Research IndicatorsGraph generated 29 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 29 August, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (7)
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)||MIRLET7C Function in Cancer||Effect|
-hepatocellular carcinoma (2)
-hepatocellular cancer stem cells (1)
|inhibit cell proliferation (1)|
induce cell cycle G1 arrest (1)
inhibit chemosensitivity (1)
promote sorafenib-induced apoptosis (1)
-prostate cancer (2)
|decrease cell proliferation (1)|
decrease clonogenicity (1)
decrease anchorage-independent cell growth (1)
inhibit cell proliferation (1)
inhibit AR signaling (1)
-acute myeloid leukemia (1)
|5088 (1)||promote granulocytic differentiation (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 let-7c 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: MIRLET7C (cancer-related)
Afshar E, Hashemi-Arabi M, Salami S, et al.Screening of acetaminophen-induced alterations in epithelial-to-mesenchymal transition-related expression of microRNAs in a model of stem-like triple-negative breast cancer cells: The possible functional impacts.
Gene. 2019; 702:46-55 [PubMed
] Related Publications
Current protocols for therapy inefficiently targets triple negative breast cancer and barely eradicate cancer stem cells. Elucidation of the pleiotropic effect of clinically proven therapeutics on cancer cells shed light on novel application of old friends. The pleiotropic effect of acetaminophen (APAP) on breast cancer was previously reported. In a cell model of triple negative breast cancer with stem-like CD44
Garcinol, a dietary factor obtained from
BACKGROUND: The Smad7 protein is negative regulator of the TGF-β signaling pathway, which is upregulated in patients with breast cancer. miRNAs regulate proteins expressions by arresting or degrading the mRNAs. The purpose of this work is to identify a miRNAs profile that regulates the expression of the mRNA coding for Smad7 in breast cancer using the data from patients with breast cancer obtained from the Cancer Genome Atlas Project.
METHODS: We develop an automatic search method based on genetic algorithms to find a predictive model based on deep neural networks (DNN) which fit the set of biological data and apply the Olden algorithm to identify the relative importance of each miRNAs.
RESULTS: A computational model of non-linear regression is shown, based on deep neural networks that predict the regulation given by the miRNA target transcripts mRNA coding for Smad7 protein in patients with breast cancer, with R
CONCLUSIONS: We developed a genetic algorithm to select best features as DNN inputs (miRNAs). The genetic algorithm also builds the best DNN architecture by optimizing the parameters. Although the confirmation of the results by laboratory experiments has not occurred, the results allow suggesting that miRNAs profile could be used as biomarkers or targets in targeted therapies.
Oztemur Islakoglu Y, Noyan S, Aydos A, Gur Dedeoglu BMeta-microRNA Biomarker Signatures to Classify Breast Cancer Subtypes.
OMICS. 2018; 22(11):709-716 [PubMed
] Related Publications
Breast cancer is one of the leading causes of morbidity and mortality that is in need of novel diagnostics and therapeutics. Meta-analysis of microarray data offers promise to combine studies and provide more robust results. We report here a molecular classification of pathological subtypes (estrogen receptor [ER], progesterone receptor [PR], and Human Epidermal Growth Factor Receptor 2 [HER2]) of breast cancers with microRNA (miRNA)-dependent signatures. A ranking-based meta-analysis approach was applied to eight independent microarray data sets and meta-miRNA lists were obtained that are specific to each breast cancer subtype. The comparison of the lists with miRCancer and the PhenomiR 2.0 databases pointed out nine prominent miRNAs: let-7b-5p, let-7c-5p, let-7e-5p, miR-130a-3p, miR-30a-5p, miR-92a-1-5p, miR-211-5p, miR-500a-3p, and miR-516b-3p. Further analysis conducted with the TCGA data showed that these miRNAs can differentiate tumors from normal samples as well as discriminate the molecular subtypes of breast cancer. According to the PAM50 classification, three of these miRNAs (let-7b-5p, let-7c-5p, and miR-30a-5p) downregulated significantly, whereas miR-130a-3p, miR-92a-1-5p, miR-211-5p, and miR-500a-3p upregulated in tumors from the luminal A to the basal-like subtypes. When the prominent meta-miRNAs and their targets were analyzed, they appeared to be taking part in important signaling pathways in cancer such as the PI3K-Akt signaling and the p53 signaling pathways. Furthermore, the regulatory genes, which are key players for ER, PR, and ErBb signaling pathways, were found to be under control of several meta-miRNAs. These meta-miRNAs and the genes they are regulating offer new promise for future translational research and potential targets for precision medicine diagnostics.
Wang M, Li Y, Xiao GD, et al.H19 regulation of oestrogen induction of symmetric division is achieved by antagonizing Let-7c in breast cancer stem-like cells.
Cell Prolif. 2019; 52(1):e12534 [PubMed
] Related Publications
OBJECTIVES: Breast cancer stem-like cells (BrCSCs) are the major reason for tumour generation, resistance and recurrence. The turbulence of their self-renewal ability could help to constrain the stem cell expansion. The way BrCSCs divided was related to their self-renewal capacity, and the symmetric division contributed to a higher ability. Non-coding long RNA of H19 was involved in multiple malignant procedures; the role and mechanistic proof of non-coding long RNA of H19 in controlling the divisions of BrCSCs were barely known.
MATERIALS AND METHODS: Indicative functions of H19 in preclinical study were analysed by using the TCGA data base. Division manners were defined by using fluorescence staining.
RESULTS: We identified the stimulation of H19 on symmetric division of BrCSCs, which subsequently resulted in self-renewing increasing. H19 inhibited the Let-7c availability by acting as its specific molecular sponge, and with Let-7c inhibition, oestrogen receptor activated Wnt signalling was unconstrained. Similarly, restoring Let-7c constrained oestrogen receptor activated Wnt factors, which sequentially inhibited the H19 decreasing of Let-7 bioavailability. Let-7c is reactivated in vitro where H19 was knockdown, and later inhibited the symmetric division of BrCSCs. Reciprocally, Wnt pathway activation leads to H19 increasing, which in turn decreased Let-7c bioavailability.
CONCLUSIONS: Our results revealed a previously undescribed double negative feedback loop between sponge H19 and targeted Let-7c through oestrogen activated Wnt signalling that dominated in stem cells' division.
Hofbauer SL, de Martino M, Lucca I, et al.A urinary microRNA (miR) signature for diagnosis of bladder cancer.
Urol Oncol. 2018; 36(12):531.e1-531.e8 [PubMed
] Related Publications
INTRODUCTION: Bladder cancer (BC) is diagnosed by cystoscopy, which is invasive, costly and causes considerable patient discomfort. MicroRNAs (miR) are dysregulated in BC and may serve as non-invasive urine markers for primary diagnostics and monitoring. The purpose of this study was to identify a urinary miR signature that predicts the presence of BC.
METHODS: For the detection of potential urinary miR markers, expression of 384 different miRs was analyzed in 16 urine samples from BC patients and controls using a Taqman™ Human MicroRNA Array (training set). The identified candidate gene signature was subsequently validated in an independent cohort of 202 urine samples of patients with BC and controls with microscopic hematuria. The final miR signature was developed from a multivariable logistic regression model.
RESULTS: Analysis of the training set identified 14 candidate miRs for further analysis within the validation set. Using backward stepwise elimination, we identified a subset of 6 miRs (let-7c, miR-135a, miR-135b, miR-148a, miR-204, miR-345) that distinguished BC from controls with an area under the curve of 88.3%. The signature was most accurate in diagnosing high-grade non-muscle invasive BC (area under the curve = 92.9%), but was capable to identify both low-grade and high-grade disease as well as non-muscle and muscle-invasive BC with high accuracies.
CONCLUSIONS: We identified a 6-gene miR signature that can accurately predict the presence of BC from urine samples, independent of stage and grade. This signature represents a simple urine assay that may help reducing costs and morbidity associated with invasive diagnostics.
PURPOSE: To test whether a microRNA (miRNA) panel may serve as an alternative biomarker of fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor sensitivity in lung cancer.
METHODS: Histologically diverse lung cancer cell lines were submitted to assays for ponatinib and AZD4547 sensitivity. miRNAs, FGFR1 messenger RNA, gene copy number, and protein expression were detected by real-time quantitative PCR, fluorescence in-situ hybridization, and immunoblotting in 34 lung cancer cell lines.
RESULTS: Among 34 cell lines, 14 exhibited ponatinib sensitivity and 20 exhibited AZD4547 sensitivity (drug concentration causing 50% inhibition values < 100 nmol/L). A total of 39 of the 377-miRNA set were initially identified from the 4 paired ponatinib-sensitive or -insensitive cell lines to have at least an 8-fold differential expression and then were detected in all the 34 cell lines. A predictive panel of 3 miRNAs (let-7c, miRNA155, and miRNA218) was developed that had an area under the curve (AUC) of 0.886 with a sensitivity of 71.4% and specificity of 77.3% to predict response to ponatinib. The miRNA panel performed similar to FGFR1 protein expression (AUC = 0.864) and messenger RNA expression (AUC = 0.939), and better than FGFR1 amplification (AUC = 0.696). Furthermore, we validated this panel using data for sensitivity to AZD4547 in the cell line cohort with an AUC of 0.931 and a sensitivity of 73.3% and specificity of 76.2%, respectively.
CONCLUSION: The developed miRNA panel (let-7c, miRNA155, and miRNA218) may be useful in predicting response to FGFR tyrosine kinase inhibitors, either ponatinib or AZD4547 in lung cancer cell lines, and warrants further validation in the clinical setting.
Peptidylarginine deiminase (PAD) enzymes convert histone arginine residues into citrulline to modulate chromatin organization and gene expression. Although PADs are expressed in anterior pituitary gland cells, their functional role and expression in pituitary adenomas are unknown. To begin to address these issues, we first examined normal human pituitaries and pituitary adenomas and found that PAD2, PAD4, and citrullinated histones are highest in prolactinomas and somatoprolactinomas. In the somatoprolactinoma-derived GH3 cell line, PADs citrullinate histone H3, which is attenuated by a pan-PAD inhibitor. RNA sequencing and chromatin immunoprecipitation (ChIP) studies show that the expression of microRNAs (miRNAs) let-7c-2, 23b, and 29c is suppressed by histone citrullination. Our studies demonstrate that these miRNAs directly target the mRNA of the oncogenes encoding HMGA, insulin-like growth factor 1 (IGF-1), and N-MYC, which are highly implicated in human prolactinoma/somatoprolactinoma pathogenesis. Our results are the first to define a direct role for PAD-catalyzed histone citrullination in miRNA expression, which may underlie the etiology of prolactinoma and somatoprolactinoma tumors through regulation of oncogene expression.
Marchesi F, Regazzo G, Palombi F, et al.Serum miR-22 as potential non-invasive predictor of poor clinical outcome in newly diagnosed, uniformly treated patients with diffuse large B-cell lymphoma: an explorative pilot study.
J Exp Clin Cancer Res. 2018; 37(1):95 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of tumors, with aggressive clinical course that renders prognostication and choice of treatment strategy difficult. Chemo-immunotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) is the current first-line treatment. MicroRNAs (miRNAs) are under investigation as novel diagnostic and prognostic biomarkers in several malignancies, including malignant lymphomas. While tissue miRNAs in DLBCL patients have been extensively studied as biomarkers, only few reports to date have evaluated the role of circulating/serum miRNAs as potential prognostic factors. Here circulating/serum miRNAs, including miR-22, were investigated as potential non-invasive biomarkers, with the aim of a better prognostic stratification of DLBCL patients.
METHODS: MiRNAs were selected by global expression profile of serum miRNAs of DLBCL patients, The Cancer Genome Atlas (TCGA) analysis and literature research. Serum and tissues miRNA expression profile in de novo DLBCL patients, consecutively enrolled for this study, were detected by quantitative real-time polymerase chain reaction. Relative expression was calculated using the comparative Ct method. Statistical significance was determined using the Mann-Whitney rank sum and Fisher's exact test. Survival analysis was conducted through the use of Kaplan-Meier method. Spearman's Rho was applied to study the correlation between miRNA distributions and days to first relapse. Experimentally validated miRNA-target interactions were assessed by miRTarBase database. Negative miRNA-mRNA correlation was evaluated in TCGA DLBCL dataset. Pathway analysis was performed by the functional annotation clustering DAVID tool.
RESULTS: We showed a significant modulation of serum miR-22 after R-CHOP treatment compared with basal values but no difference between baseline serum miRNAs values of DLBCL patients and healthy controls. High expression level of serum miR-22 in DLBCL at diagnosis (n = 36) is associated with a worse PFS and is independent of the currently used clinical prognostic index. Integrative and pathways analysis of miR-22 identified target genes involved in different important pathways such as p53 signaling.
CONCLUSIONS: Our data suggest that miR-22 is of potential interest as non-invasive biomarker to predict clinical outcome in DLBCL patients. Characterization of miR-22 pathways can pave the way to the development of targeted therapy approaches for specific subgroups of DLBCL patients.
Peng CY, Wang TY, Lee SS, et al.Let-7c restores radiosensitivity and chemosensitivity and impairs stemness in oral cancer cells through inhibiting interleukin-8.
J Oral Pathol Med. 2018; 47(6):590-597 [PubMed
] Related Publications
BACKGROUND: The let-7 family of microRNAs has been considered as tumor suppressors in various cancers; however, the role of let-7c in oral squamous cell carcinoma has not been determined yet.
METHODS: In this study, phenotypical behaviors and the radio/chemoresistance were examined subsequent to overexpression of let-7c. In addition, the expression of let-7c in cancer stem cells (CSCs) was evaluated and the effect of let-7c on stemness characteristics was assessed. Also, luciferase activity assays were performed to test whether interleukin (IL)-8 was a putative target of let-7c.
RESULTS: Our results confirmed that the expression of let-7c in CSCs was reduced, while overexpression of let-7c attenuated the oncogenicity. Moreover, ectopic expression of let-7c in CSCs downregulated the stemness hallmarks and the radio/chemoresistance. Expression and secretion of IL-8 in oral CSCs were both reduced following overexpression of let-7c. Besides, the inhibitory effect of let-7c on various stemness phenotypes was reverted by IL-8, indicating that lower expression of let-7c may confer higher cancer stemness through a failure to downregulate IL-8.
CONCLUSION: These findings revealed the significance of let-7c in the contribution of oral cancer stemness and radio/chemoresistance. Targeting let-7c and its downstream IL-8 may be beneficial to prevent cancer recurrence and metastasis of oral squamous cell carcinoma.
Dysregulation of micro (mi)RNA-let-7 has been associated with the development and prognosis of multiple cancer types. Lin28, a RNA-binding protein, plays a conserved role in regulating the maturation of let-7 family proteins. However, few studies have focused on the effects of Lin28/let-7 on Wnt-activated esophageal squamous cell carcinoma (ESCC). Analysis of the expression of let-7a, let-7b and let-7c in clinical tissues revealed that lower let-7a expression was correlated with higher tumor node metastasis staging and recurrence in patients with ESCC. Furthermore, it was demonstrated that let-7a was inversely correlated with the migration and invasion of ESCC cells. In addition, epithelial-mesenchymal transition, and the expression of VEGF-C and MMP9 were effectively decreased by let-7a-mimic or siRNA-Lin28 pretreatment. Mechanistically, Lin28 functioned as the key factor in signal transduction, which regulated the expression of let-7a and the downstream genes along the Wnt signaling pathway. Taken together, these findings identified a biochemical and functional association between Lin28/let-7a, and the Wnt pathway in ESCC cells.
Colorectal cancer (CRC) remains a primary contributor to cancer‑associated mortality. The Lin28/let‑7 axis has previously been verified to participate in numerous pathophysiological processes involved in CRC. However, the potential roles and underlying mechanisms of this axis in apoptosis during CRC remain to be fully elucidated. The present study aimed to evaluate the role and reveal the molecular mechanisms of the Lin28/let‑7 axis in the apoptosis of CRC cells. An MTT assay was conducted to assess the cell viability of HCT116 and HT29 CRC cells, and caspase‑3 activity was analyzed to measure the apoptosis of CRC cells. Western blotting and reverse transcription‑quantitative polymerase chain reaction were performed to examine the expression of Lin28, B‑cell lymphoma 2 (Bcl‑2), Bcl‑2‑associated X protein, Bcl‑2‑like 1 (BCL2L1) and let‑7c. The present study demonstrated that Lin28 was upregulated whereas let‑7c was downregulated in CRC tissues and cell lines compared with normal tissues and NCM460 normal colon epithelial cells, respectively. Forced overexpression of let‑7c promoted apoptosis in CRC cells, which was at least partially mediated via the targeting of BCL2L1. Furthermore, knockdown of Lin28 decreased viability and promoted apoptosis in CRC cells, whereas this effect was attenuated by let‑7c inhibition. The findings of the present study suggest the involvement of the Lin28/let‑7c axis in apoptosis during CRC, and indicate the potential role of this pathway as a novel therapeutic target in CRC.
Background: Chronic lung diseases such as chronic obstructive pulmonary disease (COPD) and epigenetic events underlie lung cancer (LC) development. The study objective was that lung tumor expression levels of specific microRNAs and their downstream biomarkers may be differentially regulated in patients with and without COPD.
Methods: In lung specimens (tumor and non-tumor), microRNAs known to be involved in lung tumorigenesis (miR-21, miR-200b, miR-126, miR-451, miR-210, miR-let7c, miR-30a-30p, miR-155 and miR-let7a, qRT-PCR), DNA methylation, and downstream biomarkers were determined (qRT-PCR and immunoblotting) in 40 patients with LC (prospective study, subdivided into LC-COPD and LC,
Results: Expression of miR-21, miR-200b, miR-210, and miR-let7c and DNA methylation were greater in lung tumor specimens of LC-COPD than of LC patients. Expression of downstream markers
Conclusions: Biomarkers of mechanisms involved in tumor growth, angiogenesis, migration, and apoptosis were differentially expressed in tumors of patients with underlying respiratory disease. These findings shed light into the underlying biology of the reported greater risk to develop LC seen in patients with chronic respiratory conditions. The presence of an underlying respiratory disease should be identified in all patients with LC as the differential biological profile may help determine tumor progression and the therapeutic response. Additionally, epigenetic events offer a niche for pharmacological therapeutic targets.
Huang M, Gong XLet-7c Inhibits the Proliferation, Invasion, and Migration of Glioma Cells via Targeting E2F5.
Oncol Res. 2018; 26(7):1103-1111 [PubMed
] Related Publications
As a member of the miRNA family, let-7c has been identified as a tumor suppressor in many cancers. However, the molecular biological function of let-7c in glioma has not been elucidated. The aim of this study was to explore let-7c expression levels and evaluate its function in glioma cells. We first measured the expression of let-7c in four glioma cell lines and a normal cell line by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), and the results showed that let-7c was downregulated in glioma cells. By applying gain-of-function and loss-of-function assays, the experiments suggested that dysregulation of let-7c could obviously affect cell proliferation, metastasis, and invasion. Based on online bioinformatics analysis and Dual-Luciferase Reporter assays, we found that E2F5 was a target gene of let-7c and contributed to the function of let-7c in glioma cells. Our investigations indicated that loss of let-7c contributed to the progression of glioma cells.
Xu C, Xiao G, Zhang B, et al.CCAT1 stimulation of the symmetric division of NSCLC stem cells through activation of the Wnt signalling cascade.
Gene Ther. 2018; 25(1):4-12 [PubMed
] Related Publications
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortalities worldwide, yet this condition remains a poorly understood malignancy, and the subgroup of cancer stem cells (CSCs) leading to therapeutic resistance and adverse prognosis have not been well studied. CSCs frequently undergo symmetric division, which facilitates expansion of the stem cell pool, contributing to long-term relapse and therapy failure. CCAT1 could act as a miRNA sponge to influence downstream genes; however, its roles in NSCLC stem cell are unclear. We first identified activation of Wnt signalling in NSCLC. Analysis of the clinical data from a public database showed a significant decrease of the Wnt signalling repressor Let-7c. Using biological and informatics analyses, we hypothesized that CCAT1 stimulated the main factors of the Wnt signalling pathway, of which the three most deregulated genes were further confirmed by western blotting. Axitinib, a Wnt signalling inhibitor, effectively stimulated asymmetric division, similar to Let-7c. CCAT1 inhibition decreased the ratio of symmetric division of stem cells, and both Let-7c and Axitinib significantly abolished CCAT1 induction of symmetric division by inhibiting Wnt signalling. Restoration of Let-7c blocked the CCAT1 effects, forming the CCAT1/Let-7c/Wnt regulatory axis to control the division of lung cancer stem cells. Stimulation of stem cells to divide asymmetrically by delivering Let-7c or suppressive Axitinib could represent prospective strategies for curing lung cancer patients.
Let-7 microRNAs have been reported to have tumor suppressive functions; however, the effect of Let-7 when used in combination with chemotherapies is uncertain, but may have potential for use in clinical practice. In this study, we used RT-qPCR, western blot analysis, cell proliferation assay, flow cytometry analysis, immunohistochemistry (IHC) staining, luciferase assays, cell sorting analysis and xenografted tumor model to explore the role of Let-7 in the chemotherapy sensitivity of breast cancer stem cells. The findings of the current study indicated that Let‑7 enhances the effects of endocrine therapy potentially by regulating the self‑renewal of cancer stem cells. Let‑7c increased the anticancer functions of tamoxifen and reduced the ratio of cancer stem‑like cells (CSCs), sensitizing cells to therapy-induced repression in an estrogen receptor (ER)‑dependent manner. Notably, Let‑7 decreased the tumor formation ability of estrogen‑treated breast CSCs in vivo and suppressed Wnt signaling, which further consolidated the previously hypothesis that Let‑7 decreases the self‑renewal ability, contributing to reduced tumor formation ability of stem cells. The suppressive effects exerted by Let‑7 on stem‑like cells involved Let‑7c/ER/Wnt signaling, and the functions of Let‑7c exerted with tamoxifen were dependent on ER. Taken together, the findings identified a biochemical and functional link between Let‑7 and endocrine therapy in breast CSCs, which may facilitate clinical treatment in the future using delivery of suppressive Let-7.
Zamora-Contreras AM, Alvarez-Salas LMLet-7 miRNA Precursors Co-express with LIN28B in Cervical Cells.
Microrna. 2018; 7(1):62-71 [PubMed
] Related Publications
BACKGROUND: The let-7 microRNAs (miRNAs) are frequently dysregulated in carcinogenic processes, including cervical cancer. LIN28 proteins regulate let-7 biogenesis by binding to conserved sequences within the pre-miRNA structure. Nevertheless, recent research has shown that some let-7 miRNAs may escape LIN28 regulation.
OBJECTIVE: Correlate pre-let-7 miRNAs and LIN28B levels in cervical cell lines with different malignancy and HPV content.
METHODS: Pre-let-7 levels were determined by RTqPCR. LIN28B and other let-7 targets were analyzed by immunoblot. In silico tools were used to correlate let-7 and LIN28B expression and to analyze prelet- 7 sequences and structures.
RESULTS: Lin28B protein was detected in all tested cell lines although it was more expressed in tumor cell lines. High levels of pre-let-7c/f-1 and pre-miR-98 were present in almost all cell lines regardless malignancy and LIN28B expression. Pre-let-7g/i were mainly expressed in tumor cell lines, pre-let-7e and pre-let-7-a3 were absent in all cell lines and pre-let-7a-2 showed indistinct expression. LIN28B showed positive correlation with pre-let-7i/g/f-1 and pre-miR-98 in tumor cell lines, suggesting escape from regulation. Sequence alignment and analysis of pre-let-7 miRNAs showed distinctive structural features within the preE region that may influence the ideal pre-let-7 structuring for LIN28B interaction. Short preE-stems were present in pre-let-7 that may escape LIN28B regulation, but long preEstems were mostly associated with high-level pre-let-7 miRNAs.
CONCLUSION: The observed differences of pre-let-7 levels in cervical cell lines may be the result of alternative preE structuring affecting interaction with LIN28B thus resulting in differential let-7 regulation.
Wei Y, Liu Z, Fang JH19 functions as a competing endogenous RNA to regulate human epidermal growth factor receptor expression by sequestering let‑7c in gastric cancer.
Mol Med Rep. 2018; 17(2):2600-2606 [PubMed
] Related Publications
Long non‑coding RNA (lncRNA) H19 has been suggested to serve important roles in the progression of gastric cancer (GC); however, the mechanism involved is largely unknown. The present study aimed to investigate the mechanism underlying the effect of H19 on human epidermal growth factor receptor (HER2) expression. Let‑7c belongs to the let‑7 family, which has been reported to be downregulated in cancers and considered to serve as a tumor suppressor. Let‑7c has been negatively associated with the expression of human epidermal growth factor receptor 2 (HER2). Reverse transcription‑quantitative polymerase chain reaction was used to examine the expression levels of H19 and let‑7c in GC tissues and cell lines. HER2 protein expression levels were examined using immunohistochemistry and western blot analyses. The effect of H19 on let‑7c and HER2 expression was analyzed following transfection of small interfering RNA targeting H19 in GC cells. The results indicated that the expression levels of H19 lncRNA in GC tissue samples were significantly higher when compared with that in matched benign adjacent tissue samples (P<0.001). H19‑silenced GC cells exhibited significantly increased let‑7c expression and decreased HER2 protein expression levels. Assessment of tumor diameter and pathological tumor stage suggested that increased H19 expression was associated with a poorer prognosis in patients with GC. The results of the present study suggest that H19 may function as a competing endogenous RNA to regulate HER2 expression by sequestering let‑7c in GC cells. The present study has aided the understanding of the mechanism of H19 lncRNA in GC, and has provided evidence for the application of lncRNA‑based diagnostic and therapeutic strategies for GC.
Prostate cancer (PC) is a very important kind of male malignancies. When PC evolves into a stage of hormone resistance or metastasis, the fatality rate is very high. Currently, discoveries and advances in miRNAs as biomarkers have opened the potential for the diagnosis of PC, especially early diagnosis. miRNAs not only can noninvasively or minimally invasively identify PC, but also can provide the data for optimization and personalization of therapy. Moreover, miRNAs have been shown to play an important role to predict prognosis of PC. The purpose of this meta-analysis is to integrate the currently published expression profile data of miRNAs in PC, and evaluate the value of miRNAs as biomarkers for PC. All of relevant records were selected via electronic databases: Pubmed, Embase, Cochrane, and CNKI based on the assessment of title, abstract, and full text. we extracted mean ± SD or fold change of miRNAs expression levels in PC versus BPH or normal controls. Pooled hazard ratios (HRs) with 95% confidence intervals (CI) for overall survival (OS) and recurrence-free survival (RFS), were also calculated to detect the relationship between high miRNAs expression and PC prognosis. Selected 104 articles were published in 2007-2017. According to the inclusion criteria, 104 records were included for this meta-analysis. The pooled or stratified analyze showed 10 up-regulated miRNAs (miR-18a, miR-34a, miR-106b, miR-141, miR-182, miR-183, miR-200a/b, miR-301a, and miR-375) and 14 down-regulated miRNAs (miR-1, miR-23b/27b, miR-30c, miR-99b, miR-139-5p, miR-152, miR-187, miR-204, miR-205, miR-224, miR-452, miR-505, and let-7c) had relatively good diagnostic and predictive potential to discriminate PC from BPH/normal controls. Furthermore, high expression of miR-32 and low expression of let-7c could be used to differentiate metastatic PC from local/primary PC. Additional interesting findings were that the expression profiles of five miRNAs (miR-21, miR-30c, miR-129, miR-145, and let-7c) could predict poor RFS of PC, while the evaluation of miR-375 was associated with worse OS. miRNAs are important regulators in PC progression. Our results indicate that miRNAs are suitable for predicting the different stages of PC. The detection of miRNAs is an effective way to control patient's prognosis and evaluate therapeutic efficacy. However, large-scale detections based on common clinical guidelines are still necessary to further validate our conclusions, due to the bias induced by molecular heterogeneity and differences in study design and detection methods.
The aim of the study was to explore the clinical significance of let-7 expression in hepatocellular carcinoma (HCC).A PCR array was conducted to screen for let-7 expression in early-stage HCC. Next, the deregulation of let-7 was confirmed by quantitative real-time RT-PCR (qRT-PCR) in another set of liver tissues, including normal control (NC), chronic hepatitis (CH), liver cirrhosis (LC), HCC, and adjacent nontumor (NT) tissues. In addition, as the potential target mRNA of let-7, alpha 2(I) collagen (COL1A2) mRNA was also quantified in the above liver tissues. Finally, an association study comparing let-7 and COL1A2 and their clinical significance in HCC was conducted.PCR array analysis revealed that the expression levels of let-7a/7b/7c were significantly downregulated in early-stage HCC compared to those in NT tissues. As compared to NC samples, qRT-PCR further confirmed that let-7a/7b/7c/7e were significantly upregulated in CH, LC, and NT tissues, while there were no significant differences in expression between the HCC and NC groups. Although COL1A2 may be the target mRNA of let-7, only let-7c expression was inversely correlated with COL1A2 mRNA expression in CH tissues. In HCC tissues, levels of let-7a/7b/7c/7e were positively correlated with that of COL1A2 mRNA. The clinical significance study revealed that elevated let-7a expression was significantly correlated with serosal and vein invasion, while elevated let-7c expression was significantly correlated with vein invasion and advanced TNM stage. Elevated let-7e expression was significantly correlated with vein invasion in HCC. Significantly shorter postoperative overall survival was observed in HCC patients with high let-7c expression.The results suggest that aberrant expression of let-7a/7b/7c/7e occurs in benign liver diseases and HCC. The upregulation of let-7 expression is associated with the progression and poor prognosis of HCC, and further mechanistic studies are warranted.
Fu X, Mao X, Wang Y, et al.Let-7c-5p inhibits cell proliferation and induces cell apoptosis by targeting ERCC6 in breast cancer.
Oncol Rep. 2017; 38(3):1851-1856 [PubMed
] Related Publications
In this study, we found that let-7c-5p expression was clearly downregulated in breast cancer tissues compared with that of corresponding adjacent tissues. Furthermore, overexpression of let-7c-5p in MCF-7 breast cancer cells could significantly inhibit cell proliferation and induce cell apoptosis. The target genes of let-7c-5p were predicted by the way of bioinformatics, and validated by dual luciferase reporter assay and western blotting demonstrating that excision repair cross complementing 6 (ERCC6) gene was a direct target. Collectively, the present study suggested that let-7c-5p acted as a tumor suppressor in breast cancer possibly by negatively regulating ERCC6, which took an important part in nucleotide excision repair and it may provide a new potential strategy for breast cancer therapy.
Fedorko M, Juracek J, Stanik M, et al.Detection of let-7 miRNAs in urine supernatant as potential diagnostic approach in non-metastatic clear-cell renal cell carcinoma.
Biochem Med (Zagreb). 2017; 27(2):411-417 [PubMed
] Free Access to Full Article Related Publications
INTRODUCTION: Urinary microRNAs (miRNAs) are emerging as a clinically useful tool for early and non-invasive detection of various types of cancer. The aim of this study was to evaluate whether let-7 family miRNAs differ in their urinary concentrations between renal cell carcinoma (RCC) cases and healthy controls.
MATERIALS AND METHODS: In the case-control study, 69 non-metastatic clear-cell RCC patients and 36 gender/age-matched healthy controls were prospectively enrolled. Total RNA was purified from cell-free supernatant of the 105 first morning urine specimens. Let-7 family miRNAs were determined in cell-free supernatant using quantitative miRNA real-time reverse-transcription PCR and absolute quantification approach.
RESULTS: Concentrations of all let-7 miRNAs (let-7a, let-7b, let-7c, let-7d, let-7e and let-7g) were significantly higher in urine samples obtained from RCC patients compared to healthy controls (P < 0.001; P < 0.001; P = 0.005; P = 0.006; P = 0.015 and P = 0.002, respectively). Subsequent ROC analysis has shown that let-7a concentration possesses good ability to differentiate between cases and controls with area under curve being 0.8307 (sensitivity 71%, specificity 81%).
CONCLUSIONS: We have shown that let-7 miRNAs are abundant in the urine samples of patients with clear-cell RCC, and out of six let-7 family members, let-7a outperforms the others and presents promising non-invasive biomarker for the detection of RCC.
Spolverini A, Fuchs G, Bublik DR, Oren Mlet-7b and let-7c microRNAs promote histone H2B ubiquitylation and inhibit cell migration by targeting multiple components of the H2B deubiquitylation machinery.
Oncogene. 2017; 36(42):5819-5828 [PubMed
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Monoubiquitylation of histone H2B (H2Bub1) is catalyzed mainly by the RNF20/RNF40 complex and erased by multiple deubiquitylating enzymes (DUBs). H2Bub1 influences many aspects of chromatin function, including transcription regulation and DNA repair. Cancer cells often display reduced levels of H2Bub1, and this reduction may contribute to cancer progression. The let-7 family of microRNAs (miRNAs) comprises multiple members with reported tumor-suppressive features, whose expression is frequently downregulated in cancer. We now report that let-7b and let-7c can positively regulate cellular H2Bub1 levels. Overexpression of let-7b and let-7c in a variety of non-transformed and cancer-derived cell lines results in H2Bub1 elevation. The positive effect of let-7b and let-7c on H2Bub1 levels is achieved through targeting of multiple mRNAs, coding for distinct components of the H2B deubiquitylation machinery. Specifically, let-7b and let-7c bind directly and inhibit the mRNAs encoding the DUBs USP42 and USP44, and also the mRNA encoding the adapter protein ATXN7L3, which is part of the DUB module of the SAGA complex. RNF20 knockdown (KD) strongly reduces H2Bub1 levels and increases the migration of non-transformed mammary epithelial cells and breast cancer-derived cells. Remarkably, overexpression of let-7b, which partly counteracts the effect of RNF20 KD on H2Bub1 levels, also reverses the pro-migratory effect of RNF20 KD. Likewise, ATXN7L3 KD also increases H2Bub1 levels and reduces cell migration, and this anti-migratory effect is abolished by simultaneous KD of RNF20. Together, our findings uncover a novel function of let-7 miRNAs as regulators of H2B ubiquitylation, suggesting an additional mechanism whereby these miRNAs can exert their tumor-suppressive effects.
Malignant pleural mesothelioma (MPM) is an aggressive human cancer and miRNAs can play a key role for this disease. In order to broaden the knowledge in this field, the miRNA expression was investigated in a large series of MPM to discover new pathways helpful in diagnosis, prognosis and therapy. We employed nanoString nCounter system for miRNA profiling on 105 MPM samples and 10 healthy pleura. The analysis was followed by the validation of the most significantly deregulated miRNAs by RT-qPCR in an independent sample set. We identified 63 miRNAs deregulated in a statistically significant way. MiR-185, miR-197, and miR-299 were confirmed differentially expressed, after validation study. In addition, the results of the microarray analysis corroborated previous findings concerning miR-15b-5p, miR-126-3p, and miR-145-5p. Kaplan-Meier curves were used to explore the association between miRNA expression and overall survival (OS) and identified a 2-miRNA prognostic signature (Let-7c-5p and miR-151a-5p) related to hypoxia and energy metabolism respectively. In silico analyses with DIANA-microT-CDS highlighted 5 putative targets in common between two miRNAs. With the present work we showed that the pattern of miRNAs expression is highly deregulated in MPM and that a 2-miRNA signature can be a new useful tool for prognosis in MPM.
Schwertheim S, Wein F, Lennartz K, et al.Curcumin induces G2/M arrest, apoptosis, NF-κB inhibition, and expression of differentiation genes in thyroid carcinoma cells.
J Cancer Res Clin Oncol. 2017; 143(7):1143-1154 [PubMed
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PURPOSE: The therapy of unresectable advanced thyroid carcinomas shows unfavorable outcome. Constitutive nuclear factor-κB (NF-κB) activation in thyroid carcinomas frequently contributes to therapeutic resistance; the radioiodine therapy often fails due to the loss of differentiated functions in advanced thyroid carcinomas. Curcumin is known for its anticancer properties in a series of cancers, but only few studies have focused on thyroid cancer. Our aim was to evaluate curcumin's molecular mechanisms and to estimate if curcumin could be a new therapeutic option in advanced thyroid cancer.
METHODS: Human thyroid cancer cell lines TPC-1 (papillary), FTC-133 (follicular), and BHT-101 (anaplastic) were treated with curcumin. Using real-time PCR analysis, we investigated microRNA (miRNA) and mRNA expression levels. Cell cycle, Annexin V/PI staining, and caspase-3 activity analysis were performed to detect apoptosis. NF-κB p65 activity and cell proliferation were analyzed using appropriate ELISA-based colorimetric assay kits.
RESULTS: Treatment with 50 μM curcumin significantly increased the mRNA expression of the differentiation genes thyroglobulin (TG) and sodium iodide symporter (NIS) in all three cell lines and induced inhibition of cell proliferation, apoptosis, and decrease of NF-κB p65 activity. The miRNA expression analyses showed a significant deregulation of miRNA-200c, -21, -let7c, -26a, and -125b, known to regulate cell differentiation and tumor progression. Curcumin arrested cell growth at the G2/M phase.
CONCLUSIONS: Curcumin increases the expression of redifferentiation markers and induces G2/M arrest, apoptosis, and downregulation of NF-κB activity in thyroid carcinoma cells. Thus, curcumin appears to be a promising agent to overcome resistance to the conventional cancer therapy.
Cigarette smoking is a primary risk factor for the development of lung cancer, which is regarded as the leading cause of cancer-related deaths. The process of malignant transformation of cells, however, is complex and elusive. The present study investigated the roles of an lncRNA, CCAT1, and a transcriptional factor, c-Myc, in human bronchial epithelial (HBE) cell transformation induced by cigarette smoke extract. With acute and chronic treatment of HBE cells, cigarette smoke extract induced increases of CCAT1 and c-Myc levels and decreases of levels of let-7c, a microRNA. Down-regulation of c-Myc reduced the degree of malignancy and the invasion/migration capacity of HBE cells transformed by cigarette smoke extract. ChIP assays established that c-Myc, increased by cigarette smoke extract, binds to the promoter of CCAT1, activating its transcription. Further, let-7c suppressed the expression of c-Myc through binding to its 3'-UTR. In turn, CCAT1 promoted the accumulation of c-Myc through binding to let-7c and decreasing free let-7c, which influenced the neoplastic capacity of HBE cells transformed by cigarette smoke extract. These results indicate that a positive feedback loop ensures expression of cigarette smoke extract-induced CCAT1 and c-Myc via let-7c, which is involved in cigarette smoke extract-induced malignant transformation of HBE cells. Thus, the present research establishes a new mechanism for the reciprocal regulation between CCAT1 and c-Myc and provides an understanding of cigarette smoke extract-induced lung carcinogenesis.
Hepatocellular carcinoma (HCC) has a high recurrence rate, and patients exhibit poor survival mainly because intrahepatic metastasis is common. We previously reported that let-7c down-regulation is significantly associated with poor differentiation level in HCC. In the present study, we demonstrate that miR-199a-5p and let-7c are frequently down-regulated in HCC cells and tissues, and low expression of miR-199a-5p is correlated with tumor size, liver envelope invasion. Furthermore, miR-199a-5p and let-7c cooperatively inhibit HCC cell migration and invasion in vitro. MAP4K3 is identified as the direct target of miR-199a-5p and let-7c and this regulation is further confirmed by luciferase reporter assays and Western blotting. In addition, MAP4K3 functions as a metastasis promoter since the results demonstrate that MAP4K3 could promote HCC cell migration and invasion. We also find that miR-199a-5p and let-7c increase the sensitivity of HCC cells to sorafenib.
CONCLUSIONS: We report that miR-199a-5p and let-7c cooperatively and efficiently inhibit HCC cell migration and invasion by targeting the metastasis promoter MAP4K3 and MAP4K3-mediated drug sensitization, suggesting that the use of miRNAs and sorafenib in combination therapy may be a powerful approach to the treatment of HCC.
Foj L, Ferrer F, Serra M, et al.Exosomal and Non-Exosomal Urinary miRNAs in Prostate Cancer Detection and Prognosis.
Prostate. 2017; 77(6):573-583 [PubMed
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BACKGROUND: MicroRNAs (miRNAs) are non-coding small RNAs, involved in post-transcriptional regulation of many target genes.
METHODS: Five miRNAs that have been consistently found deregulated in PCa (miR-21, miR-141, miR-214, miR-375, and let-7c) were analyzed in urinary pellets from 60 prostate cancer (PCa) patients and 10 healthy subjects by qRT-PCR. Besides, urinary exosomes were isolated by differential centrifugation and analyzed for those miRNAs.
RESULTS: Significant upregulation of miR-21, miR-141, and miR-375 was found comparing PCa patients with healthy subjects in urinary pellets, while miR-214 was found significantly downregulated. Regarding urinary exosomes, miR-21 and miR-375 were also significantly upregulated in PCa but no differences were found for miR-141. Significant differences were found for let-7c in PCa in urinary exosomes while no differences were observed in urinary pellets. A panel combining miR-21 and miR-375 is suggested as the best combination to distinguish PCa patients and healthy subjects, with an AUC of 0.872. Furthermore, the association of miRNAs with clinicopathological characteristics was investigated. MiR-141 resulted significantly correlated with Gleason score in urinary pellets and let-7c with clinical stage in urinary exosomes. Additionally, miR-21, miR-141, and miR-214 were found significantly deregulated in intermediate/high-risk PCa versus low-risk/healthy subjects in urinary pellets. Significant differences between both groups were found in urinary exosomes for miR-21, miR-375, and let-7c.
CONCLUSIONS: These findings suggest that the analysis of miRNAs-especially miRNA-21 and miR-375- in urine could be useful as biomarkers in PCa. Prostate 77: 573-583, 2017. © 2016 Wiley Periodicals, Inc.
OBJECTIVE: Early diagnosis of epithelial ovarian cancer is critical for patient survival. The objective of this pilot study is to identify a circulating micro (mi)RNA as a potential biomarker for epithelial ovarian cancer.
METHODS: A total of 135 epithelial ovarian cancer patients and 54 benign ovarian tumor patients were recruited for this study. Using customized TaqMan low density miRNA arrays, we first screened expression levels of 48 miRNAs in sera from 18 epithelial ovarian cancer patients and 16 benign ovarian tumor patients. The most significantly and differentially expressed miRNA was then further examined in all serum samples using real-time polymerase chain reaction. Its expression was further analyzed in relationship with clinicopathological factors and patient survival.
RESULTS: Array screening data showed that expression levels of serum miRNA-20a, miRNA-125b, miRNA-126, miRNA-355, and let-7c were significantly different between malignant and benign ovarian tumor patients. Subsequent real-time polymerase chain reaction results showed that serum miRNA-125b levels were significantly higher in epithelial ovarian cancer patients compared to benign controls. Moreover, serum miRNA-125b levels were significantly higher in ovarian cancer patients in early stages I and II, and in patients having no residual tumor following surgery, but were not associated with differentiation and histological types of ovarian cancer. Notably, the higher level of miR-125b was significantly positively correlated with progression-free survival (P = 0.035) and marginally, with overall survival (P = 0.069).
CONCLUSIONS: miRNA-125b plays an important role in the pathogenesis and progression of epithelial ovarian cancer. Circulating miRNA-125b has the potential to become a novel biomarker for early diagnosis and prognosis prediction of epithelial ovarian cancer.
Chemoresistance remains one of the major obstacles in clinical treatment of lung adenocarcinoma (LAD). Indeed, docetaxel-resistant LAD cells present chemoresistance and epithelial-to-mesenchymal transition phenotypes. Long non-coding RNAs (lncRNAs) are known to promote tumorigenesis in many cancer types. Here, we showed that the lncRNA colon cancer-associated transcript-1 (CCAT1) was upregulated in docetaxel-resistant LAD cells. Furthermore, downregulation of CCAT1 decreased chemoresistance, inhibited proliferation, enhanced apoptosis and reversed the epithelial-to-mesenchymal transition phenotype of docetaxel-resistant LAD cells. We also found that the oncogenic function of CCAT1 in docetaxel-resistant LAD cells depended on the sponging of let-7c. In turn, the sponging of let-7c by CCAT1 released Bcl-xl (a let-7c target), thereby promoting the acquisition of chemoresistance and epithelial-to-mesenchymal transition phenotypes in docetaxel-resistant LAD cells. Our data reveal a novel pathway underlying chemoresistance and the epithelial-to-mesenchymal transition in docetaxel-resistant LAD cells.