Bioinformatic Analysis Divulged Novel Prognostic Circulating MicroRNAs and Their Potential Target Genes in Breast Cancer.

Breast cancer (BC) is both an inherited and environmental-based disease which is the leading cause of death among women. Early detection of BC can prevent invasion and metastasis in patients. Currently, researchers endeavor to find non-invasive biological markers from body fluids. Circulating non-coding RNAs such as microRNAs (miRNAs) can potentially be valuable prognostic and detective biomarkers. To identify novel miRNA-based biomarkers, we utilized bioinformatic tools. To reach this goal, the miRNA expression profiles of GSE31309, GSE 44,281, GSE98181, and GSE118782 were analyzed through a limma package of R. Target gene prediction of differentially expressed miRNAs, called differentially expressed miRNAs (DEMs), between samples of healthy individuals and BC patients was implemented through Multimir package of R. Functional enrichment analysis of predicted target genes through Enrich R (online database) revealed that most of the genes are enriched in the mitochondrial outer membrane for cellular component, intrinsic apoptotic signaling regulations for biological processes, transcription co-receptor activity for molecular functions, and dopaminergic synapse pathway. Furthermore, our survival analysis results revealed that miR-29c and mir-361 have the potential to serve as prognostic biomarkers.

Promoter methylation of matrix metallopeptidase 9 in peripheral blood mononuclear cells: A novel biomarker in a promising source for noninvasive colorectal cancer diagnosis.

OBJECTIVES: Colorectal cancer (CRC) has been described as a "silent disease," which can be readily treated in most patients when discovered in its early stages. Considering the limitations of the current conventional tests for the diagnosis of CRC, researchers strive to find noninvasive and more valid biomarkers for the early detection of CRC. It has been shown that tumor-specific methylation patterns can also be identified in peripheral blood mononuclear cells (PBMCs) and are reliable sources of methylation analysis for CRC screening. MATERIALS AND METHODS: We carried out a quantitative methylation analysis on matrix metallopeptidase 9 (MMP9) promoter using methylation quantification endonuclease-resistant DNA (MethyQESD) method. A total of 70 patients with CRC and 70 normal controls were enrolled in this study for methylation analysis in the PBMCs. RESULTS: Our findings discovered a considerable hypermethylation of MMP9 promoter in CRC patients compared with healthy controls (mean: 47.30% and 20.31%, respectively; P > 0.001). The sensitivity and specificity of the MMP9 gene for the diagnosis of CRC were 88% and 78%, respectively. In addition, on the basis of area under the curve values, the diagnostic power of the MMP9 gene was 0.976 (P < 0.001). Moreover, our analysis established that MMP9 methylation was significantly different between the different stages of CRC (P: 0.034). CONCLUSIONS: Our results showed that MMP9 promoter methylation in PBMCs can be used as an outstanding biomarker for CRC diagnosis. Besides, we confirmed that PBMCs are reliable sources of methylation analysis for CRC screening and MethyQESD is an accurate and fast method for quantitative methylation analyses.

Mesenchymal stem cell (MSC)-derived exosomes as novel vehicles for delivery of miRNAs in cancer therapy.

Mesenchymal stem cells (MSCs) are known as promising sources for cancer therapy and can be utilized as vehicles in cancer gene therapy. MSC-derived exosomes are central mediators in the therapeutic functions of MSCs, known as the novel cell-free alternatives to MSC-based cell therapy. MSC-derived exosomes show advantages including higher safety as well as more stability and convenience for storage, transport and administration compared to MSCs transplant therapy. Unmodified MSC-derived exosomes can promote or inhibit tumors while modified MSC-derived exosomes are involved in the suppression of cancer development and progression via the delivery of several therapeutics molecules including chemotherapeutic drugs, miRNAs, anti-miRNAs, specific siRNAs, and suicide gene mRNAs. In most malignancies, dysregulation of miRNAs not only occurs as a consequence of cancer progression but also is directly involved during tumor initiation and development due to their roles as oncogenes (oncomiRs) or tumor suppressors (TS-miRNAs). MiRNA restoration is usually achieved by overexpression of TS-miRNAs using synthetic miRNA mimics and viral vectors or even downregulation of oncomiRs using anti-miRNAs. Similar to other therapeutic molecules, the efficacy of miRNAs restoration in cancer therapy depends on the effectiveness of the delivery system. In the present review, we first provided an overview of the properties and potentials of MSCs in cancer therapy as well as the application of MSC-derived exosomes in cancer therapy. Finally, we specifically focused on harnessing the MSC-derived exosomes for the aim of miRNA delivery in cancer therapy.

Down-regulation of MEG3, PANDA and CASC2 as p53-related lncRNAs in breast cancer.

TP53 encodes a major tumor suppressor protein which blocks carcinogenesis process in a variety of tissues including breast tissue. Expression and function of this gene is regulated by a number of long non-coding RNAs (lncRNAs) among them are PANDA, MEG3 and CASC2. We measured expression of TP53 and these transcripts in a cohort of Iranian breast cancer patients. Expression levels of TP53, MEG3, CASC2 and PANDA were significantly lower in tumoral samples compared with non-tumoral samples (Posterior mean differences = -4.26, -1.66, -5.98 and -3.13, respectively; P values < 0.0001). Expression of CASC2 was higher in Her2 1+ cases compared with Her2 negative cases (Beta = 1.85, P value = 0.037). Expression levels of MEG3 and TP53 were lower in grade 2 samples compared with grade 1 (Beta = -1.86, P value = 0.006 and Beta = -2.24, P value = 0.003, respectively). There was no other significant association between expression of genes and clinical variables. CASC2 had the best performance among these genes with area under curve value of 0.78 and sensitivity and specificity values of 56.33% and 88.73%, respectively (P value < 0.0001). The current investigation supports the role of TP53-related lncRNAs in the pathogenesis of breast cancer.

Epi-miRNAs: Regulators of the Histone Modification Machinery in Human Cancer.

Cancer is a leading cause of death and disability worldwide. Epigenetic deregulation is one of the most critical mechanisms in carcinogenesis and can be classified into effects on DNA methylation and histone modification. MicroRNAs are small noncoding RNAs involved in fine-tuning their target genes after transcription. Various microRNAs control the expression of histone modifiers and are involved in a variety of cancers. Therefore, overexpression or downregulation of microRNAs can alter cell fate and cause malignancies. In this review, we discuss the role of microRNAs in regulating the histone modification machinery in various cancers, with a focus on the histone-modifying enzymes such as acetylases, deacetylases, methyltransferases, demethylases, kinases, phosphatases, desumoylases, ubiquitinases, and deubiquitinases. Understanding of microRNA-related aberrations underlying histone modifiers in pathogenesis of different cancers can help identify novel therapeutic targets or early detection approaches that allow better management of patients or monitoring of treatment response.

Down-regulation of a panel of immune-related lncRNAs in breast cancer.

Breast cancer is a common neoplasm among women. This type of cancer is among malignancies in which role of long non-coding RNAs (lncRNAs) has been extensively explored. Some recently recognized lncRNAs have been less investigated in this neoplastic condition. LncRNAs that regulate tumor immunity are among those contributing in the pathogenesis of cancer. In the present expression assay, we compared expressions of nine immune-related lncRNAs namely lnc-MICAL3-2 (AC016027.1), lnc-DDX31 (AL445645.1), LINC01063, LINC02381, ENST0000615051 (AC083809.1), AC009237.14 (lnc-TRIM43B-1), ENST0000603791, LINC1234 and AC008760.1 between breast cancer samples and their paired non-cancerous samples. Expression levels of lnc-MICAL3-2, lnc-DDX31, LINC01063, LINC02381, ENST0000615051 and lnc-TRIM43B-1 were significantly decreased in breast cancer samples compared with paired control tissues (Posterior mean difference= -2.774, -2.012, -2.012, -2.015, -0.884 and -2.872; P values= 0.019, 0.0001, 0.0001, 0.0001, 0.032 and 0.0001, respectively). Expression levels of these lncRNAs have been associated with a number of clinical characteristics of breast cancer patients. Lnc-TRIM43B-1 had the highest performance in distinguishing between tumoral and non-tumoral tissues (AUC=0.82, Sensitivity=76%, Specificity=73.24%). As these lncRNAs could differentiate tumor samples from control samples, they might be regarded as putative tissue markers for breast cancer.