Prognostic and diagnostic values of non-coding RNAs as biomarkers for breast cancer: An umbrella review and pan-cancer analysis.

Background: Breast cancer (BC) is the most common cancer in women. The incidence and morbidity of BC are expected to rise rapidly. The stage at which BC is diagnosed has a significant impact on clinical outcomes. When detected early, an overall 5-year survival rate of up to 90% is possible. Although numerous studies have been conducted to assess the prognostic and diagnostic values of non-coding RNAs (ncRNAs) in breast cancer, their overall potential remains unclear. In this field of study, there are various systematic reviews and meta-analysis studies that report volumes of data. In this study, we tried to collect all these systematic reviews and meta-analysis studies in order to re-analyze their data without any restriction to breast cancer or non-coding RNA type, to make it as comprehensive as possible. Methods: Three databases, namely, PubMed, Scopus, and Web of Science (WoS), were searched to find any relevant meta-analysis studies. After thoroughly searching, the screening of titles, abstracts, and full-text and the quality of all included studies were assessed using the AMSTAR tool. All the required data including hazard ratios (HRs), sensitivity (SENS), and specificity (SPEC) were extracted for further analysis, and all analyses were carried out using Stata. Results: In the prognostic part, our initial search of three databases produced 10,548 articles, of which 58 studies were included in the current study. We assessed the correlation of non-coding RNA (ncRNA) expression with different survival outcomes in breast cancer patients: overall survival (OS) (HR = 1.521), disease-free survival (DFS) (HR = 1.33), recurrence-free survival (RFS) (HR = 1.66), progression-free survival (PFS) (HR = 1.71), metastasis-free survival (MFS) (HR = 0.90), and disease-specific survival (DSS) (HR = 0.37). After eliminating low-quality studies, the results did not change significantly. In the diagnostic part, 22 articles and 30 datasets were retrieved from 8,453 articles. The quality of all studies was determined. The bivariate and random-effects models were used to assess the diagnostic value of ncRNAs. The overall area under the curve (AUC) of ncRNAs in differentiated patients is 0.88 (SENS: 80% and SPEC: 82%). There was no difference in the potential of single and combined ncRNAs in differentiated BC patients. However, the overall potential of microRNAs (miRNAs) is higher than that of long non-coding RNAs (lncRNAs). No evidence of publication bias was found in the current study. Nine miRNAs, four lncRNAs, and five gene targets showed significant OS and RFS between normal and cancer patients based on pan-cancer data analysis, demonstrating their potential prognostic value. Conclusion: The present umbrella review showed that ncRNAs, including lncRNAs and miRNAs, can be used as prognostic and diagnostic biomarkers for breast cancer patients, regardless of the sample sources, ethnicity of patients, and subtype of breast cancer.

Notch signaling pathway: a comprehensive prognostic and gene expression profile analysis in breast cancer.

Breast cancer is a complex disease exhibiting a great degree of heterogeneity due to different molecular subtypes. Notch signaling regulates the differentiation of breast epithelial cells during normal development and plays a crucial role in breast cancer progression through the abnormal expression of the Notch up-and down-stream effectors. To date, there are only a few patient-centered clinical studies using datasets characterizing the role of Notch signaling pathway regulators in breast cancer; thus, we investigate the role and functionality of these factors in different subtypes using publicly available databases containing records from large studies. High-throughput genomic data and clinical information extracted from TCGA were analyzed. We performed Kaplan-Meier survival and differential gene expression analyses using the HALLMARK_NOTCH_SIGNALING gene set. To determine if epigenetic regulation of the Notch regulators contributes to their expression, we analyzed methylation levels of these factors using the TCGA HumanMethylation450 Array data. Notch receptors and ligands expression is generally associated with the tumor subtype, grade, and stage. Furthermore, we showed gene expression levels of most Notch factors were associated with DNA methylation rate. Modulating the expression levels of Notch receptors and effectors can be a potential therapeutic approach for breast cancer. As we outline herein, elucidating the novel prognostic and regulatory roles of Notch implicate this pathway as an essential mediator controlling breast cancer progression.

The potential key genes and pathways associated with Wilms tumor in quest of proper candidates for diagnostic and therapeutic purposes.

To designate the probable most important differentially expressed genes and genetic pathways in Wilms tumor and assess their expression and diagnostic potential by RT-PCR and statistical analysis. Systematic review of the literature and various bioinformatics analysis was carried out to gather and narrow down data. The expression of end-resulting genes was compared in Wilms tumor and normal tissue samples using RT-PCR. Statistical tests reported the diagnostic accuracy of genes and their correlation with clinicopathological features. Four genes including CDH1, NCAM1, EGF, and IGF2 were designated. The panel combining them has 100% sensitivity and specificity in differentiating tumors from normal tissue. Eight pathways, most involved in cell-cell and cell-basal matrix junction interactions, were found to be associated with disease pathogenesis. The suggested genes should undergo further evaluation to be validated as diagnostic biomarkers. Further research on the eight proposed pathways is recommended.

The role of the tumor microenvironment in colorectal cancer and the potential therapeutic approaches.

BACKGROUND: Colorectal cancer (CRC) with a high prevalence is recognized as the fourth most common cause of cancer-related death globally. Over the past decade, there has been growing interest in the network of tumor cells, stromal cells, immune cells, blood vessel cells, and fibroblasts that comprise the tumor microenvironment (TME) to identify new therapeutic interventions. METHODS: Databases, such as Google Scholar, PubMed, and Scopus, were searched to provide an overview of the recent research progress related to targeting the TME as a novel therapeutic approach. RESULTS: Tumor microenvironment as a result of the cross talk between these cells may result in either advantages or disadvantages in tumor development and metastasis, affecting the signals and responses from the surrounding cells. Whilst chemotherapy has led to an improvement in CRC patients' survival, the metastatic aspect of the disease remains difficult to avoid. CONCLUSIONS: The present review emphasizes the structure and function of the TME, alterations in the TME, its role in the incidence and progression of CRC, the effects on tumor development and metastasis, and also the potential of its alterations as therapeutic targets. It should be noted that providing novel studies in this field of research might help us to achieve practical therapeutic strategies based on their interaction.

microRNAs as novel diagnostic biomarkers in endometriosis patients: a systematic review and meta-analysis.

OBJECTIVE: To investigate whether miRNAs have a remarkable pooled diagnostic accuracy, sensitivity, and specificity as noninvasive biomarkers to distinguish endometriosis patients from non-endometriosis women. METHODS: A comprehensive literature search of PubMed, Embase, and ProQuest was performed through February 21, 2021 to find relevant studies. Two reviewers independently screened each article, and discrepancies were resolved by consensus. Deeks' funnel plot asymmetry test was performed to assess the publication bias of included studies. The STATA software and RevMan 5.4 were used for data analysis and quality assessment, respectively. RESULTS: The overall quality of the studies was moderate to high. In total 87 datasets were assessed miRNAs' performance which results in sensitivity: 0.82, specificity: 0.79, DOR: 18, NPV: 0.80, PPV: 0.78, PLR: 3.97, and NLR: 022. We conducted subgroup analyses, which showed panels of miRNAs (DOR: 54) and serum (DOR: 43) as a target tissue was more reliable to utilize as biomarkers. Deeks' funnel plot showed that there is no publication bias (P-value = 0.25). CONCLUSIONS: Panels of miRNAs differentiate endometriosis patients from non-endometriosis women with high sensitivity and specificity; therefore, it has the potential to use as a noninvasive biomarker.

The Role of miRNAs 340-5p, 92a-3p, and 381-3p in Patients with Endometriosis: A Plasma and Mesenchymal Stem-Like Cell Study.

BACKGROUND: Endometriosis is the most prevalent gynecological disease with elusive etiology. The mysterious entity and the lack of noninvasive diagnostic methods affect women's lives negatively. This study is aimed at finding the relationship between miR-340-5p, 92a-3p, and miR-381-3p and the pathogenesis of endometriosis in endometrial mesenchymal stem-like cells (eMSCs) of endometriosis and assessing their potential as a noninvasive biomarker in plasma. METHODS: Peripheral blood and eMSC specimens were collected from suspected women of endometriosis before laparoscopy. Total RNA was isolated from plasma and cultured eMSCs to synthesize complementary DNA. The expression of miR-340-5p, miR-92a-3p, and miR-381-3p was analyzed by RT-qPCR. To understand these miRNAs' role, we also did a bioinformatic analysis. RESULTS: There was a downregulation of miR-340-5p, miR-92a-3p, and miR-381-3p in plasma, and the upregulation of miR-340-5p and the downregulation of miR-92a-3p and miR-381-3p in eMSCs of women with endometriosis. There was a positive concordance between the expression of miR-92a-3p and miR-381-3p in plasma and eMSCs. Our study also showed three genes, Solute Carrier Family 6 Member 8 (SLC6A8), Zinc Finger Protein 264 (ZNF264), and mouse double minute 2 (MDM2), as common targets of these miRNAs. CONCLUSIONS: This study has been one of the first attempts to examine the expression of miR-340-5p, miR-92a-3p, and miR-381-3p in both plasma and eMSCs and revealed their possible role in endometriosis based on in silico analysis. Biomarkers pave the way to develop a new therapeutic approach to the management or treatment of endometriosis patients. Our result as a first report shows that combined levels of miRNAs 340-5p and 381-3p may have the potential to be utilized as diagnostic biomarkers for endometriosis.

A Panel of Plasma miRNAs 199b-3p, 224-5p and Let-7d-3p as Non-Invasive Diagnostic Biomarkers for Endometriosis.

The objective of this study was to investigate whether the combination of miR-224-5p, miR-199-3p, and let-7d-3p is a suitable diagnostic panel for endometriosis. Twenty-five women with endometriosis (case) and twenty-five women without any sign of endometriosis (controls) were included. Peripheral blood specimens were collected from all these women who were a proper candidate for laparoscopy before surgery. Total RNA was isolated to synthesize complementary DNA. Expression of miR-199b-3p, miR-224-5p, and let-7d-3p was analyzed by RT-qPCR. To estimate the performance of the identified miRNAs for endometriosis diagnosis, we performed ROC curves analysis. There was an upregulation of miRNAs 199b-3p (P value < 0.001) and down-regulation of 224-5p (P value < 0.001) and miRNA let-7d-3p (P value < 0.05) in women with endometriosis compared to non-endometriosis women. The diagnostic accuracy of miRNAs 199b-3p, 224-5p, and let-7d-3p was measured by AUC which was 0.843 (sensitivity = 96% and specificity = 80%), 0.914 (sensitivity = 84% and specificity = 80%), and 0.696 (sensitivity = 80% and specificity = 56%) for miRNAs 199b-3p, 224-5p, and let-7d-3p, respectively. In combination, they showed the highest accuracy with the AUC 0.992 (sensitivity = 96% and specificity = 100%). In conclusion(s) the levels of miRNAs 199b-3p, 224-5p, and Let-7d-3p in plasma are potential diagnostic biomarkers for endometriosis patients.