Research IndicatorsGraph generated 31 August 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (5)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
Numbers shown below represent number of publications held in OncomiRDB database for Oncogenic and Tumor-Suppressive MicroRNAs.
|Tissue||Target Gene(s)||Regulator(s)||MIR100 Function in Cancer||Effect|
|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)
-esophageal squamous cell carcinoma (1)
|MTOR (1)||induce apoptosis (1)||tumor-suppressive
-acute myeloid leukemia (1)
|CTDSPL (1)||promote cell proliferation (1)|
inhibit cell diferentiation (1)
regulate cell cycle G1/S transition (1)
regulate cell cycle S entry (1)
-prostate cancer (1)
|inhibit cell growth (1)||tumor-suppressive
-hepatocellular carcinoma (1)
|PLK1 (1)||inhibit cell growth (1)|
inhibit colony formation (1)
-bladder carcinoma (1)
|reduce cell proliferation (1)|
reduce colony formation (1)
-epithelial ovarian cancer (1)
|PLK1 (1)||inhibit cell growth (1)||tumor-suppressive
|ATM (1)||increase radiation sensitivity (1)|
-lung adenocarcinoma (1)
|PLK1 (1)||reduce docetaxel chemoresistance (1)|
inhibit cell proliferation (1)
induce cell cycle G2/M arrest (1)
induce apoptosis (1)
|adrenal gland (1)|
-childhood adrenocortical tumor (1)
Source: OncomiRDB Wang D. et al. Bioinformatics 2014, 30(15):2237-2238.
miRBase, University of Manchester
Annotated database entry including the location and sequence of the mature miRNA sequence.
miRCancer, East Carolina University
Search miRCancer for miR-100 associations with cancer and associated genes.
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: MIR100 (cancer-related)
Chen L, Liu S, Li K, et al.Evaluation of microRNA expression profiling in highly metastatic laryngocarcinoma cells.
Acta Otolaryngol. 2018; 138(12):1105-1111 [PubMed
] Related Publications
BACKGROUND: Until now, little is known about the role of miRNAs in the invasion and metastasis of Laryngeal squamous cell carcinoma (LSCC).
OBJECTIVES: This study aimed to explore the relationship between microRNA and the invasion and metastasis of LSCC.
MATERIAL AND METHODS: The highly metastatic laryngocarcinoma cells were obtained from the established animal model with spontaneous lymph node metastasis of LSCC in our previous study. MicroRNA expression profiling and bioinformatic analysis were performed to analyze the microRNA expression changes in the highly metastatic laryngocarcinoma cells and the parental tumor cells (HEP-2). RT-PCR was performed for further validation of the result of microarray.
RESULTS: A total of 40 microRNAs were found to be significantly altered in the highly metastatic laryngocarcinoma cells compared to controls. Bioinformatic analysis identified that 19 key microRNAs might involve in LSCC development. Moreover, RT-PCR confirmed that miR-25, miR-100, miR-125b-5p and let-7g were differentially expressed in different laryngocarcinoma cells and human tumor specimens.
CONCLUSIONS AND SIGNIFICANCE: Our findings suggest that microRNA play an important role in the invasion and metastasis of LSCC, and provide the clues for studying the function of microRNA as well as opportunities to analyze the complex molecular abnormalities driving LSCC progression.
Introduction and Objectives: MicroRNA (miRNA) expression is altered in urologic malignancies, including urothelial carcinoma of the bladder (UCB). Individual miRNAs have been shown to modulate multiple signaling pathways that contribute to BC. To identify a panel of miRNA signature that can predict aggressive phenotype from normal nonaggressive counterpart using miRNA expression levels and to assess the prognostic value of this specific miRNA markers in patients with UCB.
Methods: To determine candidate miRNAs as prognostic biomarkers for dividing aggressive type of UCB, miRNA expression was profiled in patients' samples with an aggressive phenotype or nonaggressive phenotype using 3D-Gene miRNA labeling kit (Toray, Japan). To create a prognostic index model, we used the panel of 9-miRNA signature based on Cancer Genome Atlas (TCGA) data portal (TCGA Data Portal (https://tcgadata.nci.nih.gov/tcga/tcgaHome2.jsp)). miRNA expression data and corresponding clinical data, including outcome and staging information of 84 UCB patients, were obtained. The Kaplan-Meier and log-rank test were performed to quantify the survival functions in two groups.
Results: Deregulation of nine miRNAs (hsa-miR-99a-5p, hsa-miR-100-5p, hsa-miR-125b-5p, hsa-miR-145-5p, hsa-miR-4324, hsa-miR-34b-5p, hsa-miR-29c-3p, hsa-miR-135a-3p, and hsa-miR-33b-3p) was determined in UCB patients with aggressive phenotype compared with nonaggressive subject. To validate the prognostic power of the nine-signature miRNAs using the TCGA dataset of bladder cancer, the survival status and tumor miRNA expression of all 84 TCGA UCB patients were ranked according to the prognostic score values. Of nine miRNAs, six were associated with high risk (hsa-miR-99a-5p, hsa-miR-100-5p, hsa-miR-125b-5p, hsa-miR-4324, hsa-miR-34b-5p, and hsa-miR-135a-3p) and three were shown to be protective (hsa-miR-145-5p, hsa-miR-29c-3p, and hsa-miR-33b-3p). Patients with the high-risk miRNA signature exhibited poorer OS than patients expressing the low-risk miRNA profile (HR = 7.05,
Conclusions: The miRNA array identified nine dysregulated miRNAs from clinical samples. This panel of nine-miRNA signature provides predictive and prognostic value of patients with UCB.
Wu G, Zhou W, Pan X, et al.miR-100 Reverses Cisplatin Resistance in Breast Cancer by Suppressing HAX-1.
Cell Physiol Biochem. 2018; 47(5):2077-2087 [PubMed
] Related Publications
BACKGROUND/AIMS: Breast cancer (BC) is the most common cancer in women worldwide. Despite great advancements in cancer therapy in recent years, surgery and chemotherapy are still the mainstays of BC treatment. However, cancer cells usually develop mechanisms to evade cell death induced by chemotherapy. Thus, strategies are needed to reverse the chemoresistance of cancer cells.
METHODS: We established cisplatin-resistant BC models in MDA-MB-231 and MCF-7 BC cell lines through long-term exposure to cisplatin. Quantitative reverse transcription PCR was used to examine the expression of microRNA (miR)-100. MTT cell viability assays were performed to determine cell viability. Regulation of hematopoietic cell-specific protein 1-associated protein X-l (HAX-1) targeted by miR-100 was confirmed by western blotting and luciferase reporter assays. The mitochondrial membrane potential and apoptosis were measured by flow cytometry. Release of cytochrome c from the mitochondria into the cytoplasm, HAX-1 expression, and activation of caspase-9 and caspase-3 were detected by western blotting.
RESULTS: A clear decrease in miR-100 expression was observed in cisplatin-resistant MDA-MB-231 and MCF-7 cells (MDA-MB-231/R and MCF-7/R). Overexpression of miR-100 increased the sensitivity of MDA-MB-231/R and MCF-7/R cells to cisplatin treatment and promoted cisplatin-induced mitochondrial apoptosis by targeting HAX-1 gene.
CONCLUSIONS: MiR-100 targeted HAX-1 to increase the chemosensitivity of BC by mediating the mitochondrial apoptosis pathway.
TGF-β/Activin induces epithelial-to-mesenchymal transition and stemness in pancreatic ductal adenocarcinoma (PDAC). However, the microRNAs (miRNAs) regulated during this response have remained yet undetermined. Here, we show that TGF-β transcriptionally induces MIR100HG lncRNA, containing miR-100, miR-125b and let-7a in its intron, via SMAD2/3. Interestingly, we find that although the pro-tumourigenic miR-100 and miR-125b accordingly increase, the amount of anti-tumourigenic let-7a is unchanged, as TGF-β also induces LIN28B inhibiting its maturation. Notably, we demonstrate that inactivation of miR-125b or miR-100 affects the TGF-β-mediated response indicating that these miRNAs are important TGF-β effectors. We integrate AGO2-RIP-seq with RNA-seq to identify the global regulation exerted by these miRNAs in PDAC cells. Transcripts targeted by miR-125b and miR-100 significantly overlap and mainly inhibit p53 and cell-cell junctions' pathways. Together, we uncover that TGF-β induces an lncRNA, whose encoded miRNAs, miR-100, let-7a and miR-125b play opposing roles in controlling PDAC tumourigenesis.
MicroRNAs (miRNAs) are post-transcriptional gene regulators that play important roles in the control of cell fitness, differentiation, and development. The CRISPR-Cas9 gene-editing system is composed of the Cas9 nuclease in complex with a single guide RNA (sgRNA) and directs DNA cleavage at a predetermined site. Several CRISPR-Cas9 libraries have been constructed for genome-scale knockout screens of protein function; however, few libraries have included miRNA genes. Here we constructed a miRNA-focused CRISPR-Cas9 library that targets 1594 (85%) annotated human miRNA stem-loops. The sgRNAs in our LX-miR library are designed to have high on-target and low off-target activity, and each miRNA is targeted by four to five sgRNAs. We used this sgRNA library to screen for miRNAs that affect cell fitness of HeLa or NCI-N87 cells by monitoring the change in frequency of each sgRNA over time. By considering the expression in the tested cells and the dysregulation of the miRNAs in cancer specimens, we identified five HeLa pro-fitness and cervical cancer up-regulated miRNAs (miR-31-5p, miR-92b-3p, miR-146b-5p, miR-151a-3p, and miR-194-5p). Similarly, we identified six NCI-N87 pro-fitness and gastric cancer up-regulated miRNAs (miR-95-3p, miR-181a-5p, miR-188-5p, miR-196b-5p, miR-584-5p, and miR-1304-3p), as well as three anti-fitness and down-regulated miRNAs (let-7a-3p, miR-100-5p, and miR-149-5p). Some of those miRNAs are known to be oncogenic or tumor-suppressive, but others are novel. Taken together, the LX-miR library is useful for genome-wide unbiased screening to identify miRNAs important for cellular fitness and likely to be useful for other functional screens.
Lundberg IV, Wikberg ML, Ljuslinder I, et al.MicroRNA Expression in
Anticancer Res. 2018; 38(2):677-683 [PubMed
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BACKGROUND/AIM: KRAS and BRAF are two genes commonly mutated in colorectal cancer (CRC). Even though BRAF is a downstream target of KRAS in the MAPK signalling pathway, KRAS- and BRAF-mutated CRCs are found to display several different clinical and histopathological features. We investigated whether a differential expression of microRNAs (miRNAs) could explain the clinicopathological differences seen between KRAS- and BRAF-mutated CRCs.
MATERIALS AND METHODS: Using a PCR array, we analyzed the expression of 84 different miRNAs in CRC cell lines wild-type in KRAS and BRAF, or mutated in KRAS or BRAF.
RESULTS: Ten miRNAs were selected for further analyses in tumor tissue specimens (let-7a, let-7i, miR-10a, miR-10b, miR-31, miR-100, miR-181a, miR-181b, miR-372, and miR-373). BRAF-mutated tumors were found to express significantly higher levels of miR-31 as well as significantly lower levels of miR-373, compared to wild-type tumors.
CONCLUSION: Our results suggest that KRAS- and BRAF-mutated CRCs may have different miRNA signatures compared to CRC tumors wild-type in KRAS and BRAF. However, no difference in expression levels between KRAS- and BRAF-mutated tumors was evident for the miRNAs analyzed in this study.
Chen JF, Wu P, Xia R, et al.STAT3-induced lncRNA HAGLROS overexpression contributes to the malignant progression of gastric cancer cells via mTOR signal-mediated inhibition of autophagy.
Mol Cancer. 2018; 17(1):6 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Long noncoding RNAs (lncRNAs) are an important class of functional regulators involved in human cancers development, including gastric cancer (GC). Studying aberrantly expressed lncRNAs may provide us with new insights into the occurrence and development of gastric cancer by acting as oncogenes or tumor suppressors. In this study, we aim to examine the expression pattern of lncRNA HAGLROS in GC and its clinical significance as well as its biological role in tumor progression.
METHODS: Bioinformatics analysis and qRT-PCR were performed to detect the relative expression of HAGLROS in GC tissues and cell lines. Gain or loss of function approaches were used to investigate the biological functions of HAGLROS. The effect of HAGLROS on proliferation was evaluated by MTT, colony formation assay and nude mouse xenograft model. Wound healing and Transwell assays were used to study the invasion and migration of GC cells. FISH, RIP, RNA-seq, Luciferase report assays, RNA pulldown and Western blot were fulfilled to measure molecular mechanisms. Results are shown as means ± S.D. and differences were tested for significance using Student's t-test (two-tailed).
RESULTS: We screened out HAGLROS, whose expression was significantly increased and correlated with outcomes of GC patients by publicly available lncRNAs expression profiling and integrating analyses. Exogenous down-regulation of HAGLROS expression significantly suppressed the cell proliferation, invasion and migration. Mechanistic investigations showed that HAGLROS was a direct target of transcriptional factor STAT3. Moreover, HAGLROS knockdown decreased mTOR expression and increased autophagy-related genes ATG9A and ATG9B expression. Further investigation showed that HAGLROS regulated mTOR signals in two manners. In the one hand, HAGLROS competitively sponged miR-100-5p to increase mTOR expression by antagonizing miR-100-5p-mediated mTOR mRNA inhibition. On the other hand, HAGLROS interacted with mTORC1 components to activate mTORC1 signaling pathway which was known to be an important negative signal of autophagy. Here activation of mTORC1 signaling pathway by HAGLROS inhibited autophagy, thereby promoted excessive proliferation and maintained the malignant phenotype of GC cells.
CONCLUSION: The present study demonstrates that HAGLROS overexpression contributes to GC development and poor prognosis and will be a target for GC therapy and further develop as a potential prognostic biomarker.
Danesh H, Hashemi M, Bizhani F, et al.Association study of miR-100, miR-124-1, miR-218-2, miR-301b, miR-605, and miR-4293 polymorphisms and the risk of breast cancer in a sample of Iranian population.
Gene. 2018; 647:73-78 [PubMed
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MicroRNAs (miRNAs) regulate genes expression by directly binding to the 3' untranslated region (3'UTR) of specific target mRNAs. Single nucleotide polymorphisms (SNPs) in microRNAs (miRNAs) are proposed to be important in the development of breast cancer (BC). In the present study, we conducted a case-control study with 266 BCE patients and 288 control women to examine the possible association of miRNAs polymorphisms (miR-100 rs1834306, miR-124-1 rs531564, miR-218-2 rs11134527, miR-301b rs384262, miR-605 rs2043556, and miR-4293 rs12220909) with BC susceptibility. Genotyping was done by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The findings showed miR-218-2 rs11134527 variant increased the risk of BC (OR = 7.70, 95%CI = 3.84-15.43, P < .0001, GA vs GG and OR = 6.86, 95%CI = 3.47-13.57, P < .0001, A vs G). Regarding miR-301b rs384262 polymorphism, we observed that this variant significantly increased the risk of BC (OR = 3.12, 95%CI = 2.20-4.45, P < .0001, AG vs AA and OR = 2.22, 95%CI = 1.68-2.93, P < .0001, G vs A). Our findings did not support an association between miR-100 rs1834306, miR-124-1 rs531564, miR-605 rs2043556 and miR-4293 rs12220909 polymorphism and the risk of BC. In conclusion, the finding showed that miR-218-2 rs11134527 and miR-301b rs384262 variant might contribute to increase the risk of BC in a sample of Iranian population. Additional studies with larger sample sizes and different ethnicities are necessary to confirm our finding.
Patients with clear cell renal cell carcinoma (ccRCC) are often diagnosed with both von Hippel-Lindau (VHL) mutations and the constitutive activation of hypoxia-inducible factor-dependent signaling. In this study, we investigated the effects of long-term hypoxia in 786-O, a VHL-defective renal cell carcinoma cell line, to identify potential genes and microRNAs associated with tumor malignancy. The transcriptomic profiles of 786-O under normoxia, short-term hypoxia and long-term hypoxia were analyzed using next-generation sequencing. The results showed that long-term hypoxia promoted the ability of colony formation and transwell migration compared to normoxia. In addition, the differentially expressed genes induced by long-term hypoxia were involved in various biological processes including cell proliferation, the tumor necrosis factor signaling pathway, basal cell carcinoma and cancer pathways. The upregulated (
Shamsi R, Seifi-Alan M, Behmanesh A, et al.A bioinformatics approach for identification of miR-100 targets implicated in breast cancer.
Cell Mol Biol (Noisy-le-grand). 2017; 63(10):99-105 [PubMed
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MicroRNAs (miRNAs) are small endogenous non-coding RNAs with principal roles in regulation of protein expression via translation repression and mRNA degradation. Based on these roles they are implicated in tumourigenesis processes as well. Among them is miR-100 which can exert both tumor suppressor and oncogenic functions in various cancer types. In breast cancer, it has been shown to affect apoptosis, epithelial-mesenchymal transition as well as tumor-related signaling pathways. In the present study, we introduce a novel approach for identification of miR-100 target genes which are possibly implicated in breast cancer pathogenesis. We applied 14 online tools for prediction of miR-100 target genes and used gene expression data produced by DNA microarray technology. By combining these two sets of data we proposed a list of miR-100 target genes with possible involvement in breast cancer. Considering the role of miR-100 as a context-dependent chief regulator of the cancer-related signaling pathways and a potential target for therapeutic modalities, identification of its targets would pave the way for designing new approaches for cancer treatment or sensitization of cancer cells to standard treatments.
Mizrahi A, Barzilai A, Gur-Wahnon D, et al.Alterations of microRNAs throughout the malignant evolution of cutaneous squamous cell carcinoma: the role of miR-497 in epithelial to mesenchymal transition of keratinocytes.
Oncogene. 2018; 37(2):218-230 [PubMed
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Skin carcinogenesis is known to be a multi-step process with several stages along its malignant evolution. We hypothesized that transformation of normal epidermis to cutaneous squamous cell carcinoma (cSCC) is causally linked to alterations in microRNAs (miRNA) expression. For this end we decided to evaluate their alterations in the pathologic states ending in cSCC. Total RNA was extracted from formalin fixed paraffin embedded biopsies of five stages along the malignant evolution of keratinocytes towards cSCC: Normal epidermis, solar elastosis, actinic keratosis KIN1-2, advanced actinic keratosis KIN3 and well-differentiated cSCC. Next-generation small RNA sequencing was performed. We found that 18 miRNAs are overexpressed and 28 miRNAs are underexpressed in cSCC compared to normal epidermis. miR-424, miR-320, miR-222 and miR-15a showed the highest fold change among the overexpressed miRNAs. And miR-100, miR-101 and miR-497 showed the highest fold change among the underexpressed miRNAs. Heat map of hierarchical clustering analysis of significantly changed miRNAs and principle component analysis disclosed that the most prominent change in miRNAs expression occurred in the switch from 'early' stages; normal epidermis, solar elastosis and early actinic keratosis to the 'late' stages of epidermal carcinogenesis; late actinic keratosis and cSCC. We found several miRNAs with 'stage specific' alterations while others display a clear 'gradual', either progressive increase or decrease in expression along the malignant evolution of keratinocytes. The observed alterations focused in miRNAs involved in the regulation of AKT/mTOR or in those involved in epithelial to mesenchymal transition. We chose to concentrate on the evaluation of the molecular role of miR-497. We found that it induces reversion of epithelial to mesenchymal transition. We proved that SERPINE-1 is its biochemical target. The present study allows us to further study the pathways that are regulated by miRNAs along the malignant evolution of keratinocytes towards cSCC.
To improve the clinical decision-making regarding further treatment management and follow-up scheduling for patients with muscle-invasive bladder cancer (MIBC) after radical cystectomy (RC), a better prediction accuracy of prognosis for these patients is urgently needed. The objective of this study was to evaluate the validity of differentially expressed microRNAs (miRNAs) based on a previous study as prognostic markers for overall survival (OS) after RC in models combined with clinicopathological data. The expression of six miRNAs (miR-100-5p, miR-130b-3p, miR-141-3p, miR-199a-3p, miR-205-5p, and miR-214-3p) was measured by RT-qPCR in formalin-fixed, paraffin-embedded tissue samples from 156 MIBC patients who received RC in three urological centers. Samples from 2000 to 2013 were used according to their tissue availability, with follow-up until June 2016. The patient cohort was randomly divided into a training (n = 100) and test set (n = 56). Seventy-three samples from adjacent normal tissue were used as controls. Kaplan-Meier, univariate and multivariate Cox regression, and decision curve analyses were carried out to assess the association of clinicopathological variables and miRNAs to OS. Both increased (miR-130b-3p and miR-141-3p) and reduced (miR-100-5p, miR-199a-3p, and miR-214-3p) miRNA expressions were found in MIBC samples in comparison to nonmalignant tissue samples (P < 0.0001). miR-199a-3p and miR-214-3p were independent markers of OS in Cox regression models with the significant clinicopathological variables age, tumor status, and lymph node status. The prediction model with the clinicopathological variables was improved by these two miRNAs in both sets. The predictive benefit was confirmed by decision curve analysis. In conclusion, the inclusion of both miRNAs into models based on clinical data for the outcome prediction of MIBC patients after RC could be a valuable approach to improve prognostic accuracy.
Eguía-Aguilar P, Gutiérrez-Castillo L, Pérezpeña-Díazconti M, et al.Expression of microRNAs in tumors of the central nervous system in pediatric patients in México.
Childs Nerv Syst. 2017; 33(12):2117-2128 [PubMed
] Related Publications
PURPOSE: MicroRNAs were identified as molecules that participate in gene regulation; alterations in their expression characterize central nervous system (CNS). Information in pediatrics is scarce, so the objective of this work was to determine and then compare the patterns of expression of microRNAs in astrocytomas, ependymomas, and medulloblastomas, as well as in non-neoplastic brain.
METHODS: Low-density arrays were utilized to evaluate 756 microRNAs in three samples of each type of tumor and non-neoplastic brain. The relative expression was calculated in order to identify the three microRNAs whose expression was modified notably. This was verified using RT-qPCR in more number of tumor samples.
RESULTS: The microRNAs selected for testing were miR-100-5p, miR-195-5p, and miR-770-5p. A higher expression of miR-100-5p was observed in the astrocytomas and ependymomas compared to the medulloblastomas: on average 3.8 times (p < 0.05). MiR-770-5p was expressed less in medulloblastomas compared to astrocytomas four times (p = 0.0162). MiR-195-5p had a low expression in medulloblastomas compared to non-neoplastic cerebellum (p = 0.049). In all three tumor types, expression of miR-770-5p was lower than in non-neoplastic brain (p < 0.001).
CONCLUSIONS: These microRNAs may represent potential markers in these tumors.
Chen P, Lin C, Quan J, et al.Oncogenic miR-100-5p is associated with cellular viability, migration and apoptosis in renal cell carcinoma.
Mol Med Rep. 2017; 16(4):5023-5030 [PubMed
] Related Publications
As influencing factors of genesis and progression in several types of human tumor, microRNAs (miRs) serves roles in the regulation of tumor cell viability, migration, and apoptosis. The present research aimed to investigate the association between the function of miR‑100‑5p and renal cell carcinoma (RCC). miR‑100‑5p expression was determined in RCC tissue and paired normal tissue samples using reverse transcription‑quantitative polymerase chain reaction. To assess the effects of miR‑100‑5p on cell viability, migration and apoptosis, multiple methods were used, including scratch wound assays, MTT assays, and flow cytometry. It was demonstrated that miR‑100‑5p was significantly upregulated in RCC tissue compared with in normal adjacent tissue samples. Furthermore, the viability and migration of 786‑O and, ACHN cells tranfected with miR‑100‑5p was significantly increased compared with the negative control group. In addition, miR‑100‑5p‑transfected 786‑O and ACHN cells demonstrated significantly reduced cellular apoptotic rates compared with the negative control group. To the best of our knowledge, the present study is the first to report an association between miR‑100‑5p and RCC. The results of the current study suggest that tumor oncogene miR‑100‑5p could be used as a diagnostic biomarker for RCC.
MicroRNAs (miRNAs) are crucial regulators of gene expression in tumorigenesis and are of great interest to researchers, but miRNA profiles are often inconsistent between studies. The aim of this study was to confirm candidate miRNA biomarkers for esophageal cancer from integrated-miRNA expression profiling data and TCGA (The Cancer Genome Atlas) data in tissues. Here, we identify five significant miRNAs by a comprehensive analysis in esophageal cancer, and two of them (hsa-miR-100-5p and hsa-miR-133b) show better prognoses with significant difference for both 3-year and 5-year survival. Additionally, they participate in esophageal cancer occurrence and development according to KEGG and Panther enrichment analyses. Therefore, these five miRNAs may serve as miRNA biomarkers in esophageal cancer. Analysis of differential expression for target genes of these miRNAs may also provide new therapeutic alternatives in esophageal cancer.
Carcinoma of the prostate is the most common cancer in men. Treatment of aggressive prostate cancer involves a regiment of radical prostectomy, radiation therapy, chemotherapy and hormonal therapy. Despite significant improvements in the last decade, the treatment of prostate cancer remains unsatisfactory, because a significant fraction of prostate cancers develop resistance to multiple treatments and become incurable. This prompts an urgent need to investigate the molecular mechanisms underlying the evolution of therapy-induced resistance of prostate cancer either in the form of castration-resistant prostate cancer (CRPC) or transdifferentiated neuroendocrine prostate cancer (NEPC). By analyzing micro-RNA expression profiles in a set of patient-derived prostate cancer xenograft tumor lines, we identified miR-100-5p as one of the key molecular components in the initiation and evolution of androgen ablation therapy resistance in prostate cancer. In vitro results showed that miR-100-5p is required for hormone-independent survival and proliferation of prostate cancer cells post androgen ablation. In Silico target predictions revealed that miR-100-5p target genes are involved in key aspects of cancer progression, and are associated with clinical outcome. Our results suggest that mir-100-5p is a possible therapeutic target involved in prostate cancer progression and relapse post androgen ablation therapy.
Qin X, Yu S, Zhou L, et al.Cisplatin-resistant lung cancer cell-derived exosomes increase cisplatin resistance of recipient cells in exosomal miR-100-5p-dependent manner.
Int J Nanomedicine. 2017; 12:3721-3733 [PubMed
] Free Access to Full Article Related Publications
Exosomes derived from lung cancer cells confer cisplatin (DDP) resistance to other cancer cells. However, the underlying mechanism is still unknown. A549 resistance to DDP (A549/DDP) was established. Microarray was used to analyze microRNA (miRNA) expression profiles of A549 cells, A549/DDP cells, A549 exosomes, and A549/DDP exosomes. There was a strong correlation of miRNA profiles between exosomes and their maternal cells. A total of 11 miRNAs were significantly upregulated both in A549/DDP cells compared with A549 cells and in exosomes derived from A549/DDP cells in contrast to exosomes from A549 cells. A total of 31 downregulated miRNAs were also observed. miR-100-5p was the most prominent decreased miRNA in DDP-resistant exosomes compared with the corresponding sensitive ones. Downregulated miR-100-5p was proved to be involved in DDP resistance in A549 cells, and mammalian target of rapamycin (mTOR) expression was reverse regulated by miR-100-5p. Exosomes confer recipient cells' resistance to DDP in an exosomal miR-100-5p-dependent manner with mTOR as its potential target both in vitro and in vivo. Exosomes from DDP-resistant lung cancer cells A549 can alter other lung cancer cells' sensitivity to DDP in exosomal miR-100-5p-dependent manner. Our study provides new insights into the molecular mechanism of DDP resistance in lung cancer.
Osteosarcoma (OS) is a prevalent cancer worldwide. MicroRNAs (miRNAs) play critical roles in the growth, invasion and carcinogenesis of OS, whereas the underlying mechanisms remain ill-defined. Here, we addressed these questions. We detected significantly higher levels of ZNRF2, a ubiquitin ligase of the RING superfamily, and significantly lower levels of miR-100 in the OS specimens, compared to the paired normal bone tissues. The levels of ZNRF2 and miR-100 inversely correlated in the OS specimens. In addition, low miR-100 levels are associated with poor prognosis of the OS patients. Either ZNRF2 overexpression or miR-100 depletion increased in vitro OS cell growth and improved cell survival at the presence of Doxorubicin. Mechanistically, with the help of bioinformatics analysis and luciferase-reporter assay, we found that miR-100 might bind to the 3'-UTR of ZNRF2 mRNA to prevent its protein translation. Thus, our data suggest that re-expression of miR-100 may inhibit OS cell growth and decrease OS cell chemo-resistance.
Pezuk JA, Brassesco MS, de Oliveira RS, et al.PLK1-associated microRNAs are correlated with pediatric medulloblastoma prognosis.
Childs Nerv Syst. 2017; 33(4):609-615 [PubMed
] Related Publications
PURPOSE: Medulloblastoma (MB) is the most common malignant tumor of the central nervous system (CNS) in children. Despite its relative good survival rates, treatment can cause long time sequels and may impair patients' lifespan and quality, making the search for new treatment options still necessary. Polo like kinases (PLKs) constitute a five-member serine/threonine kinases family (PLK 1-5) that regulates different stages during cell cycle. Abnormal PLKs expression has been observed in several cancer types, including MB. As gene regulators, miRNAs have also been described with variable expression in cancer.
METHODS: We evaluated gene expression profiles of all PLK family members and related miRNAs (miR-100, miR-126, miR-219, and miR-593*) in MB cell lines and tumor samples.
RESULTS: RT-qPCR analysis revealed increased levels of PLK1-4 in all cell lines and in most MB samples, while PLK5 was found underexpressed. In parallel, miR-100 was also found upregulated while miR-129, miR-216, and miR-593* were decreased in MB cell lines. Variable miRNAs expression patterns were observed in MB samples. However, a correlation between miR-100 and PLK4 expression was observed, and associations between miR-100, miR-126, and miR-219 expression and overall and event free survival were also evinced in our cohort. Moreover, despite the lack of association with clinico-pathological features, when comparing primary tumors to those relapsed, we found a consistent decrease on PLK2, miR-219, and miR-598* and an increase on miR-100 and miR-126.
CONCLUSION: Specific dysregulation on PLKs and associated miRNAs may be important in MB and can be used to predict prognosis. Although miRNAs sequences are fundamental to predict its target, the cell type may also be consider once that mRNA repertoire can define different roles for specific miRNA in a given cell.
In precision cancer nanomedicine, the key is to identify the oncogenes that are responsible for tumorigenesis, based on which these genetic drivers can be each specifically regulated by a nanovector-directed, oncogene-targeted microRNA (miRNA) for tumor suppression. Fibroblast Growth Factor Receptor 3 (FGFR3) is such an oncogene. The molecular tumor-subtype harboring FGFR3 genomic alteration has been identified via genomic sequencing and referred to as the FGFR3-driven tumors. This genomics-based tumor classification provides further rationale for the development of the FGFR3-targeted miRNA replacement therapy in treating patients with FGFR3 gene abnormity. However, successful miRNA therapy has been hampered by lacking of an efficient delivery vehicle. In this study, a nanovector is developed for microRNA-100 (miR-100) -mediated FGFR3 regulation. The nanovector is composed of the mesoporous magnetic clusters that are conjugated with ternary polymers for efficient miRNA
DE Oliveira DT, Savio AL, Marcondes JP, et al.Cytotoxic and toxicogenomic effects of silibinin in bladder cancer cells with different TP53 status.
J Biosci. 2017; 42(1):91-101 [PubMed
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Silibinin is a natural phenol found in the seeds of the milk thistle plant. Recent data have shown its effectiveness for preventing/treating bladder tumours. Therefore, in this study we investigated the cytotoxic and toxicogenetic activity of silibinin in bladder cancer cells with different TP53 statuses. Two bladder urothelial carcinoma cell lines were used: RT4 (wild-type TP53 gene) and T24 (mutated TP53 gene). Cell proliferation, clonogenic survival, apoptosis rates, genotoxicity and relative expression profile of FRAP/mTOR, FGFR3, AKT2 and DNMT1 genes and of miR100 and miR203 were evaluated. Silibinin promoted decreased proliferation and increased late apoptosis in TP53 mutated cells. Increased early apoptosis rates, primary DNA damage, and decrease of cell colonies in the clonogenic survival assay were detected in both RT4 and T24 cell lines. Down-regulation of FRAP/mTOR, AKT2, FGFR3, DNMT1 and miR100 expression occurred in RT4 cells. Modulation of miR203 was observed in both cell lines. In conclusion, despite the reduction of clone formation in both cell lines, the toxicogenomic effect of silibinin on FRAP/mTOR, AKT2, FGFR3, DNMT1 and miR100 was dependent on the TP53 status. Taken together, the data confirmed the role of silibinin as an antiproliferative compound, whose mechanism of action was related to the TP53 status.
The occurrence of lymph node metastases (LNM) after endoscopic submucosal dissection (ESD) in patients with gastric cancer (GC) leads to poor prognosis. However, few biomarkers are available to predict LNM in GC patients. Thus, we measured expression of 6 cancer-related miRNAs using real-time RT-PCR in 102 GC samples that were randomized into a training set and a testing set (each, 51 cases). Using logistic regression, we identified 4-miRNA (miR-27b, miR-128, miR-100 and miR-214) signatures for predicting LNM in GC patients. Patients with high-risk scores for the 4-miRNA signature tended to have higher LNM than those with low-risk scores. Meanwhile, the ROC curve of the 4-miRNA signature was better for predicting LNM in GC patients. In addition, Cox regression analysis indicated that a 2-miRNA signature (miR-27b and miR-214) or a miR-214/N stage signature was predictive of survival for GC patients. This work describes a previously unrecognized 4-miRNA signature involved in LNM and a 2-miRNA signature or miR-214/N stage signature related to GC patients' survival.
Rokavec M, Horst D, Hermeking HCellular Model of Colon Cancer Progression Reveals Signatures of mRNAs, miRNA, lncRNAs, and Epigenetic Modifications Associated with Metastasis.
Cancer Res. 2017; 77(8):1854-1867 [PubMed
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Here, we developed and comprehensively characterized a cellular model of colon cancer progression consisting of four defined derivatives of a colon cancer cell line that resulted from consecutive epithelial-mesenchymal and mesenchymal-epithelial transitions (EMT/MET) and phenotypically recapitulate the metastatic cascade. Initial EMT was induced by prolonged exposure to IL6, a cytokine also generated by the tumor-stroma. Genome-wide characterization of transcriptional (mRNA, miRNA, and lncRNA) and epigenetic (DNA methylation, H3K4me3, H3K79me3, and H3K27me3 histone modifications) profiles of the cell derivatives, combined with correlative analyses of expression, methylation, and clinical data from the TCGA-COAD database gave insights into the molecular basis of their phenotypic changes. The signatures characterizing invasive, mesenchymal-like cell states as well as the metastases-derived epithelial-like state showed significant association with metastasis, positive nodal status, and poor survival of colon cancer patients. Global hypomethylation of gene-regulatory regions was observed during tumor progression, with the lowest degree of methylation present in cells isolated from metastases. Upregulation of an axon-guidance-related gene signature was the most significant feature of metastatic tumor cells and was also found in primary tumors from colon cancer patients with distant metastases. Furthermore, the microRNAs miR-99a, miR-100, and miR-125b showed elevated expression in mesenchymal-like cells, associated with poor survival, and promoted migration and invasion. Finally, elevated expression of
Fujino Y, Takeishi S, Nishida K, et al.Downregulation of microRNA-100/microRNA-125b is associated with lymph node metastasis in early colorectal cancer with submucosal invasion.
Cancer Sci. 2017; 108(3):390-397 [PubMed
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A majority of early colorectal cancers (CRCs) with submucosal invasion undergo surgical operation, despite a very low incidence of lymph node metastasis. Our study aimed to identify microRNAs (miRNAs) specifically responsible for lymph node metastasis in submucosal CRCs. MicroRNA microarray analysis revealed that miR-100 and miR-125b expression levels were significantly lower in CRC tissues with lymph node metastases than in those without metastases. These results were validated by quantitative real-time PCR in a larger set of clinical samples. The transfection of a miR-100 or miR-125b inhibitor into colon cancer HCT116 cells significantly increased cell invasion, migration, and MMP activity. Conversely, overexpression of miR-100 or miR-125b mimics significantly attenuated all these activities but did not affect cell growth. To identify target mRNAs, we undertook a gene expression array analysis of miR-100-silenced HCT116 cells as well as negative control cells. The Ingenuity Pathway Analysis, TargetScan software analyses, and subsequent verification of mRNA expression by real-time PCR identified mammalian target of rapamycin (mTOR) and insulin-like growth factor 1 receptor (IGF1R) as direct, and Fas and X-linked inhibitor-of-apoptosis protein (XIAP) as indirect candidate targets for miR-100 involved in lymph node metastasis. Knockdown of each gene by siRNA significantly reduced the invasiveness of HCT116 cells. These data clearly show that downregulation of miR-100 and miR-125b is closely associated with lymph node metastasis in submucosal CRC through enhancement of invasion, motility, and MMP activity. In particular, miR-100 may promote metastasis by upregulating mTOR, IGF1R, Fas, and XIAP as targets. Thus, miR-100 and miR-125b may be novel biomarkers for lymph node metastasis of early CRCs with submucosal invasion.
Zhou HC, Fang JH, Shang LR, et al.MicroRNAs miR-125b and miR-100 suppress metastasis of hepatocellular carcinoma by disrupting the formation of vessels that encapsulate tumour clusters.
J Pathol. 2016; 240(4):450-460 [PubMed
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We have previously shown that vessels that encapsulated tumour cluster (VETC), a prevalent vascular pattern in hepatocellular carcinoma (HCC), facilitates the entry of the whole tumour cluster into the bloodstream in an invasion-independent manner, and that angiopoietin 2 (Angpt2), the levels of which are increased in HCC cells, is essential for VETC formation. However, the mechanisms underlying VETC formation remains unclear. Herein, we characterized miR-125b and miR-100 as novel VETC suppressors by using human HCC specimens, and cell and animal models. We showed that reduced expression of either miR-125b or miR-100 in human HCC tissues was significantly associated with the presence of VETC, venous invasion of tumour cells, and the occurrence of endothelium-coated microemboli. To confirm the role of miR-125b and miR-100 in VETC formation and HCC metastasis, cell lines with stable miR-125b and miR-100 expression were established by using human VETC-2 cells and mouse Hepa1-6 cells, the hepatoma cells that developed xenografts with VETC patterns. Our results showed that expression of miR-125b or miR-100 in VETC-2 and Hepa1-6 cells dramatically reduced VETC formation in xenografts, and consequently inhibited in vivo metastasis, suggesting that miR-125b and miR-100 may attenuate metastasis by repressing VETC formation. Further investigation revealed that miR-125b directly suppressed the expression of Angpt2 by binding to its 3'-untranslated region, whereas miR-100 reduced the protein level of Angpt2 by targeting mechanistic target of rapamycin (MTOR) and blocking the MTOR-p70S6K signalling pathway. Moreover, the suppressive effect of miR-125b and miR-100 on VETC formation was abrogated by injecting Angpt2-expressing viruses into xenografts. Taken together, our findings imply that miR-125b and miR-100 negatively regulate Angpt2 expression through different mechanisms, in turn inhibit VETC formation, and consequently abrogate the VETC-dependent metastasis of hepatoma cells. This study uncovers new regulatory mechanisms of VETC formation, identifies novel functions of miR-125b and miR-100, and provides new targets for antimetastasis therapy of HCC. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Guo P, Xiong X, Zhang S, Peng DmiR-100 resensitizes resistant epithelial ovarian cancer to cisplatin.
Oncol Rep. 2016; 36(6):3552-3558 [PubMed
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Epithelial ovarian cancer (EOC) is one of the malignant tumors that seriously affects women's health and chemotherapy resistance is an important reason for the poor prognosis. The present study was conducted to investigate whether microRNA-100 (miR-100) can be used to modulate the tolerance to cisplatin in EOC. Expression of miR-100 was compared between ovarian cancer cells tolerant and not tolerant to cisplatin. Mimic and antisense were used to study the roles and related mechanisms of miR-100 in cisplatin sensitivity in EOC. The alternation in the cisplatin sensitivity was investigated using grafted tumors derived from SKOV3/DDP cells with upregulated or downregulated miR-100 expression. miR-100 was lower in cisplatin resistant cell line SKOV3/DDP than in cisplatin sensitive cell line SKOV3. miR-100 might increase cisplatin sensitivity by inhibiting cell proliferation and conversion from G1 to S phase and increasing apoptosis. We showed that mTOR and PLK1 are targets of miR-100 and the cells were resensitized probably due to targeted downregulation of mTOR and PLK1 by miR-100. In vivo study with nude mice showed that tumors derived from miR-100 mimic-transfected cells were more sensitive to cisplatin and had reduced expression of mTOR and PLK1. miR-100 resensitizes resistant epithelial ovarian cancer to cisplatin probably by inhibiting cell proliferation, inducing apoptosis and arresting cell cycle and by targeted downregulation of mTOR and PLK1 expression.
Aberrant miRNA expression has been reported in endometriosis and miRNA gene polymorphisms have been linked to cancer. Because certain ovarian cancers arise from endometriosis, we genotyped seven cancer-related miRNA single nucleotide polymorphisms (MiRSNPs) to investigate their possible roles in endometriosis. Genetic variants in MIR196A2 (rs11614913) and MIR100 (rs1834306) were found to be associated with endometriosis development and related clinical phenotypes, such as infertility and pain. Downstream analysis of the MIR196A2 risk allele revealed upregulation of rRNA editing and protein synthesis genes, suggesting hyper-activation of ribosome biogenesis as a driving force for endometriosis progression. Clinical studies confirmed higher levels of small nucleolar RNAs and ribosomal proteins in atypical endometriosis lesions, and this was more pronounced in the associated ovarian clear cell carcinomas. Treating ovarian clear cells with CX5461, an RNA polymerase I inhibitor, suppressed cell growth and mobility followed by cell cycle arrest at G2/M stage and apoptosis. Our study thus uncovered a novel tumorigenesis pathway triggered by the cancer-related MIR196A2 risk allele during endometriosis development and progression. We suggest that anti-RNA polymerase I therapy may be efficacious for treating endometriosis and associated malignancies.
Chen Z, Wu L, Lin Q, et al.Evaluation of miR-182/miR-100 Ratio for Diagnosis and Survival Prediction in Bladder Cancer.
Arch Iran Med. 2016; 19(9):645-51 [PubMed
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BACKGROUND: Abnormal expression of microRNAs (miRNAs) plays an important role in development of several cancer types, including bladder cancer (BCa). However, the relationship between the ratio of miR-181/miR-100 and the prognosis of BCa has not been studied yet. The aim of this study was to evaluate the expression of miR-182, miR-100 and their clinical significance in BCa.
METHODS: Upregulation of miR-182 and down-regulation of miR-100 were validated in tissue specimens of 134 BCa cases compared with 148 normal bladder epithelia (NBE) specimens using TaqMan-based real-time reverse transcription quantitative PCR (RT-qPCR). The diagnostic and prognostic evaluation of miR-182, miR-100, and miR-182/miR-100 ratio was also performed.
RESULTS: miR-182 was upregulated in BCa and miR-100 was down-regulated in BCa compared with NBE (P < 0.001). The areas under receiver operating characteristic curves (AUCs-ROC) for miR-182 and miR-100 were 0.913 and 0.810, respectively. However, miR-182/miR-100 ratio increased the diagnostic performance, yielding an AUC of 0.981 (97.01% sensitivity and 90.54% specificity). Moreover, miR-182/miR-100 ratio was associated with pT-stage, histological grade, BCa recurrence and carcinoma in situ (P < 0.05 for all). Multivariate Cox regression analysis indicated that miR-182/miR-100 ratio was an independent prognostic factor for overall survival (Hazard ratio: 7.142; 95% CI: 2.106 - 9.891; P < 0.01). Furthermore, Kaplan-Meier curve analysis revealed that high-level of miR-182/miR-100 ratio was significantly correlated with shortened survival time for BCa patients (P < 0.01).
CONCLUSION: The miR-182/miR-100 ratio may serve as a novel promising biomarker for diagnosis and survival prediction in BCa. Further studies are needed to elucidate the role of miR-182/miR-100 ratio as a non‑invasive diagnostic tool for BCa.
Amir S, Mabjeesh NJmicroRNA expression profiles as decision-making biomarkers in the management of bladder cancer.
Histol Histopathol. 2017; 32(2):107-119 [PubMed
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Bladder cancer (BC) is generally divided into non-muscle-invasive BC (NMIBC) and muscle-invasive BC (MIBC). The standard treatment protocol for MIBC patients is radical cystectomy preceded by neoadjuvant chemotherapy (NAC). About one-half of the MIBC patients show a priori resistance to chemotherapy, and are therefore exposed to the risks of disease progression and toxicity from ineffective NAC. The discovery of microRNA (miRNA) regulation in tumorigenesis has provided new directions for the development of a new type of BC biomarkers. In this review, we describe the emerging miRNAs as BC biomarkers for different purposes, including diagnosis, prognosis and therapeutic response. miRNA expression profile changes with alteration of the tissue phenotype. This phenomenon is utilized to predict tumor diagnosis, cancer subclass, disease stage, prognosis and therapeutic response. We classified the miRNAs which are involved in bladder cancer according to malignant potential, chemoresistance, discrimination between normal to cancerous and clinical outcome. Focusing on the major obstacle regarding MIBC patient's NAC response, we summarized the miRNAs that are deregulated and have the potential to identify the patients resistant to NAC, such as miR-34, miR-100, miR-146b and miR-9 and miR-193a-3p. In conclusion, miRNAs expression profile of bladder cancer patient is a promising tool that can serve as biomarker for different aims. Based on this profile we propose upfront radical cystectomy instead of standard NAC to those MIBC patients who are at higher risk for chemoresistance and poor response.
Rane JK, Erb HH, Nappo G, et al.Inhibition of the glucocorticoid receptor results in an enhanced miR-99a/100-mediated radiation response in stem-like cells from human prostate cancers.
Oncotarget. 2016; 7(32):51965-51980 [PubMed
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Radiation therapy is a major primary treatment option for both localized early stage prostate cancer, and for advanced, regionally un-resectable, cancer. However, around 30% of patients still experience biochemical recurrence after radiation therapy within 10 years. Thus, identification of better biomarkers and new targets are urgently required to improve current therapeutic strategies. The miR-99 family has been shown to play an important role in the regulation of the DNA damage response, via targeting of the SWI/SNF chromatin remodeling factors, SMARCA5 and SMARCD1 in cell line models. In the present study, we have demonstrated that low expression of miR-99a and miR-100 is present in cell populations which are relatively radiation insensitive, for example in prostate cancer stem cells and in castration-resistant prostate cancer. Additionally, treatment of cells with the synthetic glucocorticoid, Dexamethasone resulted in decreased miR-99a and 100 expression, suggesting a new mechanism of miR-99a and 100 regulation in androgen-independent prostate cells. Strikingly, treatment of prostate cells with the glucocorticoid receptor inhibitor, Mifepristone was found to sensitize prostate cells to radiation by increasing the levels of miR-99a and miR-100. These results qualify the miR99 family as markers of radiation sensitivity and as potential therapeutic targets to improve efficiency of radiotherapy.