MIR10B

Locus Summary

Gene:MIR10B; microRNA 10b
Aliases: MIRN10B, mir-10b, miRNA10B, hsa-mir-10b
Location:2q31.1
Summary:microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]
Databases:miRBase, OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 06 August, 2015

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 06 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Protein Transport
  • Transcription Factors
  • Staging
  • Western Blotting
  • Lung Cancer
  • Chromosome 2
  • Nucleic Acids
  • Phenotype
  • Databases, Genetic
  • High-Throughput Nucleotide Sequencing
  • Reproducibility of Results
  • Cell Movement
  • Gene Expression Profiling
  • Caspases
  • PTEN
  • Homeodomain Proteins
  • Flow Cytometry
  • MMP14 protein, human
  • Neoplasm Metastasis
  • Multiple Drug Resistance
  • MicroRNAs
  • Cancer Gene Expression Regulation
  • Case-Control Studies
  • Risk Assessment
  • Neoplasm Invasiveness
  • Base Sequence
  • Inhibitory Concentration 50
  • Tumor Markers
  • RT-PCR
  • rho GTP-Binding Proteins
  • Transforming Growth Factor beta
  • Pilot Projects
  • Matrix Metalloproteinase 14
  • MIRN10 microRNA, human
  • Multivariate Analysis
  • Breast Cancer
  • Mass Screening
  • Kidney Cancer
  • Stomach Cancer
  • Disease-Free Survival
Tag cloud generated 06 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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).

MicroRNA Function

Numbers shown below represent number of publications held in OncomiRDB database for Oncogenic and Tumor-Suppressive MicroRNAs.

TissueTarget Gene(s)Regulator(s)MIR10B Function in CancerEffect
brain (6)
-glioma (3)
-glioblastoma (1)
-mesenchymal subtype of glioblastoma multiforme (1)
-glioblastoma stem cells (1)
CSMD1 (1)
CDKN1A (1)
TFAP2C (1)
HOXD10 (1)
BCL2L11 (1)
CDKN2A (1)
inhibit apoptosis (3)
promote cell migration (2)
promote cell invasion (2)
increase cell invasion (1)
increase angiogenesis (1)
promote cell proliferation (1)
promote cell growth (1)
reduce cell cycle arrest (1)
reduce tumor growth (1)
oncogenic (5)
breast (4)
-breast cancer (4)
SDC1 (1)
HOXD10 (1)
TIAM1 (1)
TWIST1 (2)
SRC (1)
CD44 (1)
promote cell invasion (2)
increase cell migration (1)
increase cell invasion (1)
inhibit cell migration (1)
inhibit cell invasion (1)
promote cell migration (1)
promote metastasis (1)
oncogenic (3)
tumor-suppressive (1)
nerve (3)
-neuroblastoma (2)
-malignant peripheral nerve sheath tumor (1)
NCOR2 (1)
NF1 (1)
SRSF1 (1)
promote cell differentiation (2)
reduce cell proliferation (1)
reduce cell migration (1)
reduce cell invasion (1)
tumor-suppressive (1)
stomach (2)
-gastric cancer (2)
HOXD10 (1)
MAPRE1 (1)
DNA hypermethylation (1)
increase cell invasion (1)
decrease colony formation (1)
decrease cell growth (1)
oncogenic (1)
tumor-suppressive (1)
head and neck (1)
-nasopharyngeal carcinoma (1)
TWIST1 (1)
promote cell invasion (1)
promote metastasis (1)
oncogenic (1)
liver (1)
-hepatocellular carcinoma (1)
CADM1 (1)
increase cell migration (1)
increase cell invasion (1)
oncogenic (1)
esophagus (1)
-esophageal squamous cell carcinoma (1)
KLF4 (1)
increase cell motility (1)
increase cell invasion (1)
oncogenic (1)
colorectum (1)
-colorectal cancer (1)
BCL2L11 (1)
induce 5-FU chemoresistance (1)

Source: OncomiRDB Wang D. et al. Bioinformatics 2014, 30(15):2237-2238.

Latest Publications: MIR10B (cancer-related)

Hur K, Toiyama Y, Schetter AJ, et al.
Identification of a metastasis-specific MicroRNA signature in human colorectal cancer.
J Natl Cancer Inst. 2015; 107(3) [PubMed] Article available free on PMC after 01/03/2016 Related Publications
BACKGROUND: Distant metastasis is the major cause of mortality in colorectal cancer (CRC). We performed a systemic, comprehensive discovery for expression patterns of metastasis-specific microRNAs (miRNAs) by directly comparing primary CRCs (pCRCs) and matched liver metastases (LMs) and evaluated the feasibility of their clinical application as metastasis-specific biomarkers.
METHODS: CRC metastasis-specific miRNA profiles were generated by analyzing nine pairs of pCRC and LM tissues, followed by quantitative validation in an independent cohort of 58 pairs of matched pCRC and LM tissues. We evaluated associations between miRNA expression and patient survival and ability to predict metastasis in another 84 patients with CRC. Subsequently, associations were quantitatively validated in 175 CRC tissues and 169 serum samples. Kaplan-Meier, Cox regression, and logistic regression analyses were used. All statistical tests were two-sided.
RESULTS: Twenty-three miRNAs were identified that were differentially expressed between pCRC and LM (P < .001; FDR < .5). Four miRNAs downregulated in LM (let-7i, miR-10b, miR-221, and miR-320a) and one upregulated miR (miR-885-5p) were quantitatively validated in pCRC (P < .0001). Low let-7i expression in pCRC tissue predicted worsened prognosis (hazard ratio [HR] = 5.0, 95% confidence interval [CI] = 1.0 to 24.4, P = .0479) as well as distant metastasis (odds ratio [OR] = 5.5, 95% CI = 1.1 to 26.8, P = .0334). High miR-10b expression in pCRC tissue independently predicted distant metastasis (OR = 4.9, 95% CI = 1.2 to 19.7, P = .0248). High serum miR-885-5p expression independently predicted prognosis (HR = 2.9, 95% CI = 1.1 to 7.5, P = .0323), LN metastasis (OR = 3.0, 95% CI = 1.3 to 7.2, P = .0116), and distant metastasis (OR = 3.1, 95% CI = 1.0 to 10.0, P = .0456), whereas tissue miR-885-5p expression did not. Expression patterns of miRNAs were confirmed by in situ hybridization.
CONCLUSIONS: We discovered a metastasis-specific miRNA signature in pCRCs and discovered novel tissue- and serum-based CRC metastasis-specific miRNA biomarkers through intensive validation. These unique miRNAs may be clinically applicable to predict prognosis and distant metastasis in CRC.

Allaya N, Khabir A, Sallemi-Boudawara T, et al.
Over-expression of miR-10b in NPC patients: correlation with LMP1 and Twist1.
Tumour Biol. 2015; 36(5):3807-14 [PubMed] Related Publications
Aberrant expression of miR-10b has been described in many cancers but remains unexplored in nasopharyngeal carcinoma (NPC). Therefore, we aimed to study the miR-10b expression level in 43 NPC biopsies collected from Tunisian patients and three NPC xenografts. Then, we investigated the correlation between miR-10b expression and its upstream regulators LMP1/Twist1 as well as its adjacent gene HoxD4. We showed that miR-10b was significantly up-regulated in NPC biopsies compared to non-tumor nasopharyngeal tissues (fold change 153; p = 0.004) and associated with advanced clinical stage and young age at diagnosis (p = 0.005 and p = 0.011, respectively). In addition, over-expression of miR-10b was positively associated with the transcription factor Twist1 as well as the EBV oncoprotein LMP1 (fold change 6.32; p = 0.014, fold change 6.58; p = 0.01 respectively). Furthermore, higher level of miR-10b was observed in tumors with simultaneous expression of LMP1 and Twist1, compared to those expressing only Twist1 (fold change 2.49; p = 0.033). Meanwhile, the analysis of the link between miR-10b and its neighbor gene HoxD4 did not show any significant correlation (Fisher test p = 0.205; Mann-Whitney test p = 0.676). This study reports the first evidence of miR-10b over-expression in NPC patients. Furthermore, our findings can support hsa-miR-10b gene regulation through LMP1/Twist1 in NPC malignancy.

Singh R, Pochampally R, Watabe K, et al.
Exosome-mediated transfer of miR-10b promotes cell invasion in breast cancer.
Mol Cancer. 2014; 13:256 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
INTRODUCTION: Exosomes are 30-100 nm membrane vesicles of endocytic origin, mediating diverse biological functions including tumor cell invasion, cell-cell communication and antigen presentation through transfer of proteins, mRNAs and microRNAs. Recent evidence suggests that microRNAs can be released through ceramide-dependent secretory machinery regulated by neutral sphingomyelinase 2 (nSMase2) enzyme encoded by the smpd3 gene that triggers exosome secretion. However, whether exosome-mediated microRNA transfer plays any role in cell invasion remains poorly understood. Thus, the aim of this study was to identify the exosomal microRNAs involved in breast cancer invasion.
METHODS: The expression level of endogenous and exosomal miRNAs were examined by real time PCR and the expression level of target proteins were detected by western blot. Scanning electron and confocal microscopy were used to characterize exosomes and to study its uptake and transfer. Luciferase reporter plasmids and its mutant were used to confirm direct targeting. Furthermore, the functional significance of exosomal miR-10b was estimated by invasion assay.
RESULTS: In this study, we demonstrate that microRNA carrying exosomes can be transferred among different cell lines through direct uptake. miR-10b is highly expressed in metastatic breast cancer MDA-MB-231 cells as compared to non-metastatic breast cancer cells or non-malignant breast cells; it is actively secreted into medium via exosomes. In particular, nSMase2 or ceramide promotes the exosome-mediated miR-10b secretion whereas ceramide inhibitor suppresses this secretion. Moreover, upon uptake, miR-10b can suppress the protein level of its target genes such as HOXD10 and KLF4, indicating its functional significance. Finally, treatment with exosomes derived from MDA-MB-231 cells could induce the invasion ability of non-malignant HMLE cells.
CONCLUSION: Together, our results suggest that a set of specific microRNAs may play an important role in modulating tumor microenvironment through exosomes. Thus, a better understanding of this process may aid in the development of novel therapeutic agents.

Sandoval J, Díaz-Lagares A, Salgado R, et al.
MicroRNA expression profiling and DNA methylation signature for deregulated microRNA in cutaneous T-cell lymphoma.
J Invest Dermatol. 2015; 135(4):1128-37 [PubMed] Related Publications
MicroRNAs usually regulate gene expression negatively, and aberrant expression has been involved in the development of several types of cancers. Microarray profiling of microRNA expression was performed to define a microRNA signature in a series of mycosis fungoides tumor stage (MFt, n=21) and CD30+ primary cutaneous anaplastic large cell lymphoma (CD30+ cALCL, n=11) samples in comparison with inflammatory dermatoses (ID, n=5). Supervised clustering confirmed a distinctive microRNA profile for cutaneous T-cell lymphoma (CTCL) with respect to ID. A 40 microRNA signature was found in MFt including upregulated onco-microRNAs (miR-146a, miR-142-3p/5p, miR-21, miR-181a/b, and miR-155) and downregulated tumor-suppressor microRNAs (miR-200ab/429 cluster, miR-10b, miR-193b, miR-141/200c, and miR-23b/27b). Regarding CD30+ cALCL, 39 differentially expressed microRNAs were identified. Particularly, overexpression of miR-155, miR-21, or miR-142-3p/5p and downregulation of the miR-141/200c clusters were observed. DNA methylation in microRNA gene promoters, as expression regulatory mechanism for deregulated microRNAs, was analyzed using Infinium 450K array and approximately one-third of the differentially expressed microRNAs showed significant DNA methylation differences. Two different microRNA methylation signatures for MFt and CD30+ cALCL were found. Correlation analysis showed an inverse relationship for microRNA promoter methylation and microRNA expression. These results reveal a subgroup-specific epigenetically regulated microRNA signatures for MFt and CD30+ cALCL patients.

Cote GA, Gore AJ, McElyea SD, et al.
A pilot study to develop a diagnostic test for pancreatic ductal adenocarcinoma based on differential expression of select miRNA in plasma and bile.
Am J Gastroenterol. 2014; 109(12):1942-52 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
OBJECTIVES: Accurate peripheral markers for the diagnosis of pancreatic ductal adenocarcinoma (PDAC) are lacking. We measured the differential expression of select microRNAs (miRNAs) in plasma and bile among patients with PDAC, chronic pancreatitis (CP), and controls.
METHODS: We identified patients (n=215) with treatment-naive PDAC (n=77), CP with bile/pancreatic duct pathology (n=67), and controls (n=71) who had been prospectively enrolled in a Pancreatobiliary Biorepository at the time of endoscopic retrograde cholangiopancreatography or endoscopic ultrasound. Controls were patients with choledocholithiasis but normal pancreata. The sample was separated into training (n=95) and validation (n=120) cohorts to establish and then test the performance of PDAC Signature Panels in diagnosing PDAC. The training cohort (n=95) included age-matched patients with PDAC, CP, and controls. Panels were derived from the differential expression of 10 candidate miRNAs in plasma or bile. We selected miRNAs having excellent accuracy for inclusion in regression models.
RESULTS: Using the training cohort, we confirmed the differential expression of 9/10 miRNAs in plasma (miR-10b, -30c, -106b, -132, -155, -181a, -181b, -196a, and -212) and 7/10 in bile (excluding miR-21, -132, and -181b). Of these, five (miR-10b, -155, -106b, -30c, and -212) had excellent accuracy for distinguishing PDAC. In the training and validation cohorts, the sensitivity/specificity for a PDAC Panel derived from plasma was 95/100% and 100/100%, respectively; in bile, these were 96/100% and 100/100%.
CONCLUSIONS: Increased expression of miRNA-10b, -155, and -106b in plasma appears highly accurate in diagnosing PDAC. Additional studies are needed to confirm this Panel and explore its value as a prognostic test.

Dong W, Shen R, Cheng S
Reduction of TIP30 in esophageal squamous cell carcinoma cells involves promoter methylation and microRNA-10b.
Biochem Biophys Res Commun. 2014; 453(4):772-7 [PubMed] Related Publications
TIP30 is a putative tumor suppressor that can promote apoptosis and inhibit angiogenesis. However, the role of TIP30 in esophageal squamous cell carcinoma (ESCC) biology has not been investigated. Immunohistochemistry was used to investigate the expression of TIP30 in 70 ESCC. Hypermethylation of TIP30 was evaluated by the methylation specific PCR (MSP) method in ESCC (tumor and paired adjacent non-tumor tissues). Lost expression of TIP30 was observed in 50 of 70 (71.4%) ESCC. 61.4% (43 of 70) of primary tumors analyzed displayed TIP30 hypermethylation, indicating that this aberrant characteristic is common in ESCC. Moreover, a statistically significant inverse association was found between TIP30 methylation status and expression of the TIP30 protein in tumor tissues (p=0.001). We also found that microRNA-10b (miR-10b) targets a homologous DNA region in the 3'untranslated region of the TIP30 gene and represses its expression at the transcriptional level. Reporter assay with 3'UTR of TIP30 cloned downstream of the luciferase gene showed reduced luciferase activity in the presence of miR-10b, providing strong evidence that miR-10b is a direct regulator of TIP30. These results suggest that TIP30 expression is regulated by promoter methylation and miR-10b in ESCC.

Nassar FJ, El Sabban M, Zgheib NK, et al.
miRNA as potential biomarkers of breast cancer in the Lebanese population and in young women: a pilot study.
PLoS One. 2014; 9(9):e107566 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
Relative to western populations, the percentage of women diagnosed with breast cancer at a young age in Lebanon is high. While the younger age of the Lebanese population compared to the West certainly contributes to this difference, potential genetic, reproductive and/or biological factors likely play an important role. The objective of this study is to investigate the contribution of miRNAs in this setting through the analysis of the expression of five reported dysregulated miRNAs, miR-148b, miR-10b, miR-21, miR-221, and miR-155 in 20 normal and 57 cancerous breast tissues from Lebanese breast cancer patients. After finding their relative expression by quantitative reverse transcription real time PCR, the results were analyzed with respect to the patients' clinical and histopathology presentations. Compared to normal breast tissues, significant upregulation of miR-155, miR-21 and miR-148b, notable downregulation of miR-10b and non-significant expression of miR-221 were observed in tumor tissues. Moreover, miR-10b was significantly underexpressed in estrogen/progesterone receptor (ER/PR) negative tumors relative to ER/PR positive tumor tissues. miR-155 was also significantly overexpressed in postmenopausal patients and in those of age at diagnosis greater than 40 years old as well as in PR negative or in human epidermal growth factor 2 (Her2) positive tissues. This study is the first one to report miRNA expression patterns in Lebanese breast cancer patients. We found that differential miRNA expression in breast cancer could be variable between Lebanese and Western populations. miR-10b was positively correlated with the ER and PR status and miR-155 could be a noteworthy biomarker for the menopausal state, age at diagnosis, PR and Her2 status. Hence, miRNA can be used as biomarkers for early breast cancer detection.

Agrawal R, Pandey P, Jha P, et al.
Hypoxic signature of microRNAs in glioblastoma: insights from small RNA deep sequencing.
BMC Genomics. 2014; 15:686 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
BACKGROUND: Hypoxia is a critical aspect of the glioma microenvironment and has been associated with poor prognosis and resistance to various therapies. However, the mechanisms responsible for hypoxic survival of glioma cells remain unclear. Recent studies strongly suggest that microRNAs act as critical mediators of the hypoxic response. We thus hypothesized their prominent role in hypoxia resistance in glioblastoma (GBM) and aimed to identify those.
RESULTS: With this study, we present the first detailed analysis of small RNA transcriptome of cell line U87MG, a grade IV glioma cell line, and its alteration under hypoxic condition. Based on deep sequencing and microarray data, we identify a set of hypoxia regulated microRNAs, with the miR-210-3p and its isomiRs showing highest induction in GBM cell lines U87MG and U251MG. We show miR-210-3p, miR-1275, miR-376c-3p, miR-23b-3p, miR-193a-3p and miR-145-5p to be up-regulated, while miR-92b-3p, miR-20a-5p, miR-10b-5p, miR-181a-2-3p and miR-185-5p are down-regulated by hypoxia. Interestingly, certain hypoxia-induced miRNAs are also known to be over-expressed in GBM tumors, suggesting that hypoxia may be one of the factors involved in establishing the miRNA signature of GBM. Transcription factor binding sites for Hypoxia inducible factor 1 A (HIF1A) were identified in the promoter region (5 kb upstream) of 30 hypoxia-induced miRNAs. HIF-1A over-expression and silencing studies show regulation of specific miRNAs, including miR-210-3p, to be HIF1A dependent. On the other hand, miR-210-3p leads to an increase in transcriptional activity of HIF and its target genes vascular endothelial growth factor (VEGF) and carbonic anhydrase 9 (CA9). MiR-210-3p levels were found to be high in GBM patient samples and showed good correlation with the known hypoxia markers CA9 and VEGF. We show that miR-210-3p promotes hypoxic survival and chemoresistance in GBM cells and targets a negative regulator of hypoxic response, HIF3A. Additionally, a total of 139 novel miRNAs were discovered by the analysis of deep sequencing data and three of these were found to be differentially expressed under hypoxia.
CONCLUSIONS: Overall, our study reveals a novel miRNA signature of hypoxia in GBM and suggests miR-210-3p to be an oncogenic player and a novel potential intrinsic marker of hypoxia in glioblastoma.

Wolter JM, Kotagama K, Pierre-Bez AC, et al.
3'LIFE: a functional assay to detect miRNA targets in high-throughput.
Nucleic Acids Res. 2014; 42(17):e132 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene output at the post-transcriptional level by targeting degenerate elements primarily in 3'untranslated regions (3'UTRs) of mRNAs. Individual miRNAs can regulate networks of hundreds of genes, yet for the majority of miRNAs few, if any, targets are known. Misexpression of miRNAs is also a major contributor to cancer progression, thus there is a critical need to validate miRNA targets in high-throughput to understand miRNAs' contribution to tumorigenesis. Here we introduce a novel high-throughput assay to detect miRNA targets in 3'UTRs, called Luminescent Identification of Functional Elements in 3'UTRs (3'LIFE). We demonstrate the feasibility of 3'LIFE using a data set of 275 human 3'UTRs and two cancer-relevant miRNAs, let-7c and miR-10b, and compare our results to alternative methods to detect miRNA targets throughout the genome. We identify a large number of novel gene targets for these miRNAs, with only 32% of hits being bioinformatically predicted and 27% directed by non-canonical interactions. Functional analysis of target genes reveals consistent roles for each miRNA as either a tumor suppressor (let-7c) or oncogenic miRNA (miR-10b), and preferentially target multiple genes within regulatory networks, suggesting 3'LIFE is a rapid and sensitive method to detect miRNA targets in high-throughput.

Min W, Wang B, Li J, et al.
The expression and significance of five types of miRNAs in breast cancer.
Med Sci Monit Basic Res. 2014; 20:97-104 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
BACKGROUND: This study aimed to investigate the expression and significance of 5 types of miRNAs in breast cancer to provide a theoretical and practical foundation for using these miRNAs in the diagnosis and treatment of breast cancer, thereby improving medical services.
MATERIAL/METHODS: Stem-loop real-time RT-PCR was used to detect the expression levels of miR-145, miR-21, miR-10b, miR-125a, and miR-206 in 35 cases of breast cancer and adjacent normal breast tissues, and to analyze the relationship of miRNAs expression with clinicopathological features of breast cancer. The expression levels of estrogen receptor (ER) and progesterone receptor (PR) were examined by immunohistochemistry. Fluorescence in situ hybridization was used for the detection of HER-2 and TOP 2A.
RESULTS: The expression levels of miR-145, miR-125a, and miR-206 in breast cancer were lower than those in adjacent normal tissues. MiR-145 was negatively correlated with tumor size, lymph node metastasis, ER, HER-2, and TOP 2A (P<0.05), regardless of age, menstruation, and PR. MiR-125a was correlated with negative node status, negative HER-2 status (P<0.05), whereas tumor size, age, menstruation, ER, and PR were independent factors. MiR-206 expression was correlated with negative ER status, negative PR status, and negative HER-2 status (P<0.05), regardless of age, menstruation, lymph node metastasis, and TOP 2A. MiR-21 and miR-10b expression in breast cancer tissues was significantly higher than that in adjacent tissues (P<0.05). MiR-21 in post-menstrual patients with lymph node metastasis was highly expressed (P<0.05), and had no correlations with tumor size, ER, PR, and TOP 2A expression. MiR-10b expression was positively correlated with breast cancer tumor size, lymph node metastasis, and TOP 2A status (P<0.05), but had no correlations with age, menstruation, ER, PR, and HER-2.
CONCLUSIONS: MiR-145, miR-21, miR-10b, miR-125a, and miR-206 may play important roles in breast cancer development and invasion.

Parrella P, Barbano R, Pasculli B, et al.
Evaluation of microRNA-10b prognostic significance in a prospective cohort of breast cancer patients.
Mol Cancer. 2014; 13:142 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
BACKGROUND: MicroRNA-10b (miR-10b) has a prominent role in regulating tumor invasion and metastasis by targeting the HOXD10 transcriptional repressor and has been found up-regulated in several tumor types.
METHODS: We evaluated the expression of miR-10b in paired tumor and normal specimens obtained from a prospective cohort of breast cancer patients with at least 36 months follow-up enrolled according to the REMARK guidelines (n = 150). RNA quality was measured and only samples with RNA Integrity Number (RIN) ≥7.0 were analyzed.
RESULTS: The relative expression of miR-10b in tumor as compared to its normal counterpart (RER) was determined by RT-qPCR. miR-10b RERs were higher in the subgroup of patients with synchronous metastases (n = 11, Median 0.25; IQR 0.11-1.02) as compared with patients without metastases (n = 90, Median 0.09; IQR 0.04-0.29) (p = 0.028). In the subgroup of patients without synchronous metastases (n = 90), higher miR-10b RERs were associated with increased risk of disease progression and death in both univariable (HR 1.16, p = 0.021 and HR 1.20, p = 0.015 respectively for 0.10 unitary increase of miR-10b RERs levels) and multivariable (HR1.30, p < 0.001, and HR 1.31, p = 0.003 respectively for 0.10 unitary increase of miR-10b RERs levels) Cox regression models. The addition of miR-10b RERs to the Nottingham Prognostic Index (NPI) provided an improvement in discrimination power and risk reclassification abilities for the clinical outcomes at 36 months. Survival C-indices significantly increased from 0.849 to 0.889 (p = 0.009) for OS and from 0.735 to 0.767 (p = 0.050) for DFS.
CONCLUSIONS: Our results provide evidences that the addition of miR-10b RERs to the prognostic factors used in clinical routine could improve the prediction abilities for both overall mortality and disease progression in breast cancer patients.

Wojcicka A, Swierniak M, Kornasiewicz O, et al.
Next generation sequencing reveals microRNA isoforms in liver cirrhosis and hepatocellular carcinoma.
Int J Biochem Cell Biol. 2014; 53:208-17 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) represents the major histological subtype of liver cancer. Tumorigenic changes in hepatic cells potentially result from aberrant expression of microRNAs (miRNAs). Individual microRNA gene may give rise to miRNAs of different length, named isomiRNAs that proved to be functionally relevant. Since microRNA length heterogeneity in hepatic tissue has not been described before, we employed next-generation sequencing to comprehensively analyze microRNA transcriptome in HCC tumors (n=24) and unaffected tissue adjacent to tumors (n=24), including samples with (n=15) and without cirrhosis (n=9). We detected 374 microRNAs expressed in liver, including miR-122-5p that constituted over 39% of the hepatic miRnome. Among the liver expressed miRs, the levels of 64 significantly differed between tumor and control samples (FDR<0.05, fold change>2). Top deregulated miRNAs included miR-1269a (T/N=22.95), miR-3144-3p (T/N=5.24), miR-183-5p (T/N=4.63), miR-10b-5p (T/N=3.87), miR-490-3p (T/N=0.13), miR-199a-5p (T/N=0.17), miR-199a-3p/miR-199b-3p (T/N=0.19), miR-214-5p (T/N=0.20) and miR-214-3p (T/N=0.21). Almost all miRNA genes produced several mature molecules differing in length (isomiRNAs). The reference sequence was not the most prevalent in 38.6% and completely absent in 10.5% of isomiRNAs. Over 26.1% of miRNAs produced isoforms carrying≥2 alternative seed regions, of which 35.5% constituted novel, previously unknown seeds. This fact sheds new light on the percentage of the human genome regulated by microRNAs and their variants. Among the most deregulated miRNAs, miR-199a-3p/miR-199b-3p (T/N fold change=0.18, FDR=0.005) was expressed in 9 isoforms with 3 different seeds, concertedly leading to upregulation of TGF-beta signaling pathway (OR=1.99; p=0.004). In conclusion, the study reveals the comprehensive miRNome of hepatic tissue and provides new tools for investigation of microRNA-dependent pathways in cirrhotic liver and hepatocellular carcinoma. This article is part of a Directed Issue entitled: Rare Cancers.

Ouyang M, Li Y, Ye S, et al.
MicroRNA profiling implies new markers of chemoresistance of triple-negative breast cancer.
PLoS One. 2014; 9(5):e96228 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
OBJECTIVE: Triple-negative breast cancer (TNBC) patients with truly chemosensitive disease still represent a minority among all TNBC patients. The aim of the present study is to identify microRNAs (miRNAs) that correlate with TNBC chemoresistance.
METHODS: In this study, we conducted miRNAs profile comparison between triple-negative breast cancer (TNBCs) and normal breast tissues by microRNA array. Quantitative real-time PCR (qRT-PCR) was utilized to confirm the specific deregulated miRNAs change trend. We used starBase 2.1 and GOrilla to predict the potential targets of the specific miRNAs. Cells viability and apoptosis assays were employed to determine the effect of alteration of the specific miRNAs in TNBC cells on the chemosensitivity.
RESULTS: We identified 11 specific deregulated miRNAs, including 5 up-regulated miRNAs (miR-155-5p, miR-21-3p, miR-181a-5p, miR-181b-5p, and miR-183-5p) and 6 down-regulated miRNAs (miR-10b-5p, miR-451a, miR-125b-5p, miR-31-5p, miR-195-5p and miR-130a-3p). Thereafter, this result was confirmed by qRT-PCR. We predicted the potential targets of the candidate miRNAs and found that they are involved in cancer-associated pathways. For the first time, we found that miR-130a-3p and miR-451a were down-regulated in TNBC. 9 of the 11 specific deregulated miRNAs were found to be associated with chemoresistance. In vitro assays, we found that up-regulation of either miR-130a-3p or miR-451a in MDA-MB-231 cells significantly changed the cells sensitivity to doxorubicin. The results suggest that TNBC chemotherapy might be affected by a cluster of miRNAs.
CONCLUSION: The abnormal expression miRNAs in TNBC are mainly chemoresistance related. This might be part of reason that TNBC likely to evade from chemotherapy resulting in early relapse and high risk of death. To alter their expression status might be a potential therapeutic strategy to improve the outcome of chemotherapy for TNBC patients.

Bai W, Chen Y, Yang J, et al.
Aberrant miRNA profiles associated with chronic benzene poisoning.
Exp Mol Pathol. 2014; 96(3):426-30 [PubMed] Related Publications
Chronic occupational benzene exposure is associated with an increased risk of hematological malignancies. To gain an insight into the new biomarkers and molecular mechanisms of chronic benzene poisoning, miRNA profiles and mRNA expression pattern from the peripheral blood mononuclear cells of chronic benzene poisoning patients and health controls matched age and gender without benzene exposure were performed using the Exiqon miRNA PCR ARRAY and Gene Chip Human Gene 2.0ST Arrays, respectively. Totally, 6 up-regulated miRNAs (miR-34a, miR-205, miR-10b, let-7d, miR-185 and miR-423-5p-2) and 7 down-regulated miRNAs (miR-133a, miR-543, hsa-miR-130a, miR-27b,miR-223, miR-142-5p and miR-320b) were found in chronic benzene poisoning group compared to health controls (P ≤ 0.05). By integrating miRNA and mRNA expression data, these differential miRNAs were mainly involved in regulation of transcription from RNA polymerase II promoter, axon guidance, regulation of transcription, DNA-dependent, nervous system development, and regulation of actin cytoskeleton organization. Further, pathway analysis indicated that SMAD4, PLCB1, NFAT5, GNAI2, PTEN, VEGFA, BCL2, CTNNB1 and CCND1 were key target genes of differential miRNAs which were implicated in Adherens junction, TGF-beta signaling pathway, Wnt signaling pathway, tight junction and Pathways in cancer. In conclusion, the aberrant miRNAs might be a potential biomarker of chronic benzene poisoning.

Tezcan G, Tunca B, Bekar A, et al.
microRNA expression pattern modulates temozolomide response in GBM tumors with cancer stem cells.
Cell Mol Neurobiol. 2014; 34(5):679-92 [PubMed] Related Publications
Temozolomide (TMZ) is widely used to treat glioblastoma multiforme (GBM). Although the MGMT gene methylation status is postulated to correlate with TMZ response, some patients with a methylated MGMT gene still do not benefit from TMZ therapy. Cancer stem cells (CSCs) may be one of the causes of therapeutic resistance, but the molecular mechanism underlying this resistance is unclear. microRNA (miRNA) deregulation has been recognized as another chemoresistance modulating mechanism. Thus, we aimed to evaluate the miRNA expression patterns associated with chemoresistance that is dependent on the CSC status in GBM tumors to identify therapeutic biomarkers. CSCs were identified in 5 of 20 patients' tumor tissues using magnetic separation. CSC (+) tumors displayed a significant induction of CpG island methylation in the MGMT gene promoter (p = 0.009). Using real-time reverse transcription polymerase chain reaction (qRT-PCR), 9 miRNAs related to GBM (mir-181b, miR-153, miR-137, miR-145, miR-10a, miR-10b, let-7d, miR-9, and miR-455-3p), which are associated with cell cycle and invasion was analyzed in tumor samples. Low miR-181b and high miR-455-3p expression levels were detected (p = 0.053, p = 0.004; respectively) in CSC (+) tumors. Analysis revealed a significant correlation between miR-455-3p expression and Smad2 protein levels as analyzed by immunohistochemistry in CSC (+) tumors (p = 0.002). Thus, miR-455-3p may be involved in TMZ resistance in MGMT methylated CSC (+) GBM patients. Further studies and evaluations are required, but this miRNA may provide novel therapeutic molecular targets for GBM treatment and new directions for the development of anticancer drugs.

Xiao H, Li H, Yu G, et al.
MicroRNA-10b promotes migration and invasion through KLF4 and HOXD10 in human bladder cancer.
Oncol Rep. 2014; 31(4):1832-8 [PubMed] Related Publications
The present study was performed to investigate the effect of microRNA-10b (miR-10b) on cell migration and invasion in human bladder cancer (BC). Real-time PCR was performed to detect the expression of miR-10b in BC cell lines. miR-10b mimics, the negative control for mimics, miR-10b inhibitor and the negative control for inhibitor were transfected into BC cell lines and the effects of miR-10b on the migration and invasion of cells were investigated through Transwell assay. Meanwhile, protein levels of KLF4, HOXD10, E-cadherin and MMP14 were measured. Luciferase assays were also performed to validate KLF4 and HOXD10 as miR-10b targets. In vivo metastasis assay was performed to validate if miR-10b can promote BC cell line metastasis in vivo. miR-10b is significantly upregulated in BC cell lines and metastatic tissues. Increased miR-10b expression significantly enhanced BC cell migration and invasion, while decreased miR-10b expression reduced cell migration and invasion. In vivo metastasis assay demonstrated that overexpression of miR-10b markedly promoted BC metastasis. Moreover, KLF4 and HOXD10 were identified as direct targets of miR-10b in BC cells. Silencing of KLF4 or HOXD10 recapitulated the pro-metastatic function. Furthermore, we found that E-cadherin and MMP14 may be the downstream factors of KLF4 and HOXD10 in the suppression of BC metastasis by miR-10b. These data suggest that miR-10b may function as oncogenes in BC cells. Targeting these novel strategies, inhibition of miR-10b/KLF4/E-cadherin axis and miR-10b/HOXD10/MMP14 axis may be helpful as a therapeutic approach to block BC cell metastasis.

Han X, Yan S, Weijie Z, et al.
Critical role of miR-10b in transforming growth factor-β1-induced epithelial-mesenchymal transition in breast cancer.
Cancer Gene Ther. 2014; 21(2):60-7 [PubMed] Related Publications
Epithelial-mesenchymal transition (EMT) is a key process in the tumor metastatic cascade that is characterized by the loss of cell-cell junctions and cell polarity, resulting in the acquisition of migratory and invasive properties. Recent evidence showed that altered microRNA-10b (miR-10b) expression was implicated in the occurrence of EMT of breast cancer. However, the exact role and underlying mechanisms of miR-10b in the EMT of breast cancer still remain unknown. In this study, miR-10b was found to be upregulated in breast cancer tissues and breast cancer cell lines and the expression of miR-10b was shown to be closely correlated with aggressiveness in breast cancer. Treating breast cancer cells with the miR-10b inhibitor increased E-cadherin expression while decreasing vimentin expression. At the same time, on inhibition of miR-10b, the invasion and proliferation ability of breast cancer cells also decreased. Transforming growth factor-β (TGF-β) is a multifunctional cytokine that induces EMT in multiple cell types. Here, we identified miR-10b as a target gene of TGF-β1. The expression of miR-10b increased during TGF-β1-induced EMT of breast cancer cells. Further study showed that inhibition of miR-10b expression partially reversed the EMT, invasion and proliferation induced by TGF-β1 in breast cancer cells. Taken together, these results demonstrated a novel function for miR-10b in TGF-β1-induced EMT in breast cancer and increased their metastatic potential. MiR-10b might become a possible target for gene therapy in breast cancer.

Anfossi S, Giordano A, Gao H, et al.
High serum miR-19a levels are associated with inflammatory breast cancer and are predictive of favorable clinical outcome in patients with metastatic HER2+ inflammatory breast cancer.
PLoS One. 2014; 9(1):e83113 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
INTRODUCTION: Altered serum microRNA (miRNA) levels may be correlated with a dysregulated expression pattern in parental tumor tissue and reflect the clinical evolution of disease. The overexpression of miR-21, miR-10b, and miR-19a is associated with the acquisition of malignant characteristics (increased tumor cell proliferation, migration, invasion, dissemination, and metastasis); thus, we determined their utility as serum biomarkers for aggressive breast cancer (HER2-overexpressed or -amplified [HER2(+)] and inflammatory breast cancer [IBC]).
EXPERIMENTAL DESIGN: In this prospective study, we measured miR-21, miR-10b, and miR-19a levels using quantitative reverse transcriptase-polymerase chain reaction in the serum of 113 breast cancer patients and determined their association with clinicopathologic factors and clinical outcome. Thirty healthy donors with no history of cancer were enrolled as controls.
RESULTS: Patients with non-metastatic HER2(+) breast cancer had higher serum miR-21 median levels than patients with non-metastatic HER2(-) disease (p = 0.044); whereas patients with metastatic HER2(+) breast cancer had higher serum miR-10b median levels than patients with metastatic HER2(-) disease (p = 0.0004). There were no significant differences in serum miR-19a median levels between HER2(+) and HER2(-) groups, regardless of the presence of metastases. High serum miR-19a levels were associated with IBC (p = 0.039). Patients with metastatic IBC had significantly higher serum miR-19a median levels than patients with metastatic non-IBC (p = 0.019). Finally, high serum miR-19a levels were associated with longer progression-free survival time (10.3 vs. 3.2 months; p = 0.022) and longer overall survival time (median not reached vs. 11.2 months; p = 0.003) in patients with metastatic HER2(+) IBC.
CONCLUSION: High levels of miR-21 and miR-10b were present in the serum of patients with non-metastatic and metastatic HER2(+) breast cancer, respectively. High levels of serum miR-19a may represent a biomarker for IBC that is predictive for favorable clinical outcome in patients with metastatic HER2(+) IBC.

Visani M, de Biase D, Marucci G, et al.
Expression of 19 microRNAs in glioblastoma and comparison with other brain neoplasia of grades I-III.
Mol Oncol. 2014; 8(2):417-30 [PubMed] Related Publications
Several biomarkers have been proposed as useful parameters to better specify the prognosis or to delineate new target therapy strategies for glioblastoma patients. MicroRNAs could represent putative target molecules, considering their role in tumorigenesis, cancer progression and their specific tissue expression. Although several studies have tried to identify microRNA signature for glioblastoma, a microRNA profile is still far from being well-defined. In this work the expression of 19 microRNAs (miR-7, miR-9, miR-9∗, miR-10a, miR-10b, miR-17, miR-20a, miR-21, miR-26a, miR-27a, miR-31, miR-34a, miR-101, miR-137, miR-182, miR-221, miR-222, miR-330, miR-519d) was evaluated in sixty formalin-fixed and paraffin-embedded glioblastoma samples using a locked nucleic acid real-time PCR. Moreover, a comparison of miRNA expressions was performed between primary brain neoplasias of different grades (grades IV-I). The analysis of 14 validated miRNA expression in the 60 glioblastomas, using three different non-neoplastic references as controls, revealed a putative miRNA signature: mir-10b and miR-21 were up-regulated, while miR-7, miR-31, miR-101, miR-137, miR-222 and miR-330 were down-regulated in glioblastomas. Comparing miRNA expression between glioblastoma group and gliomas of grades I-III, 3 miRNAs (miR-10b, mir-34a and miR-101) showed different regulation statuses between high-grade and low-grade tumors. miR-10b was up-regulated in high grade and significantly down-regulated in low-grade gliomas, suggesting that could be a candidate for a GBM target therapy. This study provides further data for the identification of a miRNA profile for glioblastoma and suggests that different-grade neoplasia could be characterized by different expression of specific miRNAs.

Liang S, Chen L, Huang H, Zhi D
The experimental study of miRNA in pituitary adenomas.
Turk Neurosurg. 2013; 23(6):721-7 [PubMed] Related Publications
AIM: We investigated the differential miRNA expression in pituitary adenomas (both non-functioning and gonadotropin-secreting) and normal pituitaries.
MATERIAL AND METHODS: RNA was extracted and purified from pituitary adenomas (10 non-functioning and 10 gonadotropin-secreting) and from two normal pituitary tissue samples. The samples were analyzed by miRNA microarray. Gene expression was measured using realtime RT-PCR with SYBR GREEN I.
RESULTS: In non-functioning pituitary adenomas, 25 miRNA genes were up-regulated (six by over 5-fold) and 15 were down-regulated (six by more than 10-fold). miR-124a was the most up-regulated gene (38.58-fold), and miR-31 the most down-regulated gene (21.5-fold). In gonadotropin-secreting pituitary adenomas, 16 miRNA genes were up-regulated (six by over 4-fold) and 13 were down-regulated (seven by more than 10-fold). miR-10b was the most up-regulated gene (48.73-fold), and miR-503 the most down-regulated gene (39.8-fold). Five genes were up-regulated in both subtypes: miR-523, miR-10b, miR-520b, miR-422a, and miR-422b. The RT-PCR results were consistent with those of the gene chips.
CONCLUSION: We established miRNA expression maps of non-functioning and gonadotropin-secreting pituitary adenomas. The most strongly differentially expressed genes were miR-124a and miR-31 in non-functioning pituitary adenomas, and miR-10b and miR-503 in gonadotropin-secreting pituitary adenomas.

Liu Y, Li M, Zhang G, Pang Z
MicroRNA-10b overexpression promotes non-small cell lung cancer cell proliferation and invasion.
Eur J Med Res. 2013; 18:41 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
BACKGROUND: miRNAs are a class of small non-coding RNA molecules that play an important role in the pathogenesis of human diseases through negative regulation of gene expression. Although miRNA-10b (miR-10b) has been implicated in other tumors, its role in non-small cell lung cancer (NSCLC) is still unknown. The aim of the present study was to investigate the role of miR-10b in NSCLC.
METHODS: Expression of miR-10b was analyzed in NSCLC cell line A549 by qRT-PCR. Cell viability was evaluated using Cell Counting Kit (CCK)-8. Cell migration and invasion were evaluated by wound healing assay and transwell assays. Cell cycle and apoptosis analyses were performed. Western blotting was used to predicate the target of miR-10b.
RESULTS: The A549 cell line transfected with the miR-10b exhibited significantly increased proliferation, migration, and invasion capacities when compared with the control cells (P < 0.05). Krüppel-like factor 4 (KLF4) may be indirectly targeted by miR-10b during the proliferation increasing of A549 cells.
CONCLUSION: In this study, we found that miR-10b is a tumor enhancer in NSCLC. Thus, miR-10b may represent a potential therapeutic target for NSCLC intervention.

Severino P, Brüggemann H, Andreghetto FM, et al.
MicroRNA expression profile in head and neck cancer: HOX-cluster embedded microRNA-196a and microRNA-10b dysregulation implicated in cell proliferation.
BMC Cancer. 2013; 13:533 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
BACKGROUND: Current evidence implicates aberrant microRNA expression patterns in human malignancies; measurement of microRNA expression may have diagnostic and prognostic applications. Roles for microRNAs in head and neck squamous cell carcinomas (HNSCC) are largely unknown. HNSCC, a smoking-related cancer, is one of the most common malignancies worldwide but reliable diagnostic and prognostic markers have not been discovered so far. Some studies have evaluated the potential use of microRNA as biomarkers with clinical application in HNSCC.
METHODS: MicroRNA expression profile of oral squamous cell carcinoma samples was determined by means of DNA microarrays. We also performed gain-of-function assays for two differentially expressed microRNA using two squamous cell carcinoma cell lines and normal oral keratinocytes. The effect of the over-expression of these molecules was evaluated by means of global gene expression profiling and cell proliferation assessment.
RESULTS: Altered microRNA expression was detected for a total of 72 microRNAs. Among these we found well studied molecules, such as the miR-17-92 cluster, comprising potent oncogenic microRNA, and miR-34, recently found to interact with p53. HOX-cluster embedded miR-196a/b and miR-10b were up- and down-regulated, respectively, in tumor samples. Since validated HOX gene targets for these microRNAs are not consistently deregulated in HNSCC, we performed gain-of-function experiments, in an attempt to outline their possible role. Our results suggest that both molecules interfere in cell proliferation through distinct processes, possibly targeting a small set of genes involved in cell cycle progression.
CONCLUSIONS: Functional data on miRNAs in HNSCC is still scarce. Our data corroborate current literature and brings new insights into the role of microRNAs in HNSCC. We also show that miR-196a and miR-10b, not previously associated with HNSCC, may play an oncogenic role in this disease through the deregulation of cell proliferation. The study of microRNA alterations in HNSCC is an essential step to the mechanistic understanding of tumor formation and could lead to the discovery of clinically relevant biomarkers.

Shen Y, Tang D, Yao R, et al.
microRNA expression profiles associated with survival, disease progression, and response to gefitinib in completely resected non-small-cell lung cancer with EGFR mutation.
Med Oncol. 2013; 30(4):750 [PubMed] Related Publications
microRNAs have been implicated in regulating diverse cellular pathways. Although there is emerging evidence that some microRNAs can function as oncogenes or tumor suppressors, the role of microRNAs in mediating cancer progression remains unexplored. And whether expression levels of a panel of biologically relevant microRNAs can be used as prognostic or predictive biomarkers in radically resected non-small-cell lung carcinoma (NSCLC) patients still needs to be further validated. Our analyses involved two separated, retrospective cohorts. Firstly, microRNA expression profile was performed in a cohort consisted of 128 radically resected NSCLC patients [60 were positive to epidermal growth factor receptor (EGFR) mutation and 68 were negative] and 32 healthy providers to identify EGFR mutation-related microRNAs and to determine their association with survival. In addition, to validate our findings, we used quantitative reverse transcriptase polymerase chain reaction assays to measure microRNAs and assess their association with disease progression, survival, and response to gefitinib in an independent cohort of 201 patients with EGRF mutation. In radically resected NSCLC patients, the expression levels of miR-21, 10b in patients with EGFR mutation were much higher than those without mutation. We used Cox proportional-hazards regression to evaluate the effect of treatment on survival. In both univariate and multivariate analyses, gefitinib was associated with a significant improvement in overall survival in patients with reduced miR-21 expression. Thus, miR-21 expression emerged as an independent predictor of the response to gefitinib. Additionally, miR-10b is highly expressed in progressive disease compared with complete remission or stable disease (P < 0.001). However, miR-21 expression has no significant prognosis for disease progression (P = 0.720). Meanwhile, when overall survival was considered as the end point, miR-10b did not have a significant difference between different subgroups (P = 0.634). The expression patterns of microRNAs differ significantly between patients with positive and negative EGFR mutation. And the expression status of miR-21 and 10b in such patients is associated with disease progression, survival, and response to adjuvant therapy with gefitinib.

Vimalraj S, Miranda PJ, Ramyakrishna B, Selvamurugan N
Regulation of breast cancer and bone metastasis by microRNAs.
Dis Markers. 2013; 35(5):369-87 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
Breast cancer progression including bone metastasis is a complex process involving numerous changes in gene expression and function. MicroRNAs (miRNAs) are small endogenous noncoding RNAs that regulate gene expression by targeting protein-coding mRNAs posttranscriptionally, often affecting a number of gene targets simultaneously. Alteration in expression of miRNAs is common in human breast cancer, possessing with either oncogenic or tumor suppressive activity. The expression and the functional role of several miRNAs (miR-206, miR-31, miR-27a/b, miR-21, miR-92a, miR-205, miR-125a/b, miR-10b, miR-155, miR-146a/b, miR-335, miR-204, miR-211, miR-7, miR-22, miR-126, and miR-17) in breast cancer has been identified. In this review we summarize the experimentally validated targets of up- and downregulated miRNAs and their regulation in breast cancer and bone metastasis for diagnostic and therapeutic purposes.

Sun XJ, Liu H, Zhang P, et al.
miR-10b promotes migration and invasion in nasopharyngeal carcinoma cells.
Asian Pac J Cancer Prev. 2013; 14(9):5533-7 [PubMed] Related Publications
MicroRNA-10b (miR-10b) has been reported to play an important role in some types of cancer, but the effects and possible mechanisms of action of miR-10b in the metastasis of nasopharyngeal carcinoma cells (NPC) have not been explored. The aim of the present study was to investigate the function of miR-10b in nasopharyngeal carcinoma and to determine the molecular mechanisms underlying its action. The MTT assay was used to assess proliferation of CNE-2Z cells. Wound healing and transwell migration assays were applied to assess cell migration and invasion, while and expression of E-cadherin and MMP-9 were detected using Western blot analysis. Real-time PCR was employed to detect the expression of genes related to migration and invasion and the 2-??Ct method was used to calculate the degree of expression. MTT assay showed the expression of miR-10b to have no effect on the proliferation of NPC cell lines. The wound healing assay showed that miR-10b mimics promoted the mobility and invasion of NPC cell lines. Inhibitors of miR-10b reduced the ability of NPC cell lines to migrate and invade. In addition, the expression of genes related to migration and invasion, such as E-cadherin, vimentin, and MMP-9, were confirmed to be different in the CNE-2Z NPC cell line transfected with miR-10b mimics and with miR-10b inhibitors. In the present study, miR-10b was found to upregulate the expression of MMP-9 and knockdown of miR-10b was found to significantly downregulate the expression of E-cadherin. On the whole, these results showed that miR-10b plays an important role in the invasion and metastasis of NPC cells.

Markou A, Yousef GM, Stathopoulos E, et al.
Prognostic significance of metastasis-related microRNAs in early breast cancer patients with a long follow-up.
Clin Chem. 2014; 60(1):197-205 [PubMed] Related Publications
BACKGROUND: Stability of microRNAs (miRNAs) in formalin-fixed paraffin-embedded (FFPE) tissues enables their reliable analysis in archived FFPE tissue samples, which are an invaluable source for the evaluation of novel biomarkers. Especially in breast cancer, for which late relapses occur in many cases, analysis of miRNAs in FFPE tissues holds great potential, because it can lead to the discovery of novel biomarkers suitable for future routine clinical diagnostics for breast cancer. We investigated the prognostic significance of 6 metastasis-related miRNAs that can critically regulate various stages of migration and invasion and play critical roles in the multistep metastatic process.
METHODS: We quantified the expression of 6 mature miRNAs (namely miR-21, miR-205, miR-10b, miR-210, miR-335, and let-7a) by reverse-transcription quantitative PCR in FFPE tissues of 84 patients with early breast cancer and a long follow-up and 13 cancer-free breast tissue FFPE samples that were used as the control group. We further correlated individual miRNA over- or underexpression with the disease-free interval (DFI) and overall survival (OS).
RESULTS: Univariate analysis revealed that both miR-21 and miR-205 were significantly associated with DFI and only miR-205 with OS. Multivariate analysis demonstrated that miR-205 and miR-21 were independent factors associated with early disease relapse, whereas only miR-205 overexpression was associated with OS.
CONCLUSIONS: Our results clearly indicate that deregulation of metastasis-associated miRNAs in primary tumors is associated with clinical outcome in patients with early breast cancer and can differentiate patients with higher risk in well-characterized subgroups.

Liu S, Sun J, Lan Q
TGF-β-induced miR10a/b expression promotes human glioma cell migration by targeting PTEN.
Mol Med Rep. 2013; 8(6):1741-6 [PubMed] Related Publications
Human gliomas are associated with high rates of morbidity and mortality. In the brain, increased mRNA levels of transforming growth factor β (TGF-β) correlate with the degree of malignancy of human gliomas. miR10a/10b expression has been demonstrated to be associated with TGF-β expression in brain tumors, and it is reported that TGF-β induces miR10 expression. Therefore, miR10a/10b expression may be induced by TGF-β expression and may be involved in the TGF-β-induced migration of brain tumor cells. The present study examined the expression of TGF-β and miR10a/10b in the tissues of 10 patients with brain tumors using quantitative PCR (qPCR), and the correlation between TGF-β and miR10a or miR10b expression was analyzed. Additionally, U251 and SHG-44 cells were treated with TGF-β and the expression of miR10a/10b was examined. Further, cell migration was analyzed following transfection of U251 cells with miR10a/10b and the association between miR10a/10b and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was investigated. U251 cells were transfected with miR10a/10b inhibitors and a PTEN expression plasmid prior to TGF-β treatment and then cell migration was assessed. A significant correlation was identified between TGF-β and miR10a expression (r2=0.6936, P=0.007) and between TGF-β and miR10b expression (r2=0.5876, P=0.02) in the tissues of patients with brain tumors. The results also showed that TGF-β induces miR10a/10b expression and that TGF-β-induced miR10a/10b expression promotes cell migration through the suppression of PTEN. In conclusion, TGF-β-induced miR10a/10b promotes brain tumor migration. This study may provide a number of suggestions for the clinical treatment of brain tumors.

Ouyang H, Gore J, Deitz S, Korc M
microRNA-10b enhances pancreatic cancer cell invasion by suppressing TIP30 expression and promoting EGF and TGF-β actions.
Oncogene. 2014; 33(38):4664-74 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
Increased microRNA-10b (miR-10b) expression in the cancer cells in pancreatic ductal adenocarcinoma (PDAC) is a marker of disease aggressiveness. In the present study, we determined that plasma miR-10b levels are significantly increased in PDAC patients by comparison with normal controls. By gene profiling, we identified potential targets downregulated by miR-10b, including Tat-interacting protein 30 (TIP30). Immunoblotting and luciferase reporter assays confirmed that TIP30 was a direct miR-10b target. Downregulation of TIP30 by miR-10b or siRNA-mediated silencing of TIP30 enhanced epidermal growth factor (EGF)-dependent invasion. The actions of miR-10b were abrogated by expressing a modified TIP30 cDNA resistant to miR-10b. EGF-induced EGF receptor (EGFR) tyrosine phosphorylation and extracellular signal-regulated kinase phosphorylation were enhanced by miR-10b, and these effects were mimicked by TIP30 silencing. The actions of EGF in the presence of miR-10b were blocked by EGFR kinase inhibition with erlotinib and by dual inhibition of PI3K (phosphatidylinositol 3'-kinase) and MEK. Moreover, miR-10b, EGF and transforming growth factor-beta (TGF-β) combined to markedly increase cell invasion, and this effect was blocked by the combination of erlotinib and SB505124, a type I TGF-β receptor inhibitor. miR-10b also enhanced the stimulatory effects of EGF and TGF-β on cell migration and epithelial-mesenchymal transition (EMT) and decreased the expression of RAP2A, EPHB2, KLF4 and NF1. Moreover, miR-10b overexpression accelerated pancreatic cancer cell (PCC) proliferation and tumor growth in an orthotopic model. Thus, plasma miR-10b levels may serve as a diagnostic marker in PDAC, whereas intra-tumoral miR-10b promotes PCC proliferation and invasion by suppressing TIP30, which enhances EGFR signaling, facilitates EGF-TGF-β cross-talk and enhances the expression of EMT-promoting genes, whereas decreasing the expression of several metastasis-suppressing genes. Therefore, therapeutic targeting of miR-10b in PDAC may interrupt growth-promoting deleterious EGF-TGF-β interactions and antagonize the metastatic process at various levels.

Pizzini S, Bisognin A, Mandruzzato S, et al.
Impact of microRNAs on regulatory networks and pathways in human colorectal carcinogenesis and development of metastasis.
BMC Genomics. 2013; 14:589 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
BACKGROUND: Qualitative alterations or abnormal expression of microRNAs (miRNAs) in colon cancer have mainly been demonstrated in primary tumors. Poorly overlapping sets of oncomiRs, tumor suppressor miRNAs and metastamiRs have been linked with distinct stages in the progression of colorectal cancer. To identify changes in both miRNA and gene expression levels among normal colon mucosa, primary tumor and liver metastasis samples, and to classify miRNAs into functional networks, in this work miRNA and gene expression profiles in 158 samples from 46 patients were analysed.
RESULTS: Most changes in miRNA and gene expression levels had already manifested in the primary tumors while these levels were almost stably maintained in the subsequent primary tumor-to-metastasis transition. In addition, comparing normal tissue, tumor and metastasis, we did not observe general impairment or any rise in miRNA biogenesis. While only few mRNAs were found to be differentially expressed between primary colorectal carcinoma and liver metastases, miRNA expression profiles can classify primary tumors and metastases well, including differential expression of miR-10b, miR-210 and miR-708. Of 82 miRNAs that were modulated during tumor progression, 22 were involved in EMT. qRT-PCR confirmed the down-regulation of miR-150 and miR-10b in both primary tumor and metastasis compared to normal mucosa and of miR-146a in metastases compared to primary tumor. The upregulation of miR-201 in metastasis compared both with normal and primary tumour was also confirmed. A preliminary survival analysis considering differentially expressed miRNAs suggested a possible link between miR-10b expression in metastasis and patient survival. By integrating miRNA and target gene expression data, we identified a combination of interconnected miRNAs, which are organized into sub-networks, including several regulatory relationships with differentially expressed genes. Key regulatory interactions were validated experimentally. Specific mixed circuits involving miRNAs and transcription factors were identified and deserve further investigation. The suppressor activity of miR-182 on ENTPD5 gene was identified for the first time and confirmed in an independent set of samples.
CONCLUSIONS: Using a large dataset of CRC miRNA and gene expression profiles, we describe the interplay of miRNA groups in regulating gene expression, which in turn affects modulated pathways that are important for tumor development.

Yoshitaka T, Kawai A, Miyaki S, et al.
Analysis of microRNAs expressions in chondrosarcoma.
J Orthop Res. 2013; 31(12):1992-8 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
MicroRNAs (miRNAs) are small non-coding RNAs capable of inhibiting gene expression post-transcriptionally and expression profiling can provide therapeutic targets and tools for cancer diagnosis. Chondrosarcoma is a mesenchymal tumor with unknown cause and differentiation status. Here, we profiled miRNA expression of chondrosarcoma, namely clinical samples from human conventional chondrosarcoma tissue, established chondrosarcoma cell lines, and primary non-tumorous adult articular chondrocytes, by miRNA array and quantitative real-time PCR. A wide variety of miRNAs were differently downregulated in chondrosarcoma compared to non-tumorous articular chondrocytes; 27 miRNAs: miR-10b, 23b, 24-1*, 27b, 100, 134, 136, 136*, 138, 181d, 186, 193b, 221*, 222, 335, 337-5p, 376a, 376a*, 376b, 376c, 377, 454, 495, 497, 505, 574-3p, and 660, were significantly downregulated in chondrosarcoma and only 2: miR-96 and 183, were upregulated. We further validated the expression levels of miRNAs by quantitative real-time PCR for miR-181a, let-7a, 100, 222, 136, 376a, and 335 in extended number of chondrosarcoma clinical samples. Among them, all except miR-181a were found to be significantly downregulated in chondrosarcoma derived samples. The findings provide potential diagnostic value and new molecular understanding of chondrosarcoma.

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