Research IndicatorsGraph generated 15 March 2017 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 15 March, 2017 using data from PubMed, MeSH and CancerIndex
Specific Cancers (9)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
Numbers shown below represent number of publications held in OncomiRDB database for Oncogenic and Tumor-Suppressive MicroRNAs.
|Tissue||Target Gene(s)||Regulator(s)||MIR126 Function in Cancer||Effect|
-non-small cell lung cancer (6)
-lung cancer metastasis (1)
-small cell lung cancer (1)
-lung cancer (1)
|inhibit cell proliferation (3)|
induce cell cycle G1 arrest (2)
inhibit tumor growth (2)
inhibit cell growth (2)
inhibit cell invasion (1)
inhibit cell migration (1)
enhance gefitinib sensitivity (1)
promote irradiation induced apoptosis (1)
inhibit metastasis (1)
increase chemotherapy sensitivity (1)
suppress tumor growth (1)
decrease cell proliferation (1)
reduce the recruitment of mesenchymal stem cells and inflammatory monocytes to primary tumours (1)
decrease cell adhesion (1)
-breast cancer (3)
-breast cancer metastasis (1)
|DNA hypermethylation (1)||inhibit metastasis (1)|
decrease VEGF/PI3K/AKT signaling (1)
block cell cycle G1-G0/S transition (1)
reduce tumor growth (1)
reduce cell proliferation (1)
-colorectal cancer (2)
-colon cancer (1)
|PIK3R2 (1)||CTNNB1 (1)|
|inhibit cell growth (2)||tumor-suppressive
-acute myeloid leukemia (1)
|inhibit apoptosis (1)|
increase cell viability (1)
-pancreatic ductal adenocarcinoma (1)
-gastric cancer (1)
|SOX2 (1)||promote cell growth (1)||oncogenic
Source: OncomiRDB Wang D. et al. Bioinformatics 2014, 30(15):2237-2238.
miRBase, University of Manchester
Annotated database entry including the location and sequence of the mature miRNA sequence.
miRCancer, East Carolina University
Search miRCancer for miR-126 associations with cancer and associated genes.
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: MIR126 (cancer-related)
Gao A, Yang X, Tong J, et al.Multiplexed detection of lung cancer biomarkers in patients serum with CMOS-compatible silicon nanowire arrays.
Biosens Bioelectron. 2017; 91:482-488 [PubMed
] Related Publications
In this work, a real-time assay for highly sensitive, label-free, multiplexed electrical detection of lung cancer biomarkers was developed by using silicon nanowire field-effect (SiNW-FET) devices. Highly responsive SiNW arrays were fabricated using a CMOS-compatible anisotropic self-stop etching technique with mass reproducibility and low cost character. The SiNW nanosensor was integrated with PDMS microfluidic device, which allows rapid analyte delivery, makes the analysis to be conducted using exceedingly small samples and enables potential multiplexed detection. The nanowire arrays allowed highly selective and sensitive multiplexed detection of microRNA (miRNA)-126 and CEA. Due to high surface-to-volume ratio that the nanowire dimensions confer, the detection floor of single molecule was achieved. The potential utility in identifying clinical samples for early diagnosis of cancer was demonstrated by analyzing biomarkers in clinical related samples. The developed nanosensor with capability for multiplexed real-time monitoring of biomarkers with high sensitivity and selectivity in clinically relevant samples is highly attractive for diagnosis and treatment of cancer and other diseases.
Han IB, Kim M, Lee SH, et al.Down-regulation of MicroRNA-126 in Glioblastoma and its Correlation with Patient Prognosis: A Pilot Study.
Anticancer Res. 2016; 36(12):6691-6697 [PubMed
] Related Publications
Glioblastoma is the most common primary malignant tumor of the adult human brain. Although microRNA-126 (miR-126) has been reported to exhibit expression abnormalities in various types of cancer, to date very few studies have examined changes in miR-126 level in glioblastoma. In this pilot study, we investigated the changes in miR-126 expression in newly-dissected primary glioblastoma to explore possible roles of miR-126 in patient prognosis. Total RNA was extracted from tumoral and adjacent non-cancerous tissues from 14 patients' paired frozen specimens. Using an established quantitative reverse transcriptase-PCR protocol, the levels of miR-126 in glioblastoma and adjacent non-tumor brain tissues were compared against small nucleolar RNA U48 (RNU48) as a reference gene. The expression of miR-126 in glioblastoma samples was significantly lower than in paired non-tumoral controls (p<0.05). Importantly, age-adjusted analyses suggest that glioblastoma patients with higher relative intratumoral miR-126 expression (i.e. 53-79% relative to that of the control tissue; n=7) had significantly improved survival duration than patients whose miR-126 levels were lower (i.e. 12-48%, n=7; stratified log-rank analysis p=0.011 when the dividing threshold was set at ≥51%; total: n=14, male: 8; female: 6). Thus, intraglioblastoma miR-126 may be down-regulated relative to normal tissue and patients with less down-regulation of intratumoral miR-126 expression could have improved postsurgical prognosis. Future clinical studies with larger sample sizes should be performed to validate this observation.
BACKGROUND: Cancer has become a major public concern all over the world and early diagnosis of cancer is of great benefit for treatment and prognosis. Several studies have investigated the association between abnormal circulating microRNA-126 (miR-126) expression and the risk of various cancers, but the results are inconsistent. Therefore, this meta-analysis was carried out to assess the potential diagnostic value of miR-126 for cancer.
METHODS: Relevant studies were searched from PubMed, Embase, and Web of Science and we calculated the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the summary receiver operator characteristic curve (AUC) to assess the diagnostic value of miR-126 for cancer detection.
RESULTS: A total of 745 cancer patients and 749 controls from 11 studies of 7 papers were included in this meta-analysis. The summary estimates revealed that the pooled sensitivity was 68% (95% confidence interval [CI]: 60-75%), the specificity was 76% (95% CI: 65-85%), the PLR was 2.87 (95% CI: 1.96-4.21), the NLR was 0.42 (95% CI: 0.35-0.52), the DOR was 7 (95% CI: 4-11), and the AUC was 0.77 (95%CI: 0.73-0.80). Moreover, the sample type, cancer type, sample size, and quality score might be sources of heterogeneity.
CONCLUSION: This systematic review and meta-analysis suggests that miR-126 has great potential to be a noninvasive biomarker in the diagnosis of cancer. However, more well-designed studies with larger sample size on the diagnostic value of miR-126 for cancer are needed in the future.
Zeng MN, Ma WL, Zheng WL[Bioinformatics analysis of microRNA comprehensive regulatory network in B- cell acute lymphoblastic leukemia].
Zhonghua Xue Ye Xue Za Zhi. 2016; 37(7):585-90 [PubMed
] Related Publications
OBJECTIVE: To reveal the involvement of molecules in the pathogenesis of B-cell acute lymphoblastic leukemia (B-ALL) by bioinformatics analyses.
METHODS: The microarray data of B-ALL were downloaded from the Gene Expression Omnibus (GEO) database and Qlucore Omics Explorer software was used to screen differentially expressed miRNA. Based on the differentially expressed miRNAs, we predicted the target genes, long non-coding RNAs (lncRNA) and transcription factors (TFs). Then we constructed the miRNAs-centered comprehensive regulatory network. In addition, we performed functional enrichment analysis to analyze the functions of target genes.
RESULTS: Of all the 15 differentially expressed miRNAs, 7 miRNAs were of overexpression, 8 miRNAs underexpressed. From the miRNAs comprehensive regulatory network, we found that hsa-miR-486-3p and hsa-miR-126 regulated a large number of target genes, hsa-miR-126 including target genes MYC. The hsa-miR-29a, hsa-miR-130a and hsa-miR-181c regu- lated a lot of lncRNAs containing X-inactive-specific transcript (XIST). The hsa-miR-181a-2, hsa-miR- 181b-2 and hsa-miR-663 were regulated by a host of TFs including caudal- related homeobox transcription fact2 (CDX2). Additionally, the target genes of has-miR-126 were enriched in Wnt pathways.
CONCLUSIONS: The expression of hsa-miR-29a , hsa-miR-126 and has-miR-181 family were significantly different in B-ALL. Target gene of MYC, TFs of CDX2 and lncRNA of XIST may play important roles in the development of B-ALL, serving as a potential therapeutic target.
Chen Q, Hu H, Jiao D, et al.miR-126-3p and miR-451a correlate with clinicopathological features of lung adenocarcinoma: The underlying molecular mechanisms.
Oncol Rep. 2016; 36(2):909-17 [PubMed
] Related Publications
Lung cancer is the most common malignancy worldwide. This study aimed to identify miRNA biomarkers of lung adenocarcinoma and to investigate their molecular mechanisms. miRNA expression profiling of tumor tissues and adjacent normal tissues from 10 patients were detected using microarray. Differentially expressed miRNAs (DEMs) were identified, and were verified using quantitative reverse transcription-PCR. Thereafter, correlations between DEM expression and clinicopathological features were determined in 49 patients. Furthermore, Targetscan was utilized to predict target genes, among which transcription factors (TFs) were identified. The interactions among miRNAs, TFs and target genes were used to construct an miRNA-TF-target network. Totally, 11 DEMs were identified, among which two downregulated miRNAs (miR-126-3p and miR-451a) were validated. Low levels of miR-126-3p and miR-451a were associated with poor pathological stage, large tumor diameter and lymph node metastasis (P<0.05). Receiver operating characteristic analysis showed that both miRNAs could predict pathological stage, tumor diameter and lymph node metastasis of lung adenocarcinoma (AUC >0.65, P<0.05). For miR-126-3p, 154 target genes were predicted (e.g., PLXNB2), which were enriched in 29 pathways mainly concerning apoptosis and cancer. For miR‑451a, 397 target genes were predicted, which were enriched in 5 pathways including 'PPAR signaling pathway'. Ten genes were co-regulated by miR-126-3p and miR-451a, e.g., TSC1. Furthermore, an miRNA-TF-target network was constructed, and a sub-network was identified, including 2 miRNAs, 15 targets, and 7 TFs. In conclusion, miR-126-3p and miR-451a predicted the severity of lung adenocarcinoma. However, the possible mechanisms explored by bioinformatics need to be further validated.
Khairy A, Hamza I, Shaker O, Yosry ASerum miRNA Panel in Egyptian Patients with Chronic Hepatitis C Related Hepatocellular Carcinoma.
Asian Pac J Cancer Prev. 2016; 17(5):2699-703 [PubMed
] Related Publications
BACKGROUND: Primary hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. MicroRNAs (miRNAs) have great HCC diagnostic potential and circulating miRNAs have been reported as promising biomarkers for various pathologic conditions.
AIM: To explore the potential benefit of serum miR-126, miR-129, miR-155, miR-203 and miR-223 as non-invasive diagnostic markers of hepatitis C virus (HCV)-related HCC.
MATERIALS AND METHODS: The expression of miRNA was evaluated using real-time quantitative RT-PCR in 78 serum samples (30 treatment-naive chronic HCV, 25 post-HCV compensated cirrhosis and 23 treatment- naive HCC cases).
RESULTS: Comparing miRNA fold changes in the HCC group vs the non HCC groups, there was significant fold decrease in miR-126 (P= 0.034), miR-129 (P= 0.006), miR-155 (P= 0.011), miR-203 (<0.001) and miR-223 (P= 0.013). The highest AUC to differentiate HCC patients from non-HCC was 0.76 for miR-203.
CONCLUSIONS: Among studied miRNAs, serum miR-203 has the highest potential as a non-invasive biomarker of HCC.
Blood-circulating miRNAs could be useful as a biomarker to detect lung cancer early. We investigated the serum levels of four different miRNAs in patients with non-small cell lung cancer (NSCLC) and assessed their diagnostic value for NSCLC. Serum samples from 112 NSCLC patients and 104 controls (20 current smokers without lung cancer, 23 pneumonia patients, 21 gastric cancer patients, and 40 healthy controls) were subjected to Taqman probe-based quantitative reverse transcription-polymerase chain reaction (RT-PCR). The data showed that the serum levels of miR-182, miR-183, and miR-210 were significantly upregulated and that the miR-126 level was significantly downregulated in NSCLC patients, compared with the healthy controls. Further receiver operating characteristic (ROC) curve analysis revealed that the serum miR-182, miR-183, miR-210, or miR-126 level could serve as a diagnostic biomarker for NSCLC early detection, with a high sensitivity and specificity. The combination of these four miRNAs with carcinoembryonic antigen (CEA) further increased the diagnostic value, with an area under the curve (AUC) of 0.965 (sensitivity, 81.3%; specificity, 100.0%; and accuracy, 90.8%) using logistic regression model analysis. In addition, the relative levels of serum miR-182, miR-183, miR-210, and miR-126 could distinguish NSCLC or early-stage NSCLC from current tobacco smokers without lung cancer and pneumonia or gastric cancer patients with a high sensitivity and specificity. Data from the current study validated that the four serum miRNAs could serve as a tumor biomarker for NSCLC early diagnosis.
Tafsiri E, Darbouy M, Shadmehr MB, et al.Abberent expression of oncogenic and tumor-suppressive microRNAs and their target genes in human adenocarcinoma alveolar basal epithelial cells.
J Cancer Res Ther. 2016 Jan-Mar; 12(1):395-400 [PubMed
] Related Publications
CONTEXT: Lung cancer is one of the most serious types of cancer that often diagnosed at advanced stage. MicroRNAs (miRNAs) are small non-coding molecules which silence gene expression of target gene (s) at posttranscriptional level. They are key regulators of cell cycle, apoptosis, anti-cancer drug responsiveness and metastasis.
AIMS: Identification of the differential expression level of miR-15a/16, miR-21, miR-34a, miR-126, miR-128 and miR-210 in A549 cell line versus normal tissues and their correlation with selected corresponding target genes.
MATERIALS AND METHODS: A549 cell line was cultured in F-12K medium and miRNA was extracted from normal tissues (2-3 cm adjacent to tumor tissue) and A549 cell line. cDNA was synthesized with specific stem-loop primers for each miRNA, while OligodT primer was used for target genes cDNA synthesis. Real-time quantitative polymerase chain reaction. (RT-qPCR) was used to analyze the expression pattern of miRNAs and target genes in A549 and normal non-small cell lung carcinoma. (NSCLC) tissues.
RESULTS: miR-15a/16, miR-34a, miR-126 and miR-128 were down-regulated significantly. (>2-fold change), while miR-21 and miR.210 were up-regulated in A549. Bcl-2 as miR-34a target gene was down-regulated while Hif-1α and Akt-3 were up-regulated that might be miR-210 and miR-34a target genes, respectively.
CONCLUSION: The significant differential expression level of these miRNAs made them as candidate biomarkers in NSCLC tumor tissues of patients. Perhaps Bcl-2 down-regulation and Akt-3 up-regulation can be linked with survival signals in A549 cell line. We can conclude that Bcl-2 and Akt-3 might be therapeutic targets to inhibit cell proliferation in NSCLC.
Salajegheh A, Vosgha H, Rahman MA, et al.Interactive role of miR-126 on VEGF-A and progression of papillary and undifferentiated thyroid carcinoma.
Hum Pathol. 2016; 51:75-85 [PubMed
] Related Publications
MicroRNA-126 (miR-126) expression has been shown to be associated with angiogenesis. The aim of the current study is to evaluate the functional roles of miR-126 in dysregulation of VEGF expression and cancer progression in thyroid carcinomas. The expression of VEGF-A and miR-126 were measured in 101 thyroid carcinomas tissues (including 51 conventional papillary thyroid carcinoma, 37 follicular variant of papillary thyroid carcinoma, and 13 undifferentiated thyroid carcinomas), 13 matched lymph nodes with metastatic thyroid carcinoma, 21 benign thyroid tissues, and 5 thyroid carcinoma cell lines (both papillary and undifferentiated carcinomas). Then, exogenous miR-126 was transfected, and the expressions of VEGF-A were determined (Western blot technique). Proliferation assay, cell cycle analysis, and apoptosis assays were used to evaluate the role of miR-126 in these events. Significant underexpression of miR-126 levels in thyroid cancer tissues and cell lines was detected using real-time polymerase chain reaction. Introducing exogenous miR-126 into the cancer cell lines resulted in a significant reduction of VEGF-A protein expression. Marked inhibition in proliferation, cell cycle arrest in G0-G1, and promotion of total apoptosis were also noted. The modulatory role of miR-126 on expression of VEGF-A and its tumor suppressive roles were demonstrated for the first time in thyroid cancer. The current experiments provided specific information on the functional consequences of VEGF manipulation via microRNA on cancer.
Pençe S, Özbek E, Ozan Tiryakioğlu N, Ersoy Tunali NDeregulation of seven CpG island-harboring miRNAs in bladder cancer: miR-155 and miR-23b as the most promising oncomiRs.
Cell Mol Biol (Noisy-le-grand). 2016; 62(3):25-30 [PubMed
] Related Publications
Analyses of differential miRNA expressions in tumor and normal tissues can identify specific miRNAs involved in cancer pathogenesis, which can then be used as diagnostic, therapeutic and prognostic biomarkers. In this respect, we aimed to investigate expression levels of seven CpG island-harboring miRNAs in 50 paired UBC tissues by qRT-PCR. miR-21 and miR-155 were found to be significantly upregulated, and miR-23b, miR-126, miR-129-5p, miR-143a and miR-218-5p were downregulated. ROC analysis indicated miR-155 as the most promising candidate for discrimination of tumors from healthy tissue, and miR-23b for the discrimination of early stage from late stage tumors.
Ponomaryova AA, Morozkin ES, Rykova EY, et al.Dynamic changes in circulating miRNA levels in response to antitumor therapy of lung cancer.
Exp Lung Res. 2016; 42(2):95-102 [PubMed
] Related Publications
PURPOSE: Expression levels of cancer-associated microRNAs were reported to be altered in serum/plasma samples from lung cancer patients compared with healthy subjects. The purpose of this study was to estimate the value of five selected miRNAs plasma levels as markers of response to antitumor therapy in lung cancer patients.
MATERIALS AND METHODS: Expression levels of miR-19b, miR-126, miR-25, miR-205, and miR-125b have been evaluated by quantitative reverse transcription PCR versus control miR-16 in blood plasma samples from 23 lung cancer (LC) patients. Plasma samples were obtained from LC patients before treatment (untreated-UT), within 30 days after completing two courses of chemotherapy (postchemotherapy-PC) and 15 days after surgery (postoperative-PO).
RESULTS: Repeated Measures ANOVA demonstrated that miR-19b expression levels were decreased in PC and increased in PO samples. These changes were characterized by a significant quadratic trend (p = 0.03). Expression levels of miR-125b increased both after chemotherapy and again after surgery and demonstrated a significant linear trend (p = 0.03). The miR-125b/miR-19b ratio changed during the course of the antitumor treatment with a significant linear trend (p = 0.04). Individual analysis in the groups of patients with partial response to chemotherapy and patients with stable or progressive disease showed different trends for miR-19b, miR-125b, and miR-125b/miR-19b ratio between the groups. The Kaplan-Meier survival curves demonstrated an association of miR-125b/miR-19b ratio value with the survival time without the tumor relapse (p < 0.1).
CONCLUSIONS: Dynamic change of trends for miR-19b and miR-125b expression levels and miR-125b/miR-19b ratio in the blood plasma have shown a potentiality to discriminate types of response to antitumor therapy in lung cancer patients. Further in-depth investigation is needed to establish a direct link the miRNAs expression levels in blood plasma with therapy response and patient's survival.
UNLABELLED: BACKGROUND miR-126 has been reported to be differentially expressed in various malignancies, whereas its role in the pathogenesis of tongue squamous cell carcinoma (TSCC) remains largely unknown. MATERIAL AND METHODS In this study, we collected 21 pairs of TSCC cancerous and adjacent non-cancerous tissue samples, with which we performed real-time PCR to determine and compare the expression of 6 candidate miRNAs that are reportedly associated with tumorigenesis of TSCC, including miR-100, miR-451, miR-221, let-7a, miR-21, and miR-126. We further performed luciferase assay to validate KRAS as a target of miR-126, and conducted transfection to study the effect of miR-126 on proliferation and apoptosis of the cells. RESULTS We identified that miR-126 was significantly downregulated in the cancerous tissue samples compared with the non-cancerous control tissue samples. By using computational analysis, we identified that KRAS is a virtual target of miR-126, and such association was verified by using luciferase assay. In addition, we found that mRNA and protein expression level of KRAS was significantly higher in the tumor tissue than the control tissue samples. CONCLUSIONS The following in vitro experiment showed that both mRNA and protein KRAS expression were significantly decreased in SCC-15 cells in which miR-126 was overexpressed, in comparison with similar cells transfected with a negative control, while downregulation of miR-126 by transfecting the cells with miR-126 inhibitors significantly upregulated the mRNA and protein expression of KRAS.
CONCLUSIONS: miR-126 might be a promising diagnostic and therapeutic target in the prevention and management of TSCC patients.
Raffel S, Trumpp AmiR-126 Drives Quiescence and Self-Renewal in Leukemic Stem Cells.
Cancer Cell. 2016; 29(2):133-5 [PubMed
] Related Publications
Leukemic stem cells (LSCs) are resistant to conventional chemotherapy and promote acute myeloid leukemia (AML) progression and recurrence. In this issue of Cancer Cell, Lechman and colleagues (2016) identify the microRNA miR-126 as a regulator of PI3K-AKT-mTOR and CDK3 signaling driving LSC self-renewal and chemotherapy resistance.
To investigate miRNA function in human acute myeloid leukemia (AML) stem cells (LSC), we generated a prognostic LSC-associated miRNA signature derived from functionally validated subpopulations of AML samples. For one signature miRNA, miR-126, high bioactivity aggregated all in vivo patient sample LSC activity into a single sorted population, tightly coupling miR-126 expression to LSC function. Through functional studies, miR-126 was found to restrain cell cycle progression, prevent differentiation, and increase self-renewal of primary LSC in vivo. Compared with prior results showing miR-126 regulation of normal hematopoietic stem cell (HSC) cycling, these functional stem effects are opposite between LSC and HSC. Combined transcriptome and proteome analysis demonstrates that miR-126 targets the PI3K/AKT/MTOR signaling pathway, preserving LSC quiescence and promoting chemotherapy resistance.
Chen SW, Wang TB, Tian YH, Zheng YGDown-regulation of microRNA-126 and microRNA-133b acts as novel predictor biomarkers in progression and metastasis of non small cell lung cancer.
Int J Clin Exp Pathol. 2015; 8(11):14983-8 [PubMed
] Free Access to Full Article Related Publications
OBJECTIVE: MiRNAs play crucial roles in progression of cancer. However, the underlying mechanisms of miRNAs in non small cell lung cancer are still poorly understood. The aim of this study was to investigate the expression level of microRNA-126 (miR-126) and microRNA-133b (miR-133b) and also their association with clinicopathological features in patients with non small cell lung cancer (NSCLC).
METHODS: Total RNA was purified from NSCLC tissues and adjacent non-tumor tissues and then quantitative real-time PCR (qRT-PCR) was used to evaluate the expression rate of microRNAs. Furthermore, the association of miR-126 and miR-133b level with clinicopathological features and prognosis were evaluated.
RESULTS: Our findings showed that expression of miR-126 was decreased in NSCLC tissues compared with adjacent non-tumor tissues. On the other hand, a lower expression of miR-133b was seen in NSCLC tissues when compared with adjacent non-tumor tissues. In term of miR-126, our results showed that miR-126 was associated with tumor stage and lymph nodes metastasis (P<0.05). In term of miR-133b, our finding indicated that decreased expression of miR-133b was correlated with advanced tumor stage and lymph nodes metastasis (P<0.05). Kaplan-Meier analysis and log-rank test indicated that patients with low expression of miR-126 and miR-133b had a shorter overall survival (log-rank test; P<0.05). Multivariate Cox proportional hazards model revealed that low expression of miR-126 and miR-133b, advanced tumor stage and lymph nodes metastasis were independent prognostic factors for overall survival of NSCLC patients.
CONCLUSIONS: These findings suggested that miR-126 and miR-133b might play a key role in the progression and metastasis of NSCLC and would be applied as a novel therapeutic agent.
For quantitative microRNA analyses in formalin-fixed paraffin-embedded (FFPE) tissue, expression levels have to be normalized to endogenous controls. To investigate the most stably-expressed microRNAs in breast cancer and its surrounding tissue, we used tumor samples from primary tumors and from metastatic sites. MiRNA profiling using TaqMan(®) Array Human MicroRNA Cards, enabling quantification of 754 unique human miRNAs, was performed in FFPE specimens from 58 patients with metastatic breast cancer. Forty-two (72%) samples were collected from primary tumors and 16 (28%) from metastases. In a cross-platform analysis of a validation cohort of 32 FFPE samples from patients with early breast cancer genome-wide microRNA expression analysis using SurePrintG3 miRNA (8 × 60 K)(®) microarrays from Agilent(®) was performed. Eleven microRNAs could be detected in all samples analyzed. Based on NormFinder and geNorm stability values and the high correlation (rho ≥ 0.8) with the median of all measured microRNAs, miR-16-5p, miR-29a-3p, miR-126-3p, and miR-222-3p are suitable single gene housekeeper candidates. In the cross-platform validation, 29 human microRNAs were strongly expressed (mean log2-intensity > 10) and 21 of these microRNAs including miR-16-5p and miR-29a-3p were also stably expressed (CV < 5%). Thus, miR-16-5p and miR-29a-3p are both strong housekeeper candidates. Their Normfinder stability values calculated across the primary tumor and metastases subgroup indicate that miR-29a-3p can be considered as the strongest housekeeper in a cohort with mainly samples from primary tumors, whereas miR-16-5p might perform better in a metastatic sample enriched cohort.
Cappellesso R, Nicolè L, Caroccia B, et al.Young investigator challenge: MicroRNA-21/MicroRNA-126 profiling as a novel tool for the diagnosis of malignant mesothelioma in pleural effusion cytology.
Cancer Cytopathol. 2016; 124(1):28-37 [PubMed
] Related Publications
BACKGROUND: In pleural effusion cytology, the distinction of malignant mesothelioma (MM) from reactive mesothelial cells (RMCs) may be challenging, even with the aid of immunocytochemistry or fluorescence in situ hybridization. It has been demonstrated that several microRNAs (miRNAs) are useful for this purpose in cell lines and histologic samples. In the current study, the authors evaluated the utility of an miRNA-based classifier as a complement to cytology.
METHODS: Quantitative reverse transcriptase-polymerase chain reaction analysis of 15 miRNAs was performed in mesothelial (MET-5A) and MM (H28 and H2052) cell lines. Significant miRNAs were validated in 51 MM and 40 nonneoplastic pleural histologic samples and then were tested in 29 MM and 24 RMC cytologic specimens. The performance of individual and combined miRNAs was assessed for their ability to differentiate between MM and RMCs.
RESULTS: MiRNA-19a (MiR-19a), miR-19b, miR-21, miR-25, and miR-126 were differentially expressed in cell lines and histologic samples. MiR-126 was down-regulated in MM surgical specimens compared with nonneoplastic specimens, whereas all of the other miRNAs were overexpressed. In cytologic specimens, all miRNAs except miR-25 were confirmed, exhibiting a sensitivity or a specificity higher than the threshold of 0.80, as recommended by the International Mesothelioma Interest Group. The best classifier resulted from the combination of miR-21 and miR-126, which achieved 0.86 sensitivity and 0.87 specificity.
CONCLUSIONS: Subject to validation of the current results in further larger studies, miR-21 and miR-126 profiling could be an effective and reliable tool for the diagnosis of MM in pleural effusions complementary to cytology evaluation.
Ghosh A, Ghosh A, Datta S, et al.Hepatic miR-126 is a potential plasma biomarker for detection of hepatitis B virus infected hepatocellular carcinoma.
Int J Cancer. 2016; 138(11):2732-44 [PubMed
] Related Publications
Controversies about the origin of circulating miRNAs have encouraged us to identify organ specific circulating miRNAs as disease biomarkers. To identify liver-specific miRNAs for hepatocellular carcinoma (HCC), global expression profiling of miRNAs in liver tissue of HBV-HCC and HBV-control with no or mild fibrosis was evaluated. A total of 40 differentially expressed miRNAs were identified in HCC. Among ten highly altered miRNAs, six miRNAs were successfully validated in tissues, whereas only two miRNAs, miR-126 and miR-142-3p showed increased expression in plasma of HBV-HCC compared to HBV-non-HCC patients. Subsequently, ROC curve analysis revealed that neither miR-126 nor miR-142-3p performed better than AFP in discriminating HCC from non-HCC while combination of each with AFP showed significantly higher efficiency rather than AFP alone (AUC: 0.922, 0.908 vs. 0.88; sensitivity: 0.84, 0.86 vs. 0.82 and specificity: 0.92, 0.94 vs. 0.86 respectively). Interestingly, triple combination of markers (miR-126 + miR-142-3p + AFP) showed no additive effect on efficiency (AUC: 0.925) over the dual combination. Again, the expression of only miR-126 was noticed significantly higher in HBV-HCC patients with low-AFP [<250 ng/ml] compared to either non-HCC or liver cirrhosis (AUC: 0.77, 0.64, respectively). Furthermore, no alteration in expression of mir-126 in HCV-HCC or non-viral-HCC revealed that miR-126 + AFP might be specific to HBV-HCC. To understand the physiological role of these two miRNAs in hepato-carcinogenesis, target genes related to cancer pathways (APAF1, APC2, CDKN2A, IRS1, CRKL, LIFR, EGR2) were verified. Thus, combination of circulating miR-126 + AFP is a promising noninvasive diagnostic biomarker for HBV-HCC and may be useful in the management of HCC patients.
BACKGROUND: Lung cancer has long been the most dangerous malignant tumor among males in both well developed and poorly developed countries. Radiotherapy plays a critical role in the curative management of inoperable non-small cell lung cancer (NSCLC) and is also used as a post-surgical treatment in lung cancer patients. Radioresistance is an important factor that limits the efficacy of radiotherapy for NSCLC patients. Increasing evidence suggests that microRNAs (miRNAs) possess diverse cellular regulatory roles in radiation responses.
METHODS: In this study, we used miRNA microarray technology to identify serum miRNAs that were differentially expressed before and after radiotherapy in lung cancer patients. We further examined the biological function of miR-208a on cell viability, apoptotic death and cell cycle distribution in human lung cancer cells and explored the probable mechanism.
RESULTS: Nine miRNAs, including miR-29b-3p, miR-200a-3p, and miR-126-3p were significantly down-regulated, whereas miR-208a was the only miRNA that was up-regulated in the serum of the patients after radiation treatment (P < 0.05). The expression of miR-208a could be induced by X-ray irradiation in lung cancer cells. Forced expression of miR-208a promoted cell proliferation and induced radioresistance via targeting p21 with a corresponding activation of the AKT/mTOR pathway in lung cancer cells, whereas down-regulation of miR-208a resulted in the opposite effects. In addition, down-regulation of miR-208a increased the percentage of cells undergoing apoptosis and inhibited the G1 phase arrest in NSCLC cells. Moreover, miR-208a from the serum exosome fraction of lung cancer patients could shuttle to A549 cells in a time-dependent manner, which was likely to contribute to the subsequent biological effects.
CONCLUSIONS: The present study provides evidence that miR-208a can affect the proliferation and radiosensitivity of human lung cancer cells by targeting p21 and can be transported by exosomes. Thus, miR-208a may serve as a potential therapeutic target for lung cancer patients.
Despite advances in treatment, 30% of diffuse large B-cell lymphoma (DLBCL) cases are refractory or relapse after chemoimmunotherapy. Currently, the relationship between angiogenesis and angiomiRs in DLBCL is unknown. We classified 84 DLBCL cases according to stromal signatures and evaluated the expression of pro- and antiangiomiRs in paraffin embedded tissues of DLBCL and correlated them with microvascular density (MVD). 40% of cases were classified as stromal-1, 50% as stromal-2 and 10% were not classified. We observed increased expression of proangiomiRs Let-7f, miR-17, miR-18a, miR-19b, miR-126, miR-130a, miR-210, miR-296 and miR-378 in 14%, 57%, 30%, 45%, 12%, 12%, 56%, 58% and 48% of the cases, respectively. Among antiangiomiRs we found decreased expression of miR-16, miR-20b, miR-92a, miR-221 and miR-328 in, respectively, 27%, 71%, 2%, 44% and 11%. We found association between increased expression of proangiomiRs miR-126 and miR-130a and antiangiomiR miR-328 and the subtype non-GCB. We found higher levels of the antiangiomiRs miR-16, miR-221 and miR-328 in patients with low MVD and stromal-1 signature. IPI and CD34 confirmed independent impact on survival of the study group. None of the above angiomiRs showed significance as biomarker in an independent serum samples cohort of patients and controls. In conclusion, we confirmed association between antiangiomiRs miR-16, miR-221 and miR-328 and stromal-1 signature. Four angiomiRs emerged as potential therapeutic targets: proangiomiRs miR-17, miR-210 and miR-296 and antiangiomiR miR-20b. Although the four microRNAs seem to be important in DLBCL pathogenesis, they were not predictive of DLBCL onset or relapse in the serum independent cohort.
The dysregulation of miR‑126 has been reported to correlate with the progression of several cancer types. The present study demonstrated that miR‑126 was significantly downregulated in prostate cancer (PCa) tissues compared with normal prostate tissues. In vitro and in vivo studies indicated that forced overexpression of miR‑126 significantly suppressed the proliferation of PCa cell lines. Additionally, a Transwell assay showed that enhanced expression of miR‑126 inhibited metastasis in PCa in vitro. Furthermore, pik3r2 was confirmed to be a direct target of miR‑126 in PCa. It was also shown that pik3r2 was upregulated in PCa tissues and this inversely correlated with miR‑126 in PCa tissues. In conclusion, these results revealed that aberrant expression of miR‑126 promoted the progression of PCa and may serve as a novel therapeutic biomarker for PCa.
Liu J, Xie S, Wu Y, et al.Apoptosis of human prostate cancer cells induced by marine actinomycin X2 through the mTOR pathway compounded by MiRNA144.
Anticancer Drugs. 2016; 27(3):156-63 [PubMed
] Related Publications
The present study aimed to determine whether actinomycin X2 (AX2) intercepted the mTOR/PTEN/PI3K/Akt signaling pathway to inhibit human prostate cancer cells (PC-3) in vitro. The effects of AX2 on mTOR, PTEN, PI3K, and Akt at the protein level and mRNA were determined by western blotting and real-time reverse transcription-PCR (RT-PCR), respectively. Concurrently, the effects of AX2 on expression levels of MiRNA144 and MiRNA126 in PC-3 were measured by real-time RT-PCR. The association of MiRNA144 with 3'-UTR of mTOR was identified using the Dual-Luciferase Reporter Gene System. The direct effect of MIRNA144 on the mTOR/PTEN/PI3K/Akt pathway was determined by real-time RT-PCR and western blotting. Apoptosis of PC-3 cells induced by AX2 was determined by MTT and flow cytometry. The results indicated that mTOR/PTEN/PI3K/Akt were decreased and PTEN was increased by AX (1, 10 µmol/l) at protein and mRNA levels in a dose-dependent manner. MiRNA144 was decreased, whereas MiRNA126 was increased by AX2. MiRNA144 associated with 3'-UTR of mTOR was corroborated. Overexpression of MiRNA144 decreased mTOR, but did not affect PTEN, PI3K, or Akt. The proliferation rates of AX2 on PC-3 cells were decreased. It suggests that AX2 induces apoptosis of PC-3 cells via meddling in the mTOR/PTEN/PI3K/Akt signaling pathway, but those effects are compounded by MiRNA144. Both AX2 and MiRNA144 intercept the signaling in different ways but cross on mTOR.
MicroRNA (miR-126) was reported to be downregulated and to act as a tumor suppressor in cancers of the lung, cervix, bladder, breast, liver and prostate. However, the precise roles and underling mechanisms of miR-126 in glioma remain largely unknown. This study is aimed to study the role of miR-126 in the progression of glioma and to elucidate underlying miR-126-mediated mechanisms in glioma. Our results revealed that miR-126 was downregulated in the collected glioma specimen, compared with non-cancerous brain tissues. Restored miR-126 expression inhibited cell proliferation, colony formation, migration and invasion, and induced cell cycle arrest at G0/G1 phase and cell apoptosis of U-87 MG glioma cells. Overexpression of miR-126 was also able to suppress the growth of U-87 MG glioma xenografts in mice. Furthermore, insulin receptor substrate 1 (IRS-1) were identified as a target of miR-126, and showed that it was negatively regulated by miR-126 in glioma cells. We also demonstrated that overexpression of miR-126 suppressed PI3K and AKT activation, which contribute to suppress tumor growth of glioma. Taken together, these findings showed that miR-126 functions as a tumor suppressor in glioma cells by targeting IRS-1 expression via the PI3K/AKT signaling pathways, suggesting that miR-126 might be a novel target for therapeutic strategies in glioma.
BACKGROUND: MicroRNAs have been identified as potential cancer biomarkers due to their presence and stability in many body fluids including urine and plasma, but the relationship of the pattern of expression of these messengers across various biological media has not been addressed and could provide important information in order to translate these biomarkers for epidemiologic or clinical use.
METHODS: We analyzed microRNA of matched FFPE-tumor tissue, plasma, urine exosomes (n = 16) and WBCs (n = 11) from patients with bladder cancer, using Nanostring miRNA assays and droplet digital PCR for validation. Pearson correlations were used to compare expression between media.
RESULTS: Numerous microRNAs were detected and overlapping from specific bio-specimen sources. MiR-4454 and miR-21 overexpression was found in three sources: tumor, WBCs and urine. Additionally, miR-15b-5p, miR-126-3p, miR-93-5p, and miR-150-5p were common to tumor/WBCs, while miR-720/3007a, miR-205, miR-200c-3p and miR-29b-3p common to tumor/urine. Significant associations were noted between the log-adjusted average miRNA counts in tumor vs. WBCs (r = 0.418 p < 0.001), and tumor vs. urine (r = 0.38 p < 0.001). No association was seen tumor vs. plasma exosome miRs (r = 0.07 p = 0.06).
CONCLUSIONS: MicroRNA profiling from matched samples in patients shows a significant number of microRNAs up regulated in bladder tumors are identifiable in urine exosomes and WBCs of the same patient, but not in blood plasma. This study demonstrated varying relationships between miRNA detected in biological media from the same patient, and serves to inform the potential of urine-based microRNAs as biomarkers for bladder cancer and potentially other malignancies.
Malignant endothelial proliferative diseases including human angiosarcoma (AS) and canine hemangiosarcoma (HSA) are serious diseases with a grave prognosis. Establishing liquid biopsy-based biomarkers for screening has definite clinical utility; however, plasma miRNAs up- or down-regulated in these sarcomas have been unclear. For identifying possible diagnostic plasma miRNAs for these sarcomas, we investigated whether plasma miR-214 and miR-126, which miRNAs play important roles in angiogenesis and tumorigenesis, were elevated in malignant endothelial proliferative diseases. For this investigation, human angiosarcoma and canine hemangiosarcoma cell lines and clinical plasma samples of canine hemangiosarcoma were examined by performing miRNA qRT-PCR. We report here that human angiosarcoma and canine hemangiosarcoma cell lines over-secreted miR-214 and miR-126 via microvesicles; in addition, their levels in the plasma samples from canines with hemangiosarcoma were increased. Moreover, the surgical resection of primary tumors decreased the levels of plasma miR-214 and miR-126. Our findings suggest that these malignant endothelial proliferative diseases over-secreted miR-214 and miR-126, thus suggesting that these miRNAs have potential as diagnostic biomarkers for malignant endothelial proliferative diseases in canine and possible in human angiosarcoma.
Andersen M, Trapani D, Ravn J, et al.Methylation-associated Silencing of microRNA-126 and its Host Gene EGFL7 in Malignant Pleural Mesothelioma.
Anticancer Res. 2015; 35(11):6223-9 [PubMed
] Related Publications
BACKGROUND/AIM: We recently reported that miR-126 is down-regulated in malignant pleural mesothelioma (MPM) and can be combined into a 4-microRNA-classifier that can accurately diagnose MPM with high sensitivity and specificity. Herein we analyzed the epigenetic regulation of miR-126 and its host gene EGF-like domain, multiple 7 (EGFL7).
MATERIALS AND METHODS: Resected formalin-fixed paraffin-embedded MPM tissues from 29 patients, 14 patient-matched non-neoplastic pleura (NNP) specimens, 5 MPM diagnostic biopsies (DB), and 5 samples of pneumothorax-induced benign reactive mesothelial proliferation (PTHX) were analyzed. miR-126 and EGFL7 mRNA were quantified by RT-qPCR. CpG-islands' methylation in the EGFL7 promoter was analyzed using methylation-specific PCR and in the MIR126-containing intron 7 was quantified by pyrosequencing.
RESULTS: Relative to NNP, EGFL7 was under-expressed more than 4-fold in MPM (p<0.001). EGFL7 mRNA and miR-126 levels correlated in MPM (p<0.01) and NNP (p<0.001). The EGFL7 promoter region was hypermethylated in 69% of MPM and 80% of DB samples, but not in NNP and PTHX samples. EGFL7 promoter hypermethylation was associated with epithelioid histology (p<0.05) and reduced patient-survival (p<0.05).
CONCLUSION: In MPM, DNA-hypermethylation down-regulates miR-126 and its host gene EGFL7, therefore is a poor prognostic factor, and may represent a future therapeutic target for de-methylating strategies re-establishing EGFL7 and miR-126 expression.
Poynter JN, Bestrashniy JR, Silverstein KA, et al.Cross platform analysis of methylation, miRNA and stem cell gene expression data in germ cell tumors highlights characteristic differences by tumor histology.
BMC Cancer. 2015; 15:769 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Alterations in methylation patterns, miRNA expression, and stem cell protein expression occur in germ cell tumors (GCTs). Our goal is to integrate molecular data across platforms to identify molecular signatures in the three main histologic subtypes of Type I and Type II GCTs (yolk sac tumor (YST), germinoma, and teratoma).
METHODS: We included 39 GCTs and 7 paired adjacent tissue samples in the current analysis. Molecular data available for analysis include DNA methylation data (Illumina GoldenGate Cancer Methylation Panel I), miRNA expression (NanoString nCounter miRNA platform), and stem cell factor expression (SABiosciences Human Embryonic Stem Cell Array). We evaluated the cross platform correlations of the data features using the Maximum Information Coefficient (MIC).
RESULTS: In analyses of individual datasets, differences were observed by tumor histology. Germinomas had higher expression of transcription factors maintaining stemness, while YSTs had higher expression of cytokines, endoderm and endothelial markers. We also observed differences in miRNA expression, with miR-371-5p, miR-122, miR-302a, miR-302d, and miR-373 showing elevated expression in one or more histologic subtypes. Using the MIC, we identified correlations across the data features, including six major hubs with higher expression in YST (LEFTY1, LEFTY2, miR302b, miR302a, miR 126, and miR 122) compared with other GCT.
CONCLUSIONS: While prognosis for GCTs is overall favorable, many patients experience resistance to chemotherapy, relapse and/or long term adverse health effects following treatment. Targeted therapies, based on integrated analyses of molecular tumor data such as that presented here, may provide a way to secure high cure rates while reducing unintended health consequences.
OBJECTIVE: The aberrant expression of microRNAs has been demonstrated to play a crucial role in the initiation and progression of gastric cancer (GC). We here aimed to investigate the mechanism of microRNAs in the regulation of GC pathogenesis.
METHODS: Transwell chambers (8-μM pore size; Costar) were used in the in vitro migration and in vision assay. Dual luciferase reporter gene construct and dual luciferase reporter assay to identify the target of miR-126. CADM1 expression was evaluated by immunohistochemical staining. The clinical manifestations, treatments and survival were collected for statistical analysis.
RESULTS: Inhibition of miR-126 effectively reduced migration and invasion of gastric cancer cell lines. Bioinformatics and luciferase reporter assay revealed that miR-126 specifically targeted the 3'UTR of cell adhesion molecule 1 (CADM1) and regulated its expression. Down-regulation of CADM1 enhanced migration and invasion of GC cell lines. Furthermore, in tumor tissues obtained from gastric cancer patients, the expression of miR-126 was negatively correlated with CADM1 and the high expression of miR-126 combined with low expression of CADM1 might serve as a risk factor for stage1 gastric cancer patients.
CONCLUSIONS: Our study showed that miR-126, by down-regulation CADM1, enhances migration and invasion in GC cells.
Cui H, Mu Y, Yu L, et al.Methylation of the miR-126 gene associated with glioma progression.
Fam Cancer. 2016; 15(2):317-24 [PubMed
] Related Publications
Gliomas are the most common and the most malignant brain tumors, accouting for 45-55% of all intracranial tumors. The incidence of glioma worldwide is about 6-12 per 100,000. Recently, several studies showed that the activation of the oncogenes and the inactivation and/or loss of the tumor suppressor genes, especially for miRNA-21, let-7 and so on, are the most primary molecule event in gliomas. MicroRNAs (miRNAs) are a class of endogenously expressed small noncoding RNAs which are usually 21-23 nucleotides long. miRNAs regulate gene expression and play important roles in a variety of physiological and pathological processes, such as cell proliferation, differentiation and apoptosis. To date, Growing evidence has shown that mi RNAs are frequently dysregulated in human cancers and can act as both tumor suppressors and oncogenes. Along with the discovery of micro RNA, more and more research focusing on its relationship with glioma was carried out to investigate the biological features of glioma and to provide experimental evidence for glioma mechanism. In the present study, we aimed to verify the miRNA-126 down-regulation which showed in the results of glioma tissue miRNAs chip and discuss the miRNA-126 methylation in patients with glioma. A total of 50 samples from patients with glioma and 20 control samples from patients with cerebral trauma were included in this study. The expression levels of the miR-126 gene were detected using quantitative polymerase chain reaction (PCR), and the methylation status of miR-126 was examined using methylation-specific PCR-denaturing high-performance liquid chromatography (MSP-DHPLC). The expression level of miRNA-126 was found to be significantly higher in the control group (0.6134 ± 0.1214) than in the glioma group (0.2771 ± 0.1529; P < 0.05). The expression was also significantly elevated in low-grade gliomas (0.3117 ± 0.1474) compared with high-grade gliomas (0.1582 ± 0.1345; P < 0.05). In addition, increased methylation of miR-126 was found in 40% of glioma patients in our study (20/50 cases), resulting in significantly decreased miR-126 expression (0.1715 ± 0.1376; P < 0.05). Our results indicate that we verified successfully the miRNA-126 down-regulation phenomenon in patients with glioma which showed in the results of glioma tissue miRNAs chip and the miRNA-126 down-regulation through methylation in patients with glioma. So we could say that epigenetic modification is a crucial mechanism for controlling the expression of miR-126 in glioma.
Ebrahimi F, Gopalan V, Wahab R, et al.Deregulation of miR-126 expression in colorectal cancer pathogenesis and its clinical significance.
Exp Cell Res. 2015; 339(2):333-41 [PubMed
] Related Publications
In this study, we investigated the expression profiles and clinicopathological significance of miR-126 in large cohort of patients with colorectal cancers as well the cellular repercussions of miR-126 in colon cancer cells along with its targets in-vitro. Down regulation of miR-126 expression was associated with histological subtypes, peri-neural tumour infiltration, microsatellite instability and pathological staging of colorectal cancers (p<0.05). Low miR-126 expression was also associated with poorer survival in patients with colorectal cancer. Analysis of matched tissues from the same patient revealed that approximately 70% of the tested patients had similar levels of expression of miR-126 in primary cancer and cancer metastases in both lymph node and distant metastases. In addition, induced overexpression of miR-126 showed reduced cell proliferation, increased apoptosis and decreased accumulation of cells in the G0-G1 phase of the colon cancer cells. Furthermore, SW480(+miR-126) cells showed reduced BCL-2 and increased P53 protein expression. To conclude, deregulation of miR-126 in colorectal cancer at the tissue and cellular levels as well as its correlation with various clinicopathological parameters confirm the cancer suppressive role of miR-126 in colorectal cancer.