Locus Summary

Gene:MIR100; microRNA 100
Aliases: MIRN100, miR-100
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: 27 February, 2015

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 February 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.

  • Nuclear Receptor Co-Repressor 2
  • Chromosome 11
  • In Situ Nick-End Labeling
  • MIRN100 microRNA, human
  • Xenograft Models
  • MicroRNAs
  • Immunohistochemistry
  • Immunoblotting
  • Cell Proliferation
  • Glioblastoma
Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (1)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
-MIR100 and Glioblastoma View Publications1

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)MIR100 Function in CancerEffect
head and neck (3)
-head and neck squamous cell carcinoma (1)
-nasopharyngeal cancer (1)
-oral squamous cell carcinoma (1)
PLK1 (1)
inhibit cell proliferation (2)
inhibit cell migration (1)
induce apoptosis (1)
tumor-suppressive (2)
esophagus (1)
-esophageal squamous cell carcinoma (1)
MTOR (1)
induce apoptosis (1)
tumor-suppressive (1)
blood (1)
-acute myeloid leukemia (1)
promote cell proliferation (1)
inhibit cell diferentiation (1)
regulate cell cycle G1/S transition (1)
regulate cell cycle S entry (1)
oncogenic (1)
prostate (1)
-prostate cancer (1)
MTOR (1)
inhibit cell growth (1)
tumor-suppressive (1)
liver (1)
-hepatocellular carcinoma (1)
PLK1 (1)
inhibit cell growth (1)
inhibit colony formation (1)
tumor-suppressive (1)
bladder (1)
-bladder carcinoma (1)
reduce cell proliferation (1)
reduce colony formation (1)
tumor-suppressive (1)
ovary (1)
-epithelial ovarian cancer (1)
PLK1 (1)
inhibit cell growth (1)
tumor-suppressive (1)
brain (1)
-glioma (1)
ATM (1)
increase radiation sensitivity (1)
lung (1)
-lung adenocarcinoma (1)
PLK1 (1)
reduce docetaxel chemoresistance (1)
inhibit cell proliferation (1)
induce cell cycle G2/M arrest (1)
induce apoptosis (1)
tumor-suppressive (1)
adrenal gland (1)
-childhood adrenocortical tumor (1)
IGF1R (1)
MTOR (1)

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

Latest Publications: MIR100 (cancer-related)

Zhou S, Yang B, Zhao Y, et al.
Prognostic value of microRNA-100 in esophageal squamous cell carcinoma.
J Surg Res. 2014; 192(2):515-20 [PubMed] Related Publications
BACKGROUND: MicroRNA-100 (miR-100) has been demonstrated to be implicated in tumorigenesis and tumor progression of human esophageal squamous cell carcinoma (ESCC). However, its expression patterns in ESCC are controversial and its prognostic value in this malignancy has not been fully elucidated. The aim of this study was to investigate the expression and clinical significance of miR-100 in ESCC.
MATERIALS AND METHODS: Real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) was performed to detect expression levels of miR-100 in 120 self-paired specimens of ESCC and adjacent normal esophageal tissues. The associations of miR-100 expression with clinicopathologic features, locoregional progression-free survival (LPFS), distant progression-free survival (DPFS), and overall survival (OS) of patients with ESCC were statistically analyzed.
RESULTS: Compared with adjacent normal esophageal tissues, the expression levels of miR-100 in ESCC were significantly decreased (normal versus ESCC: 3.53 ± 1.22 versus 1.89 ± 0.38, P <0.001). Additionally, low miR-100 expression in ESCC tissues was significantly associated with the advanced clinical stage (P = 0.008), the presence of distant metastasis (P = 0.008), and the great depth of invasion (P = 0.02). Moreover, univariate analysis revealed that low miR-100 expression was associated with poor LPFS, DPFS, and OS. In multivariate analysis, miR-100 expression was identified as an independent prognostic factor for all LPFS, DPFS, and OS.
CONCLUSIONS: These findings show the reduced expression of miR-100 in human ESCC tissues and suggest a crucial role of its downregulation in ESCC progression and prognosis. More interestingly, the detection of miR-100 expression may be used to efficiently screen those ESCC patients who would benefit from radiotherapy.

Wu C, Wang C, Guan X, et al.
Diagnostic and prognostic implications of a serum miRNA panel in oesophageal squamous cell carcinoma.
PLoS One. 2014; 9(3):e92292 [PubMed] Free Access to Full Article Related Publications
BACKGROUND AND AIM: Circulating microRNAs (miRNAs) are potential biomarkers for cancer detection; however, little is known about their prognostic impact on oesophageal squamous cell carcinoma (ESCC). The current study aims to uncover novel miRNAs for prognostic biomarkers in ESCC patients.
PATIENTS AND METHODS: We initially screened the expression of 754 serum miRNAs using TaqMan Low Density Array in two pooled samples respectively from 28 ESCC and 28 normal controls. Markedly upregulated miRNAs in ESCC and some miRNAs reported to be differently expressed in ESCC tissue were then validated individually by RT-qPCR in another 83 patients and 83 controls arranged in two phases. The changes of the selected miRNAs during the esophagectomy and their prognostic value were examined.
RESULTS: Seven serum miRNAs were found to be significantly higher in ESCC than in controls; namely, miR-25, miR-100, miR-193-3p, miR-194, miR-223, miR-337-5p and miR-483-5p (P<0.0001), and the area under the receiver-operating-characteristic (ROC) curve (AUC) for the seven-miRNA panel was 0.83 (95% CI 0.75-0.90). Most of these miRNAs declined markedly in postoperative samples versus preoperative samples (P<0.05). Moreover, high level of miR-25 was significantly correlated with shorter overall survival in patients (P = 0.027). Cox regression analysis identified lymph node metastasis, miR-25 and miR-100 as the independent risk factors for overall survival (hazard ratio (HR) 2.98 [1.36-6.55], P = 0.006; HR 3.84 [1.02-14.41], P = 0.029; HR 4.18 [1.21-14.50], P = 0.024, respectively).
CONCLUSION: The seven serum miRNAs could potentially serve as novel biomarkers for ESCC; moreover, specific miRNAs such as miR-25 and miR-100 can predict poor survival in ESCC.

Peng H, Luo J, Hao H, et al.
MicroRNA-100 regulates SW620 colorectal cancer cell proliferation and invasion by targeting RAP1B.
Oncol Rep. 2014; 31(5):2055-62 [PubMed] Related Publications
MicroRNAs (miRNAs) have been demonstrated to play important roles in tumorigenesis of human cancer. Fewer studies have explored the roles of miR-100 on human colorectal cancer cell proliferation and invasion. In this study, we utilized real-time PCR to verify whether miR-100 was downregulated in human colorectal cancer tissues compared with matched adjacent normal tissues. Functional studies demonstrated that ectopic expression of miR-100 inhabits cell growth and invasion and induce apoptosis, whereas knockdown of miR-100 yielded the reverse phenotype. Mechanistic studies reveal that miR-100 repressed the activity of a reporter gene fused to the 3'-untranslated region (3'-UTR) of RAP1B, whereas miR-100 silencing upregulated the expression of the reporter gene. Furthermore, we also detected that RAP1B mRNA was inversely expressed with miR-100 in colorectal cancer tissues. These data indicate that the miR-100 plays a tumor suppressor role by regulating colorectal cancer cell growth and invasion phenotype, and could serve as a potential maker for colorectal cancer therapy.

Wang X, Wang HK, Li Y, et al.
microRNAs are biomarkers of oncogenic human papillomavirus infections.
Proc Natl Acad Sci U S A. 2014; 111(11):4262-7 [PubMed] Free Access to Full Article Related Publications
Cellular and viral microRNAs (miRNAs) are the transcriptional products of RNA polymerase II and are regulated by transcriptional factors for their differential expression. The altered expression of miRNAs in many cancer types has been explored as a marker for possible diagnosis and therapy. We report in this study that oncogenic human papillomaviruses (HPVs) induce aberrant expression of many cellular miRNAs and that HPV18 infection produces no detectable viral miRNA. Thirteen abundant host miRNAs were specifically regulated by HPV16 and HPV18 in organotypic raft cultures of foreskin and vaginal keratinocytes as determined by miRNA array in combination with small RNA sequencing. The increase of miR-16, miR-25, miR-92a, and miR-378 and the decrease of miR-22, miR-27a, miR-29a, and miR-100 could be attributed to viral oncoprotein E6, E7, or both, all of which are known to target many cellular transcription factors. The examination of 158 cervical specimens, including 38 normal, 52 cervical intraepithelial neoplasia (CIN), and 68 cervical cancer (CC) tissues, for the expression of these eight miRNAs showed a remarkable increase of miR-25, miR-92a, and miR-378 with lesion progression but no obvious change of miR-22, miR-29a, and miR-100 among the HPV-infected tissues. Further analyses indicate that an expression ratio ≥1.5 of miR-25/92a group over miR-22/29a group could serve as a cutoff value to distinguish normal cervix from CIN and from CIN to CC.

Chen D, Sun Y, Yuan Y, et al.
miR-100 induces epithelial-mesenchymal transition but suppresses tumorigenesis, migration and invasion.
PLoS Genet. 2014; 10(2):e1004177 [PubMed] Free Access to Full Article Related Publications
Whether epithelial-mesenchymal transition (EMT) is always linked to increased tumorigenicity is controversial. Through microRNA (miRNA) expression profiling of mammary epithelial cells overexpressing Twist, Snail or ZEB1, we identified miR-100 as a novel EMT inducer. Surprisingly, miR-100 inhibits the tumorigenicity, motility and invasiveness of mammary tumor cells, and is commonly downregulated in human breast cancer due to hypermethylation of its host gene MIR100HG. The EMT-inducing and tumor-suppressing effects of miR-100 are mediated by distinct targets. While miR-100 downregulates E-cadherin by targeting SMARCA5, a regulator of CDH1 promoter methylation, this miRNA suppresses tumorigenesis, cell movement and invasion in vitro and in vivo through direct targeting of HOXA1, a gene that is both oncogenic and pro-invasive, leading to repression of multiple HOXA1 downstream targets involved in oncogenesis and invasiveness. These findings provide a proof-of-principle that EMT and tumorigenicity are not always associated and that certain EMT inducers can inhibit tumorigenesis, migration and invasion.

Zhu Z, Wang CP, Zhang YF, Nie L
MicroRNA-100 resensitizes resistant chondrosarcoma cells to cisplatin through direct targeting of mTOR.
Asian Pac J Cancer Prev. 2014; 15(2):917-23 [PubMed] Related Publications
Chondrosarcomas are malignant cartilage-forming tumors of bone which exhibit resistance to both chemotherapy and radiation treatment. miRNAs have been well demonstrated to regulate gene expression and play essential roles in a variety of biological processes, including proliferation, differentiation, migration, cell cycling and apoptosis. In this study, we obtained evidence that miR-100 acts as a tumor suppressor in human chondrosarcomas. Interestingly, cisplatin resistant chondrosarcoma cells exhibit decreased expression of miR-100 compared with parental cells. In addition, we identified mTOR as a direct target of miR-100. Overexpression of miR-100 complementary pairs to the 3' untranslated region (UTR) of mTOR, resulted in sensitization of cisplatin resistant cells to cisplatin. Moreover, recovery of the mTOR pathway by overexpression of S6K desensitized the chondrosarcoma cells to cisplatin, suggesting the miR-100-mediated sensitization to cisplatin dependent on inhibition of mTOR. In summary, the present studies highlight miR-100 as a tumor suppressor in chondrosarcoma contributing to anti-chemoresistance. Overexpression of miR-100 might be exploited as a therapeutic strategy along with cisplatin-based combined chemotherapy for the treatment of clinical chondrosarcoma patients.

Xiao F, Bai Y, Chen Z, et al.
Downregulation of HOXA1 gene affects small cell lung cancer cell survival and chemoresistance under the regulation of miR-100.
Eur J Cancer. 2014; 50(8):1541-54 [PubMed] Related Publications
Chemoresistance is often developed in small cell lung cancer (SCLC) patients and leads to poor prognosis. Hox genes, a highly conserved family, play a crucial role in apoptosis, receptor signalling and differentiation. MicroRNAs (miRNAs) have also been shown to play a crucial role in these biological processes by regulating the target genes. Several studies reported that both Hox genes and miRNAs are involved in chemoresistance. The aim of our study is to characterise the clinical significance and functional roles of HOXA1 in SCLC. Expression of HOXA1 was examined in 63 cases of SCLC tissues and 29 cases of blood by immunohistochemistry and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) methods. Multivariate analysis confirmed the prognostic significance of HOXA1 in SCLC patients. Restoration of HOXA1 expression was carried out in SCLC multidrug resistant cell line H69AR and its parental cell line H69 to assess its influence on chemoresistance. Luciferase reporter assay was used to assess HOXA1 as a target of miR-100. The results showed that HOXA1 was expressed in 46% (29/63) of SCLC. Low HOXA1 expression was associated with the poor prognosis of SCLC (P<0.05 by the Fisher's Exact Test) and the shorter survival rate (P<0.001 by the Kaplan-Meier method). HOXA1 expression on both mRNA and protein levels significantly correlated with chemotherapy response. Enforced expression of HOXA1 in resistant H69AR cells led to increased chemosensitivity through increasing cell apoptosis and cell-cycle arrest. Inhibition of HOXA1 expression using HOXA1 siRNA in H69 cells resulted in cell resistance to therapeutic drugs through reducing drug-induced cell apoptosis accompanied with cell cycle arrest. Expression of endogenous miR-100 was significantly elevated in resistant H69AR cells and negatively related with HOXA1 expression. The expression of HOXA1 in SCLC tissues correlated inversely with the expression levels of miR-100. Reporter assays confirmed that miR-100 targeted predicted sites in 3'-untranslated region (3'-UTR) of HOXA1 gene. Our data suggested that HOXA1-mediated SCLC chemoresistance is under the regulation of miR-100. HOXA1 may be a prognostic predictor and potential therapeutic target in human SCLC.

Gadducci A, Sergiampietri C, Lanfredini N, Guiggi I
Micro-RNAs and ovarian cancer: the state of art and perspectives of clinical research.
Gynecol Endocrinol. 2014; 30(4):266-71 [PubMed] Related Publications
Dysregulation of microRNA (mi-RNA) expression plays a major role in the development and progression of most human malignancies. Members of the miR-200 family, miR-182, miR-214 and miR-221 are frequently up-regulated, whereas miR-100, let-7i, miR-199a, miR-125b, mir-145 and miR-335 are often down-regulated in ovarian cancer compared with normal ovarian tissue. Most mi-RNA signatures are overlapping in different tumor histotypes but some mi-RNAs seem to be histotype specific. For instance, the endometrioid type shares with the serous and clear cell types the up-regulation of miR-200 family members, but also presents over-expression of miR-21, miR-202 and miR-205. Clear cell carcinoma has a significantly higher expression of miR-30a and miR-30a*, whereas mucinous histotype has elevated levels of miR-192/194. In vitro and in vivo investigations have shown that several mi-RNAs can modulate the sensitivity of ovarian cancer to platinum and taxane, and clinical studies have suggested that mi-RNA profiling may predict the outcome of patients with this malignancy. Some mi-RNAs could be used as biomarkers to identify patients that might benefit from the addition of molecularly targeted agents (i.e. anti-angiogenic agents, MET inhibitors and poly(ADP-ribose) polymerase (PARP) inhibitors) to standard chemotherapy. Moreover, mi-RNAs could represent potential targets for the development of novel therapies.

Szabó DR, Luconi M, Szabó PM, et al.
Analysis of circulating microRNAs in adrenocortical tumors.
Lab Invest. 2014; 94(3):331-9 [PubMed] Related Publications
Differential diagnosis of adrenocortical adenoma (ACA) and carcinoma is of pivotal clinical relevance, as the prognosis and clinical management of benign and malignant adrenocortical tumors (ACTs) is entirely different. Circulating microRNAs (miRNAs) are promising biomarker candidates of malignancy in several tumors; however, there are still numerous technical problems associated with their analysis. The objective of our study was to investigate circulating miRNAs in ACTs and to evaluate their potential applicability as biomarkers of malignancy. We have also addressed technical questions including the choice of profiling and reference gene used. A total of 25 preoperative plasma samples obtained from patients with ACAs and carcinomas were studied by microarray and quantitative real-time PCR. None of the three miRNAs (hsa-miR-192, hsa-mir-197 and hsa-miR-1281) found as differentially expressed in plasma samples in our microarray screening could be validated by quantitative real-time PCR. In contrast, of the selected eight miRNAs reported in the literature as differentially expressed in ACT tissues, five (hsa-miR-100, hsa-miR-181b, hsa-miR-184, hsa-miR-210 and hsa-miR-483-5p) showed a statistically significant overexpression in adrenocortical cancer vs adenoma when normalized on hsa-miR-16 as a reference gene. Receiver operator characteristic analysis of data revealed that the combination of dCThsa-miR-210 - dCThsa-miR-181b and dCThsa-miR-100/dCThsa-miR-181b showed the highest diagnostic accuracy (area under curve 0.87 and 0.85, respectively). In conclusion, we have found significant differences in expression of circulating miRNAs between ACAs and carcinomas, but their diagnostic accuracy is not yet high enough for clinical application. Further studies on larger cohorts of patients are needed to assess the diagnostic and prognostic potential application of circulating miRNA markers.

Huang J, Gao K, Lin J, Wang Q
MicroRNA-100 inhibits osteosarcoma cell proliferation by targeting Cyr61.
Tumour Biol. 2014; 35(2):1095-100 [PubMed] Related Publications
Increasing evidence indicates that microRNAs (miRNAs) participate in almost every step of cellular processes and are often aberrantly expressed in human cancer. Therefore, the discovery of miRNAs may provide a new and powerful tool for understanding the mechanism and treatment of carcinogenesis. The aim of this study was to investigate the functional significance of miR-100 and to identify its possible target genes in osteosarcoma (OS) cells. Here, we found that expression level of miR-100 was significantly decreased in osteosarcoma tissues in comparison with the adjacent normal tissues. The enforced expression of miR-100 was able to inhibit cell proliferation in Saos-2 and MG63 cells, while its antisense oligonucleotides (antisense miR-100) promoted cell proliferation. Moreover, our results further revealed that expression of Cyr61, an extracellular matrix-associated growth factor, was negatively regulated by miR-100. Therefore, we consider that miR-100 acts as a tumor suppressor for osteosarcoma. It may provide novel diagnostic and therapeutic options for human osteosarcoma in the future.

Chen J, Zheng B, Wang C, et al.
Prognostic role of microRNA-100 in various carcinomas: evidence from six studies.
Tumour Biol. 2014; 35(4):3067-71 [PubMed] Related Publications
Recent studies have shown that microRNAs (miRNA) exhibit altered expression levels in cancers, and they may be considered as valuable prognostic biomarkers for patients with cancers. We performed this meta-analysis to provide a comprehensive evaluation of the role of miRNA-100 expression on the overall survival rate by calculating the pooled hazard ratio (HR) for overall survival (OS), which compared the high and low expression levels of miR-100 in patients of the available studies. Finally, a total of six studies dealing with various carcinomas were involved for this meta-analysis. The results indicated that lower expression of miR-100 in cancerous tissue could significantly predict poorer survival in various carcinomas with the pooled HR of 2.19 (95% CI 1.49-3.24, P = 0.0007). In conclusion, the findings from this present meta-analysis suggest that miR-100 expression is associated with OS in cancer patients and could be a useful clinical prognostic factor for those patients.

Alrfaei BM, Vemuganti R, Kuo JS
microRNA-100 targets SMRT/NCOR2, reduces proliferation, and improves survival in glioblastoma animal models.
PLoS One. 2013; 8(11):e80865 [PubMed] Free Access to Full Article Related Publications
Glioblastoma (GBM) is the most frequently diagnosed malignant human glioma, and current median patient survival is less than two years despite maximal surgery followed by temozolomide chemoradiation therapies. Novel microRNA-related therapies are now being developed for cancers such as GBM. Differential microRNA expression profiling revealed that miR-100 expression is down-regulated in GBM compared to normal controls. We report that miR-100 expression reduces GBM tumorigenicity. In vitro, four GBM lines (U87, U251, 22T, and 33T) demonstrated reduced proliferation 24 hours after transient miR100 overexpression via transfection. miR-100 triggered cell death an average 70% more than scrambled miR controls 24 hours after transient transfection (p < 0.01). miR-100 targeted inhibition of the "silencing mediator of retinoid or thyroid hormone receptor-2" (SMRT/NCOR2) gene was confirmed via reporter assays. Ki67 proliferation index was decreased 40% in tumor xenografts generated from stable miR-100 transfected GBM lines versus controls (p < 0.01). Furthermore, treatment of tumor xenografts with a single pre-mir-100 injection (60 pmol) significantly extended survival of mice bearing intracranial GBM xenografts 25% more than scrambled controls (p < 0.01; n=8). These studies establish miR-100's effect on tumor GBM growth, and suggest clinical potential for microRNA-related GBM therapy.

Lauvrak SU, Munthe E, Kresse SH, et al.
Functional characterisation of osteosarcoma cell lines and identification of mRNAs and miRNAs associated with aggressive cancer phenotypes.
Br J Cancer. 2013; 109(8):2228-36 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Osteosarcoma is the most common primary malignant bone tumour, predominantly affecting children and adolescents. Cancer cell line models are required to understand the underlying mechanisms of tumour progression and for preclinical investigations.
METHODS: To identify cell lines that are well suited for studies of critical cancer-related phenotypes, such as tumour initiation, growth and metastasis, we have evaluated 22 osteosarcoma cell lines for in vivo tumorigenicity, in vitro colony-forming ability, invasive/migratory potential and proliferation capacity. Importantly, we have also identified mRNA and microRNA (miRNA) gene expression patterns associated with these phenotypes by expression profiling.
RESULTS: The cell lines exhibited a wide range of cancer-related phenotypes, from rather indolent to very aggressive. Several mRNAs were differentially expressed in highly aggressive osteosarcoma cell lines compared with non-aggressive cell lines, including RUNX2, several S100 genes, collagen genes and genes encoding proteins involved in growth factor binding, cell adhesion and extracellular matrix remodelling. Most notably, four genes-COL1A2, KYNU, ACTG2 and NPPB-were differentially expressed in high and non-aggressive cell lines for all the cancer-related phenotypes investigated, suggesting that they might have important roles in the process of osteosarcoma tumorigenesis. At the miRNA level, miR-199b-5p and mir-100-3p were downregulated in the highly aggressive cell lines, whereas miR-155-5p, miR-135b-5p and miR-146a-5p were upregulated. miR-135b-5p and miR-146a-5p were further predicted to be linked to the metastatic capacity of the disease.
INTERPRETATION: The detailed characterisation of cell line phenotypes will support the selection of models to use for specific preclinical investigations. The differentially expressed mRNAs and miRNAs identified in this study may represent good candidates for future therapeutic targets. To our knowledge, this is the first time that expression profiles are associated with functional characteristics of osteosarcoma cell lines.

de Melo Maia B, Lavorato-Rocha AM, Rodrigues LS, et al.
microRNA portraits in human vulvar carcinoma.
Cancer Prev Res (Phila). 2013; 6(11):1231-41 [PubMed] Related Publications
Unregulated expression of microRNAs is well known and has already been demonstrated in many tumor types. However, in vulvar carcinoma this field has been unknown territory. Our study characterizes microRNA in vulvar tumors through an expression profile of 754 miRNAs, relating this with clinical and anatomopathologic data, and presence of HPV infection. Twenty HPV-negative and 20 HPV-positive samples, genotyped for high-risk HPVs (HPV16, 18, 31, 33) and a pool of seven normal vulvar skin samples were used for the identification of differentially expressed miRNAs by TLDA Quantitative Real Time PCR (qRT-PCR). Twenty-five differentially expressed microRNAs between HPV-positive and HPV-negative groups and 79 differentially expressed on the tumor compared with normal samples were obtained. A network between microRNA expression profiles and putative target mRNAs predicted by target prediction algorithms and previously demonstrated as relevant in vulvar carcinomas, such as TP53, RB, PTEN, and EGFR was constructed. Downregulation of both miR-223-5p and miR-19-b1-5p were correlated with the presence of lymph node metastasis; downregulation of miR-100-3p and miR-19-b1-5p were correlated with presence of vascular invasion; overexpression of miR-519b and miR-133a were associated with advanced FIGO staging. In conclusion, our study demonstrates that microRNAs may be clinically important in vulvar carcinomas and our findings may help for further studies on functional implications of miRNA deregulation in this type of cancer.

Li XJ, Luo XQ, Han BW, et al.
MicroRNA-100/99a, deregulated in acute lymphoblastic leukaemia, suppress proliferation and promote apoptosis by regulating the FKBP51 and IGF1R/mTOR signalling pathways.
Br J Cancer. 2013; 109(8):2189-98 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: MicroRNAs alter multiple cell processes and thus influence tumour carcinogenesis and progression. MiR-100 and miR-99a have been reported to be aberrantly expressed in acute leukaemia. In this study, we focused on their functions in acute lymphoblastic leukaemia (ALL) and the molecular networks in which they are involved.
METHODS: MiR-100 and miR-99a expression levels were measured in acute leukaemia patients by qRT-PCR. Kaplan-Meier analysis and log-rank tests were used to calculate the survival rate. Three human ALL cell lines were studied. Apoptosis and proliferation were analysed using siRNA transfection, western blot and flow cytometry.
RESULTS: In vivo, miR-100 and miR-99a were down-regulated in 111 ALL patients, especially in high-risk groups; their expression levels were correlated with the patient's 5-year survival. In vitro, the restoration of miR-100 and miR-99a in ALL cells suppressed cell proliferation and increased dexamethasone-induced cell apoptosis. Ectopic expression of miR-100 and miR-99a targeted FK506-binding protein 51 (FKBP51) and, in turn, influenced glucocorticoid receptor (GR) activity. Meanwhile, miR-100 and miR-99a overexpression inhibited the expression of IGF1R and mTOR and their downstream oncogene MCL1.
CONCLUSION: MiR-100 and miR-99a have critical roles in altering cellular processes by targeting both the FKBP51 and IGF1R/mTOR signalling pathways in vitro and might represent a potential novel strategy for ALL treatment.

Catrina Ene AM, Borze I, Guled M, et al.
MicroRNA expression profiles in Kaposi's sarcoma.
Pathol Oncol Res. 2014; 20(1):153-9 [PubMed] Related Publications
Kaposi's sarcoma (KS) is a mesenchymal tumor, caused by Human herpesvirus 8 (HHV8) with molecular and cytogenetic changes poorly understood. To gain further insight on the underlying molecular changes in KS, we performed microRNA (miRNA) microarray analysis of 17 Kaposi's sarcoma specimens. Three normal skin specimens were used as controls. The most significant differentially expressed miRNA were confirmed by quantitative reverse transcriptase polymerase chain reaction (RT-PCR). We detected in KS versus normal skin 185 differentially expressed miRNAs, 76 were upregulated and 109 were downregulated. The most significantly downregulated miRNAs were miR-99a, miR-200 family, miR-199b-5p, miR-100 and miR-335, whereas kshv-miR-K12-4-3p, kshv-miR-K12-1, kshv-miR-K12-2, kshv-miR-K12-4-5p and kshv-miR-K12-8 were significantly upregulated. High expression levels of kshv-miR-K12-1 (p = 0.004) and kshv-miR-K12-4-3p (p = 0.001) was confirmed by RT-PCR. The predicted target genes for differentially expressed miRNAs included genes which are involved in a variety of cellular processes such as angiogenesis (i.e. THBS1) and apoptosis (i.e. CASP3, MCL1), suggesting a role for these miRNAs in Kaposi's sarcoma pathogenesis.

Zhong S, Li W, Chen Z, et al.
MiR-222 and miR-29a contribute to the drug-resistance of breast cancer cells.
Gene. 2013; 531(1):8-14 [PubMed] Related Publications
Adriamycin (Adr) and docetaxel (Doc) are two chemotherapeutic agents commonly used in the treatment of breast cancer. However, patients with breast cancer who are treated by the drugs often develop resistance to them and some other drugs. Recently studies have shown that microRNAs (miRNAs, miRs) play an important role in drug-resistance. In present study, miRNA expression profiles of MCF-7/S and its two resistant variant MCF-7/Adr and MCF-7/Doc cells were analyzed using microarray and the results were confirmed by real-time quantitative polymerase chain reaction. Here, 183 differentially expressed miRNAs were identified in the two resistant sublines compared to MCF-7/S. Then, five up-regulated miRNAs (miR-100, miR-29a, miR-196a, miR-222 and miR-30a) in both MCF-7/Adr and MCF-7/Doc were selected to explore their roles in acquisition of drug-resistance using transfection experiment. The results showed that miR-222 and miR-29a mimics and inhibitors had partially changed the drug-resistance of breast cancer cells, which was also confirmed by apoptosis assay. Western blot results suggested that miR-222 and -29a could regulate the expression of PTEN, maybe through which the two miRNAs conferred Adr and Doc resistance in MCF-7 cells. Finally, pathway mapping tools were employed to further analyze signaling pathways affected by the two miRNAs. In summary, this study demonstrates that altered miRNA expression pattern is involved in acquiring resistance to Adr and Doc in breast cancer MCF-7 cells, and that there are some miRNAs who displayed consistent up- or down-regulated expression changes in the two resistant sublines. The most importance is that we identify two miRNAs (miR-222 and miR-29a) involved in drug-resistance, at least in part via targeting PTEN.

Lobert S, Graichen ME
Regulation of tubulin expression by micro-RNAs: implications for drug resistance.
Methods Cell Biol. 2013; 115:63-74 [PubMed] Related Publications
In this chapter, we provide an overview of methods for studying micro-RNA regulation of tubulin isotypes. In clinical studies, β-tubulin isotypes were found to be biomarkers for tumor formation. In addition, because changes in the levels of specific β-tubulin isotypes alter the stability of microtubules in mitotic spindles in vitro, it has been hypothesized that changes in microtubule protein levels could contribute to chemotherapy resistance. Over the past 15 years, micro-RNAs have been shown to target mRNAs in signaling pathways involved in tumor suppression, as well as tumorigenesis. Investigating micro-RNA regulation of tubulin isotypes will shed light on the mechanisms underlying the processes that implicate tubulin isotypes as biomarkers for aggressive tumors or chemotherapy resistance. The methods discussed in this chapter include the use of micro-RNA superarrays, next-generation sequencing, real-time PCR experiments, upregulation of micro-RNAs, and immunoprecipitation of RNA-induced silencing complex. We will show examples of data collected using these methods and how these data contribute to understanding paclitaxel resistance.

Ratert N, Meyer HA, Jung M, et al.
miRNA profiling identifies candidate mirnas for bladder cancer diagnosis and clinical outcome.
J Mol Diagn. 2013; 15(5):695-705 [PubMed] Related Publications
Bladder cancer is a common cancer in the Western world. The current prognosticators such as tumor grade, stage, size, and multifocality do not accurately reflect the clinical outcome. It is of clinical interest to identify biomarkers that could improve diagnostic and/or prognostic predictions. The objectives of this study were to identify deregulated miRNAs in bladder cancer samples and evaluate their potential as diagnostic and prognostic biomarkers. We screened 723 miRNAs by microarray and selected a subset of 15 distinctively deregulated miRNAs for further validation by real-time quantitative RT-(q)PCR. Seven miRNAs (miR-20a, miR-106b, miR-130b, miR-141, miR-200a, miR-200a*, and miR-205) were found to be up-regulated and eight miRNAs (miR-100, miR-125b, miR-130a, miR-139-5p, miR-145*, miR-199a-3p, miR-214, and miR-222) were found to be down-regulated in malignant bladder tissue samples compared to healthy tissue. Four miRNAs that have already been described in the literature (miR-141, miR-199a-3p, miR-205, and miR-214) were significantly differentially expressed between nonmuscle-invasive and muscle-invasive bladder cancer. Furthermore, real-time RT-qPCR of all miRNAs provided high overall correct classification (>75%) of bladder cancer diagnosis. Two miRNAs (miR-141 and miR-205) were associated with overall survival time. The verification of tumor-specific miRNA expression profile, together with the observed association of miR-141 and miR-205 expression with overall survival, underline the potential of miRNAs to function as diagnostic and/or prognostic markers of bladder cancer.

Akbari Moqadam F, Lange-Turenhout EA, Ariës IM, et al.
MiR-125b, miR-100 and miR-99a co-regulate vincristine resistance in childhood acute lymphoblastic leukemia.
Leuk Res. 2013; 37(10):1315-21 [PubMed] Related Publications
MicroRNA-125b (miR-125b), miR-99a and miR-100 are overexpressed in vincristine-resistant acute lymphoblastic leukemia (ALL). Cellular viability of ETV6-RUNX1-positive Reh cells significantly increased in presence of 9 ng/mL vincristine upon co-expression of miR-125b/miR-99a (91 ± 4%), miR-125b/miR-100 (93 ± 5%) or miR-125b/miR-99a/miR-100 (82 ± 17%) compared with miR-125b-transduced cells (38 ± 13%, P<0.05). Co-expression of these miRNAs resulted in downregulation of DNTT, NUCKS1, MALAT1, SNRPE, PNO1, SET, KIF5B, PRPS2, RPS11, RPL38 and RPL23A (fold-change 1.3-1.9, p<0.05). Similarly, 7 out of these genes are lower expressed in vincristine-resistant ALL cells of children (p<0.05). The concerted function of miR-125b in combination with miR-99a and/or miR-100 illustrates the complexity of vincristine-resistant pediatric ALL.

Guancial EA, Bellmunt J, Yeh S, et al.
The evolving understanding of microRNA in bladder cancer.
Urol Oncol. 2014; 32(1):41.e31-40 [PubMed] Related Publications
PURPOSE: Micro ribonucleic acid (miR) expression is altered in urologic malignancies, including bladder cancer (BC). Individual miRs have been shown to modulate multiple signaling pathways that contribute to BC. We reviewed the primary literature on the role of miRs in BC; we provide a general introduction to the processing, regulation, and function of miRs as tumor suppressors and oncogenes and critically evaluate the literature on the implications of altered miR expression in BC.
MATERIALS AND METHODS: We searched the English language literature for original and review articles in PubMed from 1993 to March 2013, using the terms "microRNA" and "bladder cancer," "transitional cell carcinoma," or "urothelial carcinoma." This search yielded 133 unique articles with more than 85% of them published within the last 3 years.
RESULTS: To date, the majority of miR studies in BC use profiling to describe dynamic changes in miR expression across stage and grade. Generalized down-regulation of miRs, including those that target the fibroblast growth factor 3 pathway, such as miR-145, miR-101, miR-100, and miR-99a, has been observed in low-grade, non-muscle invasive BC. In contrast, generalized increased expression of miRs is observed in high-grade, muscle-invasive BC compared with adjacent normal bladder urothelium, including miRs predicted to target p53, such as miR-21 and miR-373. Furthermore, p53 suppresses transcriptional factors that promote mesenchymal differentiation, ZEB-1 and ZEB-2, through regulation of the miR200 family.
CONCLUSIONS: Aberrations in miR expression identified between non-muscle invasive BC and muscle-invasive BC provide insight into the molecular alterations known to distinguish the two parallel pathways of bladder carcinogenesis. The heterogeneity of tumor specimens and research methods limits the reproducibility of changes in miR expression profiles between studies and underscores the importance of in vivo validation in a field that utilizes in silico miR target-prediction models.

Chen P, Zhao X, Ma L
Downregulation of microRNA-100 correlates with tumor progression and poor prognosis in hepatocellular carcinoma.
Mol Cell Biochem. 2013; 383(1-2):49-58 [PubMed] Related Publications
Increasing evidence suggests that dysregulation of microRNAs is correlated with malignant transformation and tumor development. miR-100, a potential tumor suppressor, is downregulated by many human cancers. However, the expression and functions of miR-100 in hepatocellular carcinoma (HCC) are still unclear. The aim of this study was to detect the expression of miR-100 in HCC tissues and investigate its clinicopathological and prognostic significance. Also, the effects of miR-100 on growth and apoptosis of HCC cells and its potential molecular mechanisms were analyzed. Results showed that the expression level of miR-100 in HCC tissues was significantly lower than that in matched non-cancerous liver tissues. Also, low-miR-100 expression was observed to be significantly correlated with higher tumor grade, higher incidence of lymph node metastasis, advanced TNM stage and higher incidence of tumor recurrence in HCC patients. Multivariate survival analyses suggested that low-miR-100 expression was an independent prognostic factor for HCC patients (HR = 1.66, 95 % CI 1.32-2.82, P = 0.019). In addition, we found that upregulation of miR-100 could inhibit growth and increase apoptosis of HCC cells by downregulating polo-like kinase 1 (plk1). In HCC tissues, miR-100 expression was inversely correlated with the expression of plk1 protein (r = -0.418; P = 0.029). Therefore, downregulation of miR-100 was correlated with progressive pathological feature and poor prognosis in HCC patients, and miR-100 could function as a tumor suppressor by targeting plk1. miR-100 may serve as a prognostic marker and molecular therapeutic target in HCC.

Blick C, Ramachandran A, Wigfield S, et al.
Hypoxia regulates FGFR3 expression via HIF-1α and miR-100 and contributes to cell survival in non-muscle invasive bladder cancer.
Br J Cancer. 2013; 109(1):50-9 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Non-muscle invasive (NMI) bladder cancer is characterised by increased expression and activating mutations of FGFR3. We have previously investigated the role of microRNAs in bladder cancer and have shown that FGFR3 is a target of miR-100. In this study, we investigated the effects of hypoxia on miR-100 and FGFR3 expression, and the link between miR-100 and FGFR3 in hypoxia.
METHODS: Bladder cancer cell lines were exposed to normoxic or hypoxic conditions and examined for the expression of FGFR3 by quantitative PCR (qPCR) and western blotting, and miR-100 by qPCR. The effect of FGFR3 and miR-100 on cell viability in two-dimensional (2-D) and three-dimensional (3-D) was examined by transfecting siRNA or mimic-100, respectively.
RESULTS: In NMI bladder cancer cell lines, FGFR3 expression was induced by hypoxia in a transcriptional and HIF-1α-dependent manner. Increased FGFR3 was also in part dependent on miR-100 levels, which decreased in hypoxia. Knockdown of FGFR3 led to a decrease in phosphorylation of the downstream kinases mitogen-activated protein kinase (MAPK) and protein kinase B (PKB), which was more pronounced under hypoxic conditions. Furthermore, transfection of mimic-100 also decreased phosphorylation of MAPK and PKB. Finally, knocking down FGFR3 profoundly decreased 2-D and 3-D cell growth, whereas introduction of mimic-100 decreased 3-D growth of cells.
CONCLUSION: Hypoxia, in part via suppression of miR-100, induces FGFR3 expression in bladder cancer, both of which have an important role in maintaining cell viability under conditions of stress.

Leite KR, Morais DR, Reis ST, et al.
MicroRNA 100: a context dependent miRNA in prostate cancer.
Clinics (Sao Paulo). 2013; 68(6):797-802 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: MicroRNAs are noncoding RNA molecules involved in the development and progression of tumors. We have found that miRNA-100 is underexpressed in metastatic prostate cancer compared to localized disease. Conversely higher levels of miR-100 are related to biochemical recurrence after surgery. This suggests that miR-100 may be a context-dependent miRNA, acting as oncogene or tumor suppressor miRNA. Our aim is to demonstrate the role of miR-100 in the control of predicted target genes in prostate cancer cell lines.
METHODS: Cell lines DU145 and PC3 were transfected with miR-100, antimiR-100 and after 24 h and 48 h of exposure, qRT-PCR and western blot were performed for mTOR, FGFR3, THAP2, SMARCA5 and BAZ2A.
RESULTS: There was reduction in mTOR (p=0.025), THAP2 (p=0.038), SMARCA5 (p=0.001) and BAZ2A (p=0.006) mRNA expression in DU145 cells after exposure to miR-100. In PC3 cells, mTOR expression was decreased by miR-100 (p=0.01). There was a reduction in the expression levels of proteins encoded by studied genes, ranging from 34% to 69%.
CONCLUSIONS: We demonstrate that miR-100 is a context-dependent miRNA controlling BAZ2, mTOR, FGFR3, SMARCA5 and THAP2 that might be involved in PC progression. The elucidation of the roles of miRNAs in tumors is important because they can be used as therapeutic targets in the future.

Reis ST, Timoszczuk LS, Pontes-Junior J, et al.
The role of micro RNAs let7c, 100 and 218 expression and their target RAS, C-MYC, BUB1, RB, SMARCA5, LAMB3 and Ki-67 in prostate cancer.
Clinics (Sao Paulo). 2013; 68(5):652-7 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: The aim of this study is to verify the expression of proteins that are controlled by miR-let7c, 100 and 218 using immunohistochemistry in tissue microarray representative of localized and metastasized the lymph nodes and bone prostate cancer.
METHODS: To verify the expression of proteins that are controlled by miR-let7c (C-MYC, BUB1, RAS) 100 (SMARCA5, RB) and 218 (LAMB3) and cell proliferation (Ki-67) we used immunohistochemistry and computerized image system ImageJ MacBiophotonics in three tissue microarrays representative of localized prostate cancer and lymph node and bone metastases. miRNA expression was evaluated by qRT-PCR using 60 paraffin blocks to construct the tissue microarray representative of localized disease.
RESULTS: RAS expression was increased in localized prostate cancer and bone metastases compared to the lymph nodes (p=0.017). RB showed an increase in expression from localized prostate cancer to lymph node and bone metastasis (p=0.036). LAMB3 was highly expressed in localized and lymph node metastases (p<0.001). Cell proliferation evaluated by Ki-67 showed an increase from localized prostate cancer to metastases (p<0.001). We did not found any relationship between C-MYC (p=0.253), BUB1 (p=0.649) and SMARCA5 (p=0.315) protein expression with prognosis or tumor behavior.
CONCLUSION: We found that the expression of RAS, RB, LAMB3 and Ki-67 changed in the different stages of prostate cancer. Furthermore, we confirmed the overexpression of the miRNAs let7c, 100 and 218 in localized prostate cancer but failed to show the control of protein expression by the putative controller miRNAs using immunohistochemistry.

Avci CB, Harman E, Dodurga Y, et al.
Therapeutic potential of an anti-diabetic drug, metformin: alteration of miRNA expression in prostate cancer cells.
Asian Pac J Cancer Prev. 2013; 14(2):765-8 [PubMed] Related Publications
BACKGROUND AND AIMS: Prostate cancer is the most commonly diagnosed cancer in males in many populations. Metformin is the most widely used anti-diabetic drug in the world, and there is increasing evidence of a potential efficacy of this agent as an anti-cancer drug. Metformin inhibits the proliferation of a range of cancer cells including prostate, colon, breast, ovarian, and glioma lines. MicroRNAs (miRNAs) are a class of small, non- coding, single-stranded RNAs that downregulate gene expression. We aimed to evaluate the effects of metformin treatment on changes in miRNA expression in PC-3 cells, and possible associations with biological behaviour.
MATERIALS AND METHODS: Average cell viability and cytotoxic effects of metformin were investigated at 24 hour intervals for three days using the xCELLigence system. The IC50 dose of metformin in the PC-3 cells was found to be 5 mM. RNA samples were used for analysis using custom multi-species microarrays containing 1209 probes covering 1221 human mature microRNAs present in miRBase 16.0 database.
RESULTS: Among the human miRNAs investigated by the arrays, 10 miRNAs were up-regulated and 12 miRNAs were down-regulated in the metformin-treated group as compared to the control group. In conclusion, expression changes in miRNAs of miR-146a, miR-100, miR-425, miR-193a-3p and, miR-106b in metformin-treated cells may be important. This study may emphasize a new role of metformin on the regulation of miRNAs in prostate cancer.

Fu HL, Wu de P, Wang XF, et al.
Altered miRNA expression is associated with differentiation, invasion, and metastasis of esophageal squamous cell carcinoma (ESCC) in patients from Huaian, China.
Cell Biochem Biophys. 2013; 67(2):657-68 [PubMed] Related Publications
Esophageal squamous cell carcinoma (ESCC) is the leading malignancy in Huaian, China. Recently, emerging studies have suggested that an aberrant microRNA (miRNA) expression signature exists in ESCC. However, there is discordant information available on specific miRNA expression in patients from different regions. In this study, we identified 12 miRNAs that are differentially expressed in patients with ESCC from Huaian, China. Among these miRNAs that displayed unique miRNA expression signatures, miR-1, miR-29c, miR-100, miR-133a, miR-133b, miR-143, miR-145, and miR-195 were downregulated, and miR-7, miR-21, miR-223, and miR-1246 were upregulated in cancerous tissue compared with the adjacent normal tissue. Bioinformatics analyses identified the major biological processes and signaling pathways that are targeted by these differentially expressed miRNAs. Accordingly, miR-29c, miR-100, miR-133a, and miR-133b were found to be involved in invasion and metastasis of ESCC, and miR-7 and miR-21 were found to be related to the differentiation of ESCC. Thus, our data present new evidence for the important roles of miRNAs in ESCC.

Giangreco AA, Vaishnav A, Wagner D, et al.
Tumor suppressor microRNAs, miR-100 and -125b, are regulated by 1,25-dihydroxyvitamin D in primary prostate cells and in patient tissue.
Cancer Prev Res (Phila). 2013; 6(5):483-94 [PubMed] Free Access to Full Article Related Publications
MiR-100 and miR-125b are lost in many cancers and have potential function as tumor suppressors. Using both primary prostatic epithelial cultures and laser capture-microdissected prostate epithelium from 45 patients enrolled in a vitamin D3 randomized trial, we identified miR-100 and -125b as targets of 1,25-dihydroxyvitamin D3 (1,25D). In patients, miR-100 and -125b levels were significantly lower in tumor tissue than in benign prostate. Similarly, miR-100 and -125b were lower in primary prostate cancer cells than in cells derived from benign prostate. Prostatic concentrations of 1,25D positively correlated with these miRNA levels in both prostate cancer and benign epithelium, showing that patients with prostate cancer may still benefit from vitamin D3. In cell assays, upregulation of these miRNAs by 1,25D was vitamin D receptor dependent. Transfection of pre-miR-100 and pre-miR-125b in the presence or absence of 1,25D decreased invasiveness of cancer cell, RWPE-2. Pre-miR-100 and pre-miR-125b decreased proliferation in primary cells and cancer cells respectively. Pre-miR-125b transfection suppressed migration and clonal growth of prostate cancer cells, whereas knockdown of miR-125b in normal cells increased migration indicates a tumor suppressor function. 1,25D suppressed expression of previously bona fide mRNA targets of these miRNAs, E2F3 and Plk1, in a miRNA-dependent manner. Together, these findings show that vitamin D3 supplementation augments tumor suppressive miRNAs in patient prostate tissue, providing evidence that miRNAs could be key physiologic mediators of vitamin D3 activity in prevention and early treatment of prostate cancer.

Luo D, Wilson JM, Harvel N, et al.
A systematic evaluation of miRNA:mRNA interactions involved in the migration and invasion of breast cancer cells.
J Transl Med. 2013; 11:57 [PubMed] Free Access to Full Article Related Publications
In this study we performed a systematic evaluation of functional miRNA-mRNA interactions associated with the invasiveness of breast cancer cells using a combination of integrated miRNA and mRNA expression profiling, bioinformatics prediction, and functional assays. Analysis of the miRNA expression identified 11 miRNAs that were differentially expressed, including 7 down-regulated (miR-200c, miR-205, miR-203, miR-141, miR-34a, miR-183, and miR-375) and 4 up-regulated miRNAs (miR-146a, miR-138, miR-125b1 and miR-100), in invasive cell lines when compared to normal and less invasive cell lines. Transfection of miR-200c, miR-205, and miR-375 mimics into MDA-MB-231 cells led to the inhibition of in vitro cell migration and invasion. The integrated analysis of miRNA and mRNA expression identified 35 known and novel target genes of miR-200c, miR-205, and mir-375, including CFL2, LAMC1, TIMP2, ZEB1, CDH11, PRKCA, PTPRJ, PTPRM, LDHB, and SEC23A. Surprisingly, the majority of these genes (27 genes) were target genes of miR-200c, suggesting that miR-200c plays a pivotal role in regulating the invasiveness of breast cancer cells. We characterized one of the target genes of miR-200c, CFL2, and demonstrated that CFL2 is overexpressed in aggressive breast cancer cell lines and can be significantly down-regulated by exogenous miR-200c. Tissue microarray analysis further revealed that CFL2 expression in primary breast cancer tissue correlated with tumor grade. The results obtained from this study may improve our understanding of the role of these candidate miRNAs and their target genes in relation to breast cancer invasiveness and ultimately lead to the identification of novel biomarkers associated with prognosis.

Arribas AJ, Gómez-Abad C, Sánchez-Beato M, et al.
Splenic marginal zone lymphoma: comprehensive analysis of gene expression and miRNA profiling.
Mod Pathol. 2013; 26(7):889-901 [PubMed] Related Publications
Splenic marginal zone lymphoma is a small B-cell neoplasm whose molecular pathogenesis is still essentially unknown and whose differentiation from other small B-cell lymphomas is hampered by the lack of specific markers. We have analyzed the gene expression and miRNA profiles of 31 splenic marginal zone lymphoma cases. For comparison, 7 spleens with reactive lymphoid hyperplasia, 10 spleens infiltrated by chronic lymphocytic leukemia, 12 spleens with follicular lymphoma, 6 spleens infiltrated by mantle cell lymphoma and 15 lymph nodes infiltrated by nodal marginal zone lymphoma were included. The results were validated by qRT-PCR in an independent series including 77 paraffin-embedded splenic marginal zone lymphomas. The splenic marginal zone lymphoma miRNA signature had deregulated expression of 51 miRNAs. The most highly overexpressed miRNAs were miR-155, miR-21, miR-34a, miR-193b and miR-100, while the most repressed miRNAs were miR-377, miR-27b, miR-145, miR-376a and miR-424. MiRNAs located in 14q32-31 were underexpressed in splenic marginal zone lymphoma compared with reactive lymphoid tissues and other B-cell lymphomas. Finally, the gene expression data were integrated with the miRNA profile to identify functional relationships between genes and deregulated miRNAs. Our study reveals miRNAs that are deregulated in splenic marginal zone lymphoma and identifies new candidate diagnostic molecules for splenic marginal zone lymphoma.

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