecular subtypes, and some cancer hallmark gene sets such as immune evasion, metastasis, and angiogenesis. According to the results of this study, a number of stem cell related drug resistant genes are deregulated in breast cancer patients. Furthermore, we observe negative correlations between methylation of resistance genes and mRNA expression. There is a significant difference in the expression of resistance-promoting genes between different molecular subtypes. As mRNA expression and DNA methylation are clearly related, DNA methylation might be a mechanism that regulates these genes in breast cancer cells. As indicated by the differential expression of resistance-promoting genes among various breast cancer molecular subtypes, these genes may function differently in different subtypes of breast cancer. In conclusion, significant deregulation of resistance-promoting factors indicates that these genes may play a significant role in the development of breast cancer.

NRF2 signaling pathway: A comprehensive prognostic and gene expression profile analysis in breast cancer.

Breast cancer is the most frequently diagnosed malignant tumor in women and a major public health concern. NRF2 axis is a cellular protector signaling pathway protecting both normal and cancer cells from oxidative damage. NRF2 is a transcription factor that binds to the gene promoters containing antioxidant response element-like sequences. In this report, differential expression of NRF2 signaling pathway elements, as well as the correlation of NRF2 pathway mRNAs with various clinicopathologic characteristics, including molecular subtypes, tumor grade, tumor stage, and methylation status, has been investigated in breast cancer using METABRIC and TCGA datasets. In the current report, our findings revealed the deregulation of several NRF2 signaling elements in breast cancer patients. Moreover, there were negative correlations between the methylation of NRF2 genes and mRNA expression. The expression of NRF2 genes significantly varied between different breast cancer subtypes. In conclusion, substantial deregulation of NRF2 signaling components suggests an important role of these genes in breast cancer. Because of the clear associations between mRNA expression and methylation status, DNA methylation could be one of the mechanisms that regulate the NRF2 pathway in breast cancer. Differential expression of Hippo genes among various breast cancer molecular subtypes suggests that NRF2 signaling may function differently in different subtypes of breast cancer. Our data also highlights an interesting link between NRF2 components' transcription and tumor grade/stage in breast cancer.

Molecular basis of rare congenital bleeding disorders.

Rare bleeding disorders (RBDs), including factor (F) I, FII, FV, FVII, combined FV and FVIII (CF5F8), FXI, FXIII and vitamin-K dependent coagulation factors (VKCF) deficiencies, are a heterogeneous group of hemorrhagic disorder with a variable bleeding tendency. RBDs are due to mutation in underlying coagulation factors genes, except for CF5F8 and VKCF deficiencies. FVII deficiency is the most common RBD with >330 variants in the F7 gene, while only 63 variants have been identified in the F2 gene. Most detected variants in the affected genes are missense (>50% of all RBDs), while large deletions are the rarest, having been reported in FVII, FX, FXI and FXIII deficiencies. Most were located in the catalytic and activated domains of FXI, FX, FXIII and prothrombin deficiencies. Understanding the proper molecular basis of RBDs not only can help achieve a timely and cost-effective diagnosis, but also can help to phenotype properties of the disorders.

Genotypes and phenotypes characterization of 17 Iranian patients with inherited factor X deficiency: identification of a novel mutation: Leu487Phe.

Factor X deficiency is a rare bleeding disorder that affects almost 1 : 1000 000 people worldwide. It derives from multiple mutational changes in the factor X gene (F10). The main objective of the present study was to determine a consistent correlation between the clinical presentations and causative genotype. The phenotype and genotype of 17 Iranian patients with reduced factor X activity (FX:C) from 14 unrelated families were analyzed to screen factor X gene expression for any possible mutations and function alteration. Analysis of the sequencing results led to the identification of eight different mutations besides a single nucleotide variation. One of the mutations was novel (Leu487Phe) as studied by means of online analysis programs and molecular modeling. Eight patients were homozygote; three were heterozygote, while six out of 17 patients were symptomatic cases without any mutations. The Arg40Thr missense mutation was detected in three patients including two siblings and was associated with severe bleeding symptoms. Also, two patients were identified with Gly262Asp missense mutation which commonly presented with bleeding disorder. Each of the other patients was associated with a unique missense mutation including one novel mutation in which the tentative relation of the mutation to bleeding symptoms is reported. Mutations leading to a FX:C of less than 1% are associated with severe bleeding symptoms confirming the strong correlation between clinical severity and FX:C. The novel Leu487Phe mutation with FX:C of 13% may have possible negative effects on factor X protein function resulting in minor clinical manifestation.

Investigating the inhibitory effect of miR-34a, miR-449a, miR-1827, and miR-106b on target genes including NOTCH1, c-Myc, and CCND1 in human T cell acute lymphoblastic leukemia clinical samples and cell line.

OBJECTIVES: microRNAs are small non-coding molecules that regulate gene expression in various biological processes. T-cell acute lymphoblastic leukemia (T-ALL) is a malignancy accompanied with genetic aberrations and accounts for 20% of children's and adult's ALL. Notch signaling pathway dysregulation occurs in 60% of T-ALL cases. In the present study, we aimed to determine the relationship between miRNAs and genes involved in Notch signaling pathway. MATERIALS AND METHODS: Considering the role of the pathway and its down-stream genes in proliferation, differentiation, cell cycle, and apoptosis, NOTCH1, c-Myc, and CCND1 genes were selected as target genes. Using bioinformatics studies, miR-34a, miR-449a, miR-1827, and miR-106b were selected as miRNAs targeting the above-mentioned genes. We evaluated these genes and miRNAs in T-ALL clinical samples as well as Jurkat cell line, in which NOTCH1 is overexpressed. RESULTS: Quantitative Real-Time PCR indicated that NOTCH1, c-Myc, and CCND1 were overexpressed in samples with decreased expression of miR-34a. In addition, we observed that samples with decreased expression of miR-449a showed increased expression of NOTCH1 and CCND1. Furthermore, we analyzed the expression of miR-1827 and miR-106b, which target c-Myc and CCND1, respectively. We found out that the expression of miR-1827, miR-106b, and their respective target genes were inversely correlated in 80% and 75% of the cases (r=0.8), respectively. Furthermore, in Jurkat cell line, the expression of target genes was increased while the candidate miRNAs except miR-34a were decreased. CONCLUSION: These miRNAs can be proposed as biomarkers and new therapeutic targets in T-ALL patients who have NOTCH1 overexpression.