Summary
It is now largely admitted that a pro‐inflammatory environment may curtail anti‐tumor immunity and favor cancer initiation and progression. The discovery that small non‐coding regulatory ...RNAs, namely microRNAs (miRNAs), regulate all aspects of cell proliferation, differentiation, and function has shed a new light on regulatory mechanisms linking inflammation and cancer. Thus, miRNAs such as miR‐21, miR‐125b, miR‐155, miR‐196, and miR‐210 that are critical for the immune response or hypoxia are often overexpressed in cancers and leukemias. Given the high number of their target transcripts, their deregulation may have a number of deleterious consequences, depending on the cellular context. In this review, we focus on how the factors encoded by transcripts targeted by these five miRNAs, be they transcription factors, tumor‐suppressors, or regulators of different signaling pathways, can deregulate the immune response and favor pro‐tumor immunity. Furthermore, we expose how the misdirected action of the main regulators of these miRNAs, such as nuclear factor κB (NF‐κB), activator protein‐1 (AP‐1), and signal transduction and activators of transcription (STAT) transcription factors, or AKT and transforming growth factor β (TGFβ) signaling pathways, can contribute to decrease anti‐tumor immunity and enhance cell proliferation and oncogenesis. We conclude by briefly discussing about how these discoveries may possibly lead to the development of new miRNA‐based cancer therapies.
Summary
Aging is a multifactorial process where deterioration of body functions is driven by stochastic damage while counteracted by distinct genetically encoded repair systems. To better understand ...the genetic component of aging, many studies have addressed the gene and protein expression profiles of various aging model systems engaging different organisms from yeast to human. The recently identified small non‐coding miRNAs are potent post‐transcriptional regulators that can modify the expression of up to several hundred target genes per single miRNA, similar to transcription factors. Increasing evidence shows that miRNAs contribute to the regulation of most if not all important physiological processes, including aging. However, so far the contribution of miRNAs to age‐related and senescence‐related changes in gene expression remains elusive. To address this question, we have selected four replicative cell aging models including endothelial cells, replicated CD8+ T cells, renal proximal tubular epithelial cells, and skin fibroblasts. Further included were three organismal aging models including foreskin, mesenchymal stem cells, and CD8+ T cell populations from old and young donors. Using locked nucleic acid‐based miRNA microarrays, we identified four commonly regulated miRNAs, miR‐17 down‐regulated in all seven; miR‐19b and miR‐20a, down‐regulated in six models; and miR‐106a down‐regulated in five models. Decrease in these miRNAs correlated with increased transcript levels of some established target genes, especially the cdk inhibitor p21/CDKN1A. These results establish miRNAs as novel markers of cell aging in humans.
Functional mechanisms of miR‐192 family in cancer Mishan, Mohammad Amir; Tabari, Mohammad Amin Khazeei; Parnian, Javad ...
Genes chromosomes & cancer,
December 2020, Volume:
59, Issue:
12
Journal Article
Peer reviewed
By growing research on the mechanisms and functions of microRNAs (miRNAs, miRs), the role of these noncoding RNAs gained more attention in healthcare. Due to the remarkable regulatory role of miRNAs, ...any dysregulation in their expression causes cellular functional impairment. In recent years, it has become increasingly apparent that these small molecules contribute to development, cell differentiation, proliferation, apoptosis, and tumor growth. In many studies, the miR‐192 family has been suggested as a potential prognostic and diagnostic biomarker and even as a possible therapeutic target for several cancers. However, the mechanistic effects of the miR‐192 family on cancer cells are still controversial. Here, we have reviewed each family member of the miR‐192 including miR‐192, miR‐194, and miR‐215, and discussed their mechanistic roles in various cancers.
Objectives
This study aimed to experimentally validate dysregulated expression of miRNA candidates selected through updated meta‐analysis of most commonly deregulated miRNAs in oral cancer and to ...explore their diagnostic and prognostic potential.
Materials and methods
Five miRNAs (miR‐31‐3p, miR‐135b‐5p, miR‐18a‐5p, miR‐30a‐5p and miR‐139‐5p) from updated meta‐signature were selected for validation by qRT‐PCR method in 35 oral cancer clinical specimens and adjacent non‐cancerous tissue.
Results
Updated meta‐analysis has identified 13 most commonly deregulated miRNAs in oral cancer. Seven miRNAs were consistently up‐regulated (miR‐21‐5p, miR‐31‐3p, miR‐135b‐5p, miR‐31‐5p, miR‐424‐5p, miR‐18a‐5p and miR‐21‐3p), while five were down‐regulated (miR‐139‐5p, miR‐30a‐3p, miR‐375‐3p, miR‐376c‐3p and miR‐30a‐5p). Increased expression of miR‐31‐3p and miR‐135b‐5p, and decreased expression of miR‐139‐5p and miR‐30a‐5p were confirmed in oral cancer compared to adjacent non‐cancerous tissue. A three miRNAs combination (miR‐31‐3p, miR‐139‐5p and miR‐30a‐5p) gave the most promising diagnostic potential for discriminating oral cancer from non‐cancerous tissue (AUC: 0.780 95% CI: 0.673–0.886, p < 0.0005, sensitivity 94.3%, specificity 51.4%). High expression of miR‐135b‐5p, miR‐18a‐5p and miR‐30a‐5p was associated with poor survival (p = 0.003, p = 0.048, p = 0.016 respectively).
Conclusion
miR‐31‐3p, miR‐139‐5p and miR‐30a‐5p panel was confirmed as a potential diagnostic biomarker when distinguishing oral cancer from non‐cancerous tissue. miR‐135b‐5p, miR‐18a‐5p and miR‐30a‐5p might serve as potential biomarkers of poor survival of oral cancer patients.
We previously demonstrated that acidic bile activates NF‐κB, deregulating the expression of oncogenic miRNA markers, in pre‐malignant murine laryngopharyngeal mucosa. Here, we hypothesize that the ...in vitro exposure of human hypopharyngeal cells to acidic bile deregulates cancer‐related miRNA markers that can be reversed by BAY 11‐7082, a pharmacologic NF‐κB inhibitor. We repetitively exposed normal human hypopharyngeal primary cells and human hypopharyngeal keratinocytes to bile fluid (400 μmol/L), at pH 4.0 and 7.0, with/without BAY 11‐7082 (20 μmol/L). We centred our study on the transcriptional activation of oncogenic miR‐21, miR‐155, miR‐192, miR‐34a, miR‐375, miR‐451a and NF‐κB‐related genes, previously linked to acidic bile‐induced pre‐neoplastic events. Our novel findings in vitro are consistent with our hypothesis demonstrating that BAY 11‐7082 significantly reverses the acidic bile‐induced oncogenic miRNA phenotype, in normal hypopharyngeal cells. BAY 11‐7082 strongly inhibits the acidic bile‐induced up‐regulation of miR‐192 and down‐regulation of miR‐451a and significantly decreases the miR‐21/375 ratios, previously related to poor prognosis in hypopharyngeal cancer. This is the first in vitro report that NF‐κB inhibition reverses acidic bile‐induced miR‐21, miR‐155, miR‐192, miR‐34a, miR‐375 and miR‐451a deregulations in normal human hypopharyngeal cells, suggesting that acidic bile‐induced events are directly or indirectly dependent on NF‐κB signalling.
Induced osteogenesis includes a program of microRNAs (miRs) to repress the translation of genes that act as inhibitors of bone formation. How expression of bone-related miRs is regulated remains a ...compelling question. Here we report that Runx2, a transcription factor essential for osteoblastogenesis, negatively regulates expression of the miR cluster 23a~27a~24-2. Overexpression, reporter, and chromatin immunoprecipitation assays established the presence of a functional Runx binding element that represses expression of these miRs. Consistent with this finding, exogenous expression of each of the miRs suppressed osteoblast differentiation, whereas antagomirs increased bone marker expression. The biological significance of Runx2 repression of this miR cluster is that each miR directly targets the 3' UTR of SATB2, which is known to synergize with Runx2 to facilitate bone formation. The findings suggest Runx2-negative regulation of multiple miRs by a feed-forward mechanism to cause derepression of SATB2 to promote differentiation. We find also that miR-23a represses Runx2 in the terminally differentiated osteocyte, representing a feedback mechanism to attenuate osteoblast maturation. We provide direct evidence for an interdependent relationship among transcriptional inhibition of the miR cluster by Runx2, translational repression of Runx2 and of SATB2 by the cluster miRs during progression of osteoblast differentiation. Furthermore, miR cluster gain of function (i.e., inhibition of osteogenesis) is rescued by the exogenous expression of SATB2. Taken together, we have established a regulatory network with a central role for the miR cluster 23a~27a~24-2 in both progression and maintenance of the osteocyte phenotype.
Background
Ethanol (EtOH) and nicotine are often co‐abused. However, their combined effects on fetal neural development, particularly on fetal neural stem cells (NSCs), which generate most neurons of ...the adult brain during the second trimester of pregnancy, are poorly understood. We previously showed that EtOH influenced NSC maturation in part, by suppressing the expression of specific microRNAs (miRNAs). Here, we tested in fetal NSCs the extent to which EtOH and nicotine coregulated known EtOH‐sensitive (miR‐9, miR‐21, miR‐153, and miR‐335), a nicotine‐sensitive miRNA (miR‐140‐3p), and mRNAs for nicotinic acetylcholine receptor (nAChR) subunits. Additionally, we tested the extent to which these effects were nAChR dependent.
Methods
Gestational day 12.5 mouse fetal murine cerebral cortical–derived neurosphere cultures were exposed to EtOH, nicotine, and mecamylamine, a noncompetitive nAChR antagonist, individually or in combination, for short (24 hour) and long (5 day) periods, to mimic exposure during the in vivo period of neurogenesis. Levels of miRNAs, miRNA‐regulated transcripts, and nAChR subunit mRNAs were assessed by quantitative reverse transcription polymerase chain reaction.
Results
EtOH suppressed the expression of known EtOH‐sensitive miRNAs and miR‐140‐3p, while nicotine at concentrations attained by cigarette smokers induced a dose‐related increase in these miRNAs. Nicotine's effect was blocked by EtOH and by mecamylamine. Finally, EtOH decreased the expression of nAChR subunit mRNAs and, like mecamylamine, prevented the nicotine‐associated increase in α4 and β2 nAChR transcripts.
Conclusions
EtOH and nicotine exert mutually antagonistic, nAChR‐mediated effects on teratogen‐sensitive miRNAs in fetal NSCs. These data suggest that concurrent exposure to EtOH and nicotine disrupts miRNA regulatory networks that are important for NSC maturation.
Right ventricular (RV) failure is the primary cause of death in pulmonary arterial hypertension (PAH). We hypothesized that heart‐relevant microRNAs, that is myomiRs (miR‐1, miR‐133a, miR‐208, ...miR‐499) and miR‐214, can have a role in the right ventricle in the development of PAH. To mimic PAH, male Wistar rats were injected with monocrotaline (MCT, 60 mg/kg, s.c.); control group received vehicle. MCT rats were divided into two groups, based on the clinical presentation: MCT group terminated 4 weeks after MCT administration and prematurely terminated group (ptMCT) displaying signs of terminal disease. Myocardial damage genes and candidate microRNAs expressions were determined by RT‐qPCR. Reduced blood oxygen saturation, breathing disturbances, RV enlargement as well as elevated levels of markers of myocardial damage confirmed PH in MCT animals and were more pronounced in ptMCT. MyomiRs (miR‐1/miR‐133a/miR‐208a/miR‐499) were decreased and the expression of miR‐214 was increased only in ptMCT group (P < 0.05). The myomiRs negatively correlated with Fulton index as a measure of RV hypertrophy in MCT group (P < 0.05), whereas miR‐214 showed a positive correlation (P < 0.05). We conclude that the expression of determined microRNAs mirrored the disease severity and targeting their pathways might represent potential future therapeutic approach in PAH.
Beneficial microbes induce resistance in plants (MIR), imposing both lethal and sublethal effects on herbivorous insects. We argue that herbivores surviving MIR carry metabolic and immunological ...imprints of MIR with cascading effects across food webs. We propose that incorporating such cascading effects will strongly enhance the current MIR research framework.
Beneficial microbes induce resistance in plants (MIR), imposing both lethal and sublethal effects on herbivorous insects. We argue that herbivores surviving MIR carry metabolic and immunological imprints of MIR with cascading effects across food webs. We propose that incorporating such cascading effects will strongly enhance the current MIR research framework.
Bacground Information
Lung cancer is one of the leading types of cancer deaths worldwide, with approximately 2 million people diagnosed with lung cancer each year. In this study, we aimed to ...determine the exonic and 3′UTR sequences of EGFR, PIK3CA and KRAS genes in 39 sporadic lung cancer tumors and to reveal the changes in the miRNA binding profile of tumors with somatic variation in the 3'UTR region and to examine the relationship of these changes with clinical parameters.
Results
A statistically significant correlation was found between the presence of miRNA that could not bind to the 3′UTR region due to variation in at least one of the EGFR or KRAS genes and the presence of metastasis in the tumor. At the same time, Kaplan‐Meier analysis between those with and without alterations in the miRNA profile due to somatic variation in the 3′UTR region showed that survival was lower in those with miRNA alterations and this was statistically significant.
Conclusions
In our study, it was shown that variations in the 3′UTR regions of EGFR and KRAS oncogenes may cause increased expression of these oncogenes by preventing the binding of miRNAs, and it was suggested that this may be related to metastasis, survival and drug resistance mechanism.
Significance
In this study, we show that hsa‐miR‐124‐3p, hsa‐miR‐506‐3p, hsa‐miR‐1290 and hsa‐miR‐6514‐3p are particularly prominent in lung carcinoma in relation to these biological pathways and the roles that variations in the 3′UTR regions of oncogenes may play in the carcinogenesis process.
3'UTR sequences, which are the sequences surrounding protein‐coding regions in mRNAs, are known to play a role in many biological processes. In this context, due to variations in the 3'UTR regions of oncogenes in our study, tumour cells may have acquired a selective adaptive ability in the process of tumoural evolution, enabling these miRNAs to target other pathways that trigger the carcinogenesis process. In this study, we propose that variations in the 3'UTR regions of EGFR and KRAS oncogenes may be related to the mechanism of metastasis, survival and drug resistance because they increase the expression of oncogenes by inhibiting the binding of some miRNAs. At the same time, Kaplan‐Meier analysis between those with and without changes in miRNA profile due to somatic variation in the 3'UTR region showed that survival was lower in those with miRNA changes and this was statistically significant.
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