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Alzheimer's disease (AD) is the most common cause of dementia. New strategies for the early detection of MCI and sporadic AD are crucial for developing effective treatment options. Current techniques used for diagnosis of AD are invasive and/or expensive, so they are not suitable for population screening. Cerebrospinal fluid (CSF) biomarkers such as amyloid β1-42 (Aβ1-42), total tau (T-tau), and phosphorylated tau181 (P-tau181) levels are core biomarkers for early diagnosis of AD. Several studies have proposed the use of blood-circulating microRNAs (miRNAs) as potential novel early biomarkers for AD. We therefore applied a novel approach to identify blood-circulating miRNAs associated with CSF biomarkers and explored the potential of these miRNAs as biomarkers of AD. In total, 112 subjects consisting of 28 dementia due to AD cases, 63 MCI due to AD cases, and 21 cognitively healthy controls were included. We identified seven Aβ1-42-associated plasma miRNAs, six P-tau181-associated plasma miRNAs, and nine Aβ1-42-associated serum miRNAs. These miRNAs were involved in AD-relevant biological processes, such as PI3K/AKT signaling. Based on this signaling pathway, we constructed an miRNA-gene target network, wherein miR-145-5p has been identified as a hub. Furthermore, we showed that miR-145-5p performs best in the prediction of both AD and MCI. Moreover, miR-145-5p also improved the prediction performance of the mini-mental state examination (MMSE) score. The performance of this miRNA was validated using different datasets including an RT-qPCR dataset from plasma samples of 23 MCI cases and 30 age-matched controls. These findings indicate that blood-circulating miRNAs that are associated with CSF biomarkers levels and specifically plasma miR-145-5p alone or combined with the MMSE score can potentially be used as noninvasive biomarkers for AD or MCI screening in the general population, although studies in other AD cohorts are necessary for further validation.

The rapid and accurate detection of miRNAs is of great significance for early diagnosis and treatment of cancer. Hence, a novel enzyme-free and label-free electrochemical biosensor based on bio-barcode amplification for detecting miRNAs was presented. Sandwich structures constructed of magnetic nanoparticles modified with DNA probes, gold nanoparticles with numerous barcoded DNA strands that hybridized with target miRNAs were fabricated as the amplifier. The released barcoded DNA strands then acted as the secondary targets and triggered the electrochemical sensor with a significant electrochemical response. A highly sensitive (detection limit of 0.24 fM) and selective electrochemical miRNA detection was realized, which has great potential for application in miRNA-related clinical diagnosis and biochemical research., (© 2023. The Author(s), under exclusive licence to The Japan Society for Analytical Chemistry.)

Background: Smoking is a well-recognized risk factor for esophageal carcinoma, but the underlying molecular mechanism remains unclear. Previous studies have demonstrated the predictive value of non-coding RNA (ncRNA) for the prognosis of esophageal carcinoma; however, the expression of smoking-related ncRNAs has not been systematically characterized. Herein, we comprehensively assessed the hazard of heavy smoking and its impact on ncRNA expression patterns in patients with esophageal carcinoma., Methods: Transcriptome and clinical features of patients with esophageal carcinoma were acquired from The Cancer Genome Atlas (TCGA) database. Cox regression analysis was employed to calculate the hazard ratio (HR) of smoking behavior. Differential expression analysis was conducted with the "edgeR" package. The smoking-related RNA regulatory network was based on lncRNA‒miRNA and miRNA‒mRNA pairs and visualized by Cytoscape 3.7.1. We applied Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses for functional annotation. Univariate and least absolute shrinkage and selection operator (LASSO) Cox regression analyses were used for model construction. We applied Kaplan‒Meier analysis with a log-rank test for survival analysis, with group comparison by the Wilcoxon signed ranked test., Results: Heavy smoking contributed to the poor overall survival of esophageal carcinoma, with an HR of 3.167 (95% CI: 1.077-9.312). A total of 195 lncRNAs and 73 miRNAs were differentially expressed between patients with or without smoking behavior. We constructed smoking-related RNA regulatory networks, and functional annotation enriched a series of cancer-related pathways. We generated a smoking-related prognostic risk score and found that patients with a high score had a poor prognosis. Fourteen out of 23 immune cell types differentially infiltrated into a distinct risk group, while no correlation was observed between the risk score and immune cells., Conclusion: Altogether, we profiled smoking-related ncRNA expression patterns and constructed an RNA regulatory network, providing a landscape of smoking-related molecular mechanisms of esophageal carcinoma. The smoking-related risk score, which was related to prognosis, revealed that tobacco smoking could suppress tumor immunity via the ncRNA mechanism., (© 2023. The Author(s).)

Objectives: Dental pulp stem cells (DPSCs) are a type of mesenchymal stem cell possessing self-renewal and multilineage differentiation capabilities. The dysfunction of DPSCs is related to the pathologic process of pulpitis. The participation of circular RNAs (circRNAs) in DPSC differentiation has been identified. This work focussed on exploring the functions and mechanism of circFKBP5 in DPSC dysfunction evoked by lipopolysaccharide (LPS)., Materials and Methods: The viability and apoptosis of human DPSCs (hDPSCs) were determined using Cell Counting Kit-8 assay and flow cytometry. Inflammation was analysed by measuring the release of inflammatory cytokines. The osteogenic differentiation of hDPSCs was investigated by performing alkaline phosphatase (ALP) staining and alizarin red S staining and detecting the changes of ALP and runt-related transcription factor 2 (RUNX2) proteins. The dual-luciferase reporter, RNA immunoprecipitation (RIP), and pull-down assays were used to confirm the binding between miR-708-5p and circFKBP5 or G-protein-coupled receptor (GPCR)-kinase interacting protein 2 (GIT2)., Results: CircFKBP5 expression was decreased in hDPSCs and, functionally, reexpression of circFKBP5 attenuated LPS-induced apoptosis, inflammation, and inhibition of proliferation ability and osteogenic differentiation in hDPSCs. Mechanistically, circFKBP5 acted as a sponge for miR-708-5p, which was verified to target GIT2. LPS induced miR-708-5p expression in hDPSCs, and knockdown of miR-708-5p protected against LPS-evoked hDPSC dysfunction. Besides, GIT2 expression was decreased in hDPSCs after LPS treatment. Rescue experiments showed that GIT2 could mediate the protective functions of circFKBP5 on hDPSCs under LPS treatment., Conclusions: CircFKBP5 could protect against LPS-induced apoptosis, inflammation, and osteogenic differentiation inhibition in hDPSCs via the miR-708-5p/GIT2 axis., Competing Interests: Conflict of interest None disclosed., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The abnormal immune response mediated by malignant melanoma is related to PD1. Paeonol has pharmacological antitumor activity. Previous studies have indicated that paeonol induces tumor cell apoptosis, but its underlying mechanism in tumor immunity remains unknown. In this study, malignant melanoma was established in normal and thymectomized mice to determine the important role of the thymus in the antitumor effects of paeonol. Paeonol-treated thymocytes were cocultured with melanoma cell spheres to further evaluate the regulatory role of thymocytes in tumor immune dysfunction. Studies have shown that PD1 may be targeted by miR-139-5p. Our results revealed that tumor-induced thymic atrophy was significantly accompanied by high PD1 expression and low miR-139-5p expression. Interestingly, paeonol significantly reversed thymic atrophy and largely protected thymocytes against low PD1 expression and high miR-139-5p expression. Dual-luciferase assays indicated that miR-139-5p interacted with the 3' untranslated region (3'-UTR) of PD1. These results showed that paeonol alleviates PD1-mediated antitumor immunity by reducing miR-139-5p expression and demonstrated a novel mechanism for melanoma immunotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests exist., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Tumour repopulation initiated by residual tumour cells in response to cytotoxic therapy has been described clinically and biologically, but the mechanisms are unclear. Here, we aimed to investigate the mechanisms for the tumour-promoting effect in dying cells and for tumour repopulation in surviving tongue cancer cells., Methods: Tumour repopulation in vitro and in vivo was represented by luciferase activities. The differentially expressed cytokines in the conditioned medium (CM) were identified using a cytokine array. Gain or loss of function was investigated using inhibitors, neutralising antibodies, shRNAs and ectopic overexpression strategies., Results: We found that dying tumour cells undergoing cytotoxic therapy increase the growth of living tongue cancer cells in vitro and in vivo. Dying tumour cells create amphiregulin (AREG)- and basic fibroblast growth factor (bFGF)-based extracellular environments via cytotoxic treatment-induced endoplasmic reticulum stress. This environment stimulates growth by activating lysine acetyltransferase 6B (KAT6B)-dependent nuclear factor-kappa B (NF-κB) signalling in living tumour cells. As direct targets of NF-κB, miR-22 targets KAT6B to repress its expression, but long noncoding RNAs (lncRNAs) (XLOC_003973 and XLOC_010383) counter the effect of miR-22 to enhance KAT6B expression. Moreover, we detected increased AREG and bFGF protein levels in the blood of tongue cancer patients with X-box binding protein-1 (XBP1) activation in tumours under cytotoxic therapy and found that XBP1 activation is associated with poor prognosis of patients. We also detected activation of miR-22/lncRNA/KAT6B/NF-κB signalling in recurrent cancers compared to paired primary tongue cancers., Conclusions: We identified the molecular mechanisms of cell death-induced tumour repopulation in tongue cancer. Such insights provide new avenues to identify predictive biomarkers and effective strategies to address cancer progression., (© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Background: Pancreatic cancer (PC) is a highly malignant tumor which threatens human's health. Long non-coding RNAs (lncRNAs) are implicated in many cancers, including PC, but their mechanisms in PC have not yet been entirely clarified. We focused on revealing the potential function of lncRNA SOX21-AS1 in PC., Methods: Functional assays assessed SOX21-AS1 function on PC progression. Bioinformatics analysis, along with mechanism assays were taken to unmask the regulatory mechanism SOX21-AS1 may exert in PC cells., Results: SOX21-AS1 possessed a high expression level in PC cells. SOX21-AS1 absence suppressed PC cell proliferation, migration, stemness and epithelial-mesenchymal transition (EMT) while elevated cell apoptosis. SOX21-AS1 positively regulated its nearby gene SRY-box transcription factor 21 (SOX21) at post-transcriptional level. Through mechanism assays, we uncovered that SOX21-AS1 sponged SOX21-AS1 to elevate SOX21 mRNA and recruited ubiquitin-specific peptidase 10 (USP10) to deubiquitinate and stabilize SOX21 protein. Moreover, signal transducer and activator of transcription 6 (STAT6) could transcriptionally activate SOX21-AS1 and SOX21 expression., Conclusions: SOX21-AS1 aggravated the malignant development of PC, which might provide the utility value for PC treatment., (© 2022. The Author(s).)

Alzheimer's disease (AD) is a neurodegenerative disease that eventually affects memory and behavior. The identification of biomarkers based on risk factors for AD provides insight into the disease since the exact cause of AD remains unknown. Several studies have proposed microRNAs (miRNAs) in blood as potential biomarkers for AD. Exposure to heavy metals is a potential risk factor for onset and development of AD. Blood cells of subjects that are exposed to lead detected in the circulatory system, potentially reflect molecular responses to this exposure that are similar to the response of neurons. In this study we analyzed blood cell-derived miRNAs derived from a general population as proxies of potentially AD-related mechanisms triggered by lead exposure. Subsequently, we analyzed these mechanisms in the brain tissue of AD subjects and controls. A total of four miRNAs were identified as lead exposure-associated with hsa-miR-3651, hsa-miR-150-5p and hsa-miR-664b-3p being negatively and hsa-miR-627 positively associated. In human brain derived from AD and AD control subjects all four miRNAs were detected. Moreover, two miRNAs (miR-3651, miR-664b-3p) showed significant differential expression in AD brains versus controls, in accordance with the change direction of lead exposure. The miRNAs' gene targets were validated for expression in the human brain and were found enriched in AD-relevant pathways such as axon guidance. Moreover, we identified several AD relevant transcription factors such as CREB1 associated with the identified miRNAs. These findings suggest that the identified miRNAs are involved in the development of AD and might be useful in the development of new, less invasive biomarkers for monitoring of novel therapies or of processes involved in AD development., (© 2022. The Author(s).)

Background: The aim of this study was to investigate the role of ILF3-AS1 in regulating the survival of melanoma and its molecular mechanism., Methods: The relative expression level of ILF3-AS1 in melanoma was assessed by qPCR. The effect of ILF3-AS1 and PDK1 on the cell viability was tested by MTT assay. Glucose uptake colorimetric assay, lactate assay, the measurements of extracellular acidification rate (ECAR) and Oxygen consumption rate (OCR) were performed to test the effect of ILF3-AS1 and PDK1 on the cellular glycolysis. Luciferase assay was conducted to detect the interactions of ILF3-AS1, miR-493-5p and PDK1. RNA immunoprecipitation chip (RIP) assay was used to detect the enrichments of ILF3-AS1 and miR-493-5p in the complex. Protein level of PDK1 was detected by western blot analysis., Results: qPCR revealed that ILF3-AS1 was upregulated in human melanoma cell lines. MTT assay showed that ILF3-AS1 knockdown blunted cell proliferation, which was rescued by the overexpression of PDK1. Glucose uptake colorimetric assay, lactate assay, the measurements of ECAR and OCR indicated that ILF3-AS1 promoted glycolysis through PDK1. Western blotting results showed that ILF3-AS1 overexpression promoted PDK1 expression, which was prevented by miR-493-5p overexpression in SK-MEL-1 cells., Conclusions: ILF3-AS1 promotes the aerobic glycolysis and survival of melanoma cells involving miR-493-5p/PDK1 pathway.

Everolimus is a kind of mammalian target of rapamycin (mTOR) inhibitors. Activated mitogen-activated protein kinase interacting kinases/eukaryotic translation initiation factor 4E (MNK/eIF4E) axis plays a crucial role in resistance to Everolimus in non-small cell lung cancer (NSCLC). The eIF4E phosphorylation increased by mTOR inhibitors is mainly mediated by MNKs. However, the mechanisms are poorly understood. Recently, extensive reprogramming of miRNA profiles has also been found after long-term mTOR inhibitor exposure. Our previous studies have confirmed that tumor suppressor miR-7-5p is decreased in A549 cells after treatment with Everolimus. Exactly, MNK1 is the target of miR-7-5p. In this study, we investigated the biological functions and potential molecular mechanisms of miR-7-5p in the NSCLC undergoing treatment with Everolimus. We confirmed that Everolimus targeted mTORC1 inducing NSCLC cells to secrete miR-7-5p-loaded exosomes in Rab27A and Rab27B-dependent manners. Loss of intracellular miR-7-5p induced phosphorylation of MNK/eIF4E axis, but a supplement of extra exosomal miR-7-5p could reverse it. Of note, both low expression of miR-7-5p and elevated MNK1 protein were associated with a poor prognosis of NSCLC. Both endogenous miR-7-5p and exo-miR-7-5p enhanced the therapeutic efficacy of Everolimus by inhibiting the proliferation, migration, and metastasis of NSCLC in vitro and in vivo. The combination of miR-7-5p with Everolimus induced apoptosis to exhibit a synergistic anticancer therapeutic efficacy through dual abrogation of MNK/eIF4E and mTOR in NSCLC. In conclusion, Everolimus decreases the intracellular miR-7-5p by releasing of miR-7-5p loaded exosomes from NSCLC cells in Rab27A and Rab27B dependent manners. Either endogenous miR-7-5p or exo-miR-7-5p combined with Everolimus can enhance the anticancer efficacy by targeting MNK/eIF4E axis and mTOR. Besides, both low levels of miR-7-5p and positive expression of MNK1 act as independent poor prognostic biomarkers for NSCLC. Therefore, restoring miR-7-5p carried by exosome may be a promising novel combined therapeutic strategy with Everolimus for NSCLC., (© 2022. The Author(s).)

Background: Previous studies have confirmed that the microglial activation and subsequent inflammatory responses in the trigeminal nucleus caudalis (TNC) are involved in the central sensitization of chronic migraine (CM). MicroRNA-155-5p has been shown to modulate the polarization of microglia and participate in inflammatory processes in a variety of neurological diseases. However, its role in CM remains unclear. The purpose of this study was to determine the precise role of miR-155-5p in CM., Methods: A model of CM in C57BL/6 mice was established by recurrent intraperitoneal injection of nitroglycerin (NTG). Mechanical and thermal hyperalgesia were evaluated by Von Frey filaments and radiant heat. The expression of miR-155-5p was examined by qRT-PCR, and the mRNA and protein levels of silent information regulator 1(SIRT1) were measured by qRT-PCR, Western blotting (WB) and immunofluorescence (IF) analysis. The miR-155-5p antagomir, miR-155-5p agomir, SRT1720 (a SIRT1 activator) and EX527 (a SIRT1 inhibitor) were administered to confirm the effects of miR-155-5p and SIRT1 on neuroinflammation and the central sensitization of CM. ELISA, WB and IF assays were applied to evaluate the expression of TNF-α, myeloperoxidase (MPO), IL-10, p-ERK, p-CREB, calcitonin gene-related peptide (CGRP), c-Fos and microglial activation. The cellular localization of SIRT1 was illustrated by IF., Results: After the NTG-induced mouse model of CM was established, the expression of miR-155-5p was increased. The level of SIRT1 was decreased, and partly colocalized with Iba1 in the TNC. The miR-155-5p antagomir and SRT1720 downregulated the expression of p-ERK, p-CREB, CGRP, and c-Fos, alleviating microglial activation and decreasing inflammatory substances (TNF-α, MPO). The administration of miR-155-5p agomir or EX527 exacerbated neuroinflammation and central sensitization. Importantly, the miR-155-5p agomir elevated CGRP and c-Fos expression and microglial activation, which could subsequently be alleviated by SRT1720., Conclusions: These data demonstrate that upregulated miR-155-5p in the TNC participates in the central sensitization of CM. Inhibiting miR-155-5p alleviates neuroinflammation by activating SIRT1 in the TNC of CM mice., (© 2021. The Author(s).)

Background: Parkinson disease is a neurodegenerative disease and is characterized by resting tremor, dementia, and gait disorder. Previous studies have indicated that long noncoding RNA participates in the regulation of the pathogenesis of Parkinson disease. The study aimed to reveal the effects of long noncoding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) on 1-methyl-4-phenylpyridine (MPP + )-induced human neuroblastoma cell injury and the underlying mechanism., Methods: The expressions of NEAT1, microRNA (miR)-519a-3p, and transcription factor specific protein 1 (SP1) were detected by quantitative real-time polymerase chain reaction. The protein expressions of SP1 and inflammation-related factors were determined by Western blot. Cell viability was determined by 3-(4,5-dimethylthazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell apoptosis was investigated by flow cytometry analysis. The targeting relationship between miR-519a-3p and NEAT1 or SP1 was predicted by starBase online database and verified by a dual-luciferase reporter assay., Results: NEAT1 and SP1 expressions were significantly upregulated, whereas miR-519a-3p was downregulated in MPP + -treated neuroblastoma cells in a dose- and time-dependent manner when compared with control groups. NEAT1 knockdown restrained MPP + -induced repression of cell viability and promotion of cell apoptosis and inflammation. Additionally, NEAT1 served as a sponge of miR-519a-3p and regulated MPP + -caused cell injury by interacting with miR-519a-3p. Also, SP1, a target gene of miR-519a-3p, rescued miR-519a-3p-mediated actions under MPP + treatment. Importantly, NEAT1 stimulated SP1 expression through interaction with miR-519a-3p., Conclusions: NEAT1 silencing protected against MPP + -induced neuroblastoma cell injury by regulating the miR-519a-3p/SP1 pathway. This finding provides a novel direction for the development of therapeutic strategies for Parkinson disease., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: To investigate the role of Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in acute myeloid leukemia (AML) and analyze the potential regulatory network of MALAT1/miR-146a/ CXCR4., Methods: The expressions of MALAT1, miR-146a and CXCR4 were performed by qRT-PCR and Western Blot. We conducted trans-well assay, CCK-8 assay and flow cytometry to evaluate the migration, proliferation and apoptosis of AML cells. Also by using luciferase reporter assay, we investigated the interaction between miR-146a and MALAT1 or CXCR4., Results: Firstly, MALAT1 and CXCR4 were upregulated while miR-146a was downregulated in AML patients compared with healthy controls. We observed a negative correlation between miR-146a and MALAT1 or CXCR4, but a positive correlation between MALAT1 and CXCR4 in AML patients. MALAT1 knockdown inhibited migration and proliferation but induced apoptosis of HL-60 cells. MALAT1 restrained miR-146a expression by acting as a ceRNA. miR-146a regulated HL-60 cells migration, proliferation and apoptosis by directly targeting CXCR4 expression. Finally, we found that CXCR4 expression was downregulated by MALAT1 knockdown and partially restored by miR-146a abrogation., Conclusions: Our results showed that MALAT1 regulates migration, proliferation and apoptosis by sponging miR-146a to regulate CXCR4 expression in AML cells, providing novel insights into the role of MALAT1 as a therapeutic target in AML.

The pathological mechanism underlying heat stroke (HS) is associated with the dysbalanced inflammation and coagulation cascade. Cell-derived circulating extracellular vesicles (EVs), as a novel pathway mediating intercellular communication, are associated with the immune response and inflammation in critical inflammatory syndromes, such as sepsis. Although these vesicles contain genetic material correlated with their biological function, their molecular cargo during HS remains unknown. In this study, we evaluate the presence of microRNAs (miRNAs) and messenger RNAs (mRNAs) associated with inflammatory responses and coagulation cascade in exosomes of patients with HS. Blood samples were collected from three patients with HS at the time of admission to the intensive care unit; three healthy volunteers were selected as control. Exosomes were isolated using ultracentrifugation, and their miRNA content was profiled using next-generation sequencing; mRNA content was evaluated using qPCR array. Compared with those from healthy volunteers, exosomes from patients with HS showed substantial changes in the expression of 202 exosomal miRNAs (154 upregulated and 48 downregulated miRNAs). The most upregulated miRNAs included miR-511-3p, miR-122-5p, miR-155-3p, miR-1290, and let7-5p, whereas the most downregulated ones included miR-150-3p, 146a-5p, and 151a-3p. Gene ontology enrichment of the miRNAs of patients with HS compared with control subjects were associated mostly with inflammatory response, including T cell activation, B cell receptor signaling, dendritic cell chemotaxis and leukocyte migration, and platelet activation and blood coagulation. The identified miRNAs were primarily enriched to the signal transduction pathways namely, T cell receptor signaling, Ras signaling, chemokine signaling, platelet activation, and leukocyte transendothelial migration, all of which are associated with inflammation and hemostasis. Multiple targeted mRNAs associated with the inflammatory response, blood coagulation, and platelet activation were further verified in serum exosomes. Exosomes from patients with HS convey miRNAs and mRNAs associated with pathogenic pathways, including inflammatory response and coagulation cascade. Exosomes may represent a novel mechanism for intercellular communication during HS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Wen, Chen, Wu, Liu, Li, Su and Tong.)

Background: Cluster of differentiation molecules are markers of immune cells that have been identified as a potential immunotherapeutic target for cancer treatment. MicroRNAs are small non-coding RNAs that act as tumor suppressors or oncogenes whose importance in diagnosis, prognosis, and treatment of gastric and colorectal cancers has been widely reported. However, their association with cluster of differentiation molecules in gastrointestinal cancers has not been well studied. Therefore, our study aimed to analyze the relationship between microRNAs and cluster of differentiation molecules in gastrointestinal cancers, and to identify cluster of differentiation molecule-associated microRNAs as prognostic biomarkers for gastrointestinal cancer patients., Methods: Targetscan, Starbase, DIANA microT, and miRDB were used to investigate microRNA profiles that might be correlated with cluster of differentiation molecules in gastrointestinal cancers. Moreover, The Cancer Genome Atlas data analysis was used to investigate the association between cluster of differentiation molecules and microRNA expression in patients with gastric, colon, rectal, pancreatic, and esophageal cancers. The Kaplan-Meier plotter was used to identify the association between overall survival and cluster of differentiation molecule-associated microRNA expression in gastrointestinal cancer patients., Results: miR-200a, miR-559, and miR-1236 were negatively associated with CD86, CD81, and CD160, respectively, in almost all types of gastrointestinal cancers, which were further verified in the in vitro studies by transfecting microRNA mimics in gastric cancer, colon cancer, pancreatic, and esophageal cell lines., Conclusion: Our study showed that miR-200a, miR-1236, and miR-559 are identified as cluster of differentiation-associated microRNAs in gastrointestinal cancers, providing a novel perspective to identify new therapeutic targets for cancer immunotherapy in gastrointestinal cancer patients.

Shell-color polymorphism is a common phenomenon in several mollusk species and has been associated with thermal capacity, developmental stability, shell strength, and immunity. Shell-color polymorphism has been related to the differential expression of genes in several signal transduction pathways; however, the functions of micro-RNAs (miRNAs) in shell-color formation remain unclear. In the present study, we compared high-quality, small-RNA transcriptomes in three strains of the Manila clam Ruditapes philippinarum with specific shell-color patterns, artificially selected for six generations. Totals of 114 known and 208 novel miRNAs were identified by high-throughput sequencing, of which nine known and one novel miRNA were verified by stem-loop quantitative real time-polymerase chain reaction. Predicted miRNA targets were subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. miR-137 and miR-216b and the Hedgehog signaling pathway and Wnt signaling pathway were identified as being potentially involved in pigment formation and regulation in R. philippinarum. These results may help to clarify the role of miRNAs in shell coloration and shed light on the mechanisms regulating color formation in bivalve shells.

Cytochrome P450 (CYP) gene expression exhibits large interindividual variation attributable to diverse regulatory factors including microRNAs (miRNAs) and hepatic transcription factors (TFs). We used real-time qPCR with 106 human liver samples to measure the expression and interindividual variation of seven miRNAs and four TFs that have been reported to regulate the expression of CYPs; we also identified factors that influence their expression. The results show that expression of the seven miRNAs and the four TFs exhibits a non-normal distribution and the expression variability is high (89- to 618-fold for miRNA and 12- to 85-fold for TFs). Age contributed to the interindividual variation for miR-148a, miR-27b and miR-34a, whereas cigarette smoking and alcohol consumption significantly reduced HNF4α mRNA levels. Association analysis showed significant correlations among the seven miRNAs as well as the four TFs. Furthermore, we systematically evaluated the impact of the seven miRNAs and four TFs on protein content, mRNA levels, translation efficiency and activity of 10 CYPs. The results show that numerous associations (positive and negative) are present between the seven miRNAs or the four TFs and the 10 CYP phenotypes (as indicated by mRNA, protein and activity); specifically, miR-27b, miR-34a and all four TFs played key roles in the interindividual variation of CYPs. Our results extend previous findings and suggest that miR-27b and miR-34a may be potential direct or indirect master regulators of CYP expression and thereby contribute to the interindividual variations in CYP-mediated drug metabolism., (Copyright © 2021 Elsevier Inc. All rights reserved.)

MicroRNAs (miRNAs) have played a vital role in the regulation of gene expression and have been considered as potential biomarker candidates for early cancer diagnosis. Rapid and sensitive detection of microRNAs is highly desired. Here, we present a new method to rapidly and sensitively determine microRNAs based on the technology of gold nanoparticle catalyzed silver staining enhancement. The new method involves the sandwich hybridization of a capture probe immobilized on a magnetic bead, a reporter probe assembled on gold nanoparticles and a miRNA target, catalytic silver precipitation by gold nanoparticles, magnetic collection of the enhanced sandwich complex, dissolution of the silver precipitation and stripping detection. Using the proposed method the microRNA-7a assay was successfully carried out in less than 70 min and the detection limit was as low as 15 fM. The proposed biosensor may hold great promise in biological monitoring of microRNAs.

Hepatocellular carcinoma (HCC) is one of the most prevalent types of cancer worldwide. Long non‑coding RNAs (lncRNAs) have been reported to frequently participate in the carcinogenesis and development of various types of cancer, including HCC. However, the molecular mechanisms of lncRNA ST8SIA6‑AS1 in HCC remain poorly understood. The present study performed bioinformatics analysis, in addition to using reverse transcription‑quantitative PCR (RT‑qPCR), nuclear‑cytoplasmic fractionation, RNA immunoprecipitation, and Transwell, wound healing, and dual‑luciferase reporter assays, to determine the biological role and regulatory mechanisms of ST8SIA6‑AS1 in HCC. The results revealed that the expression levels of ST8SIA6‑AS1 were upregulated in HCC tissues and cell lines, which were associated with a poor prognosis. Moreover, the genetic knockdown of ST8SIA6‑AS1 inhibited the hypoxia‑induced HCC cell migration and invasion. Additionally, microRNA (miR)‑338, which exhibited downregulated expression levels in HCC tissues and cell lines, was discovered to bind with ST8SIA6‑AS1. The inhibition of miR‑338 partially reversed the inhibitory effects of ST8SIA6‑AS1‑knockdown on the migration and invasion of HCC cells under hypoxia. Subsequently, methylphosphate capping enzyme (MEPCE) was identified to be targeted and negatively regulated by miR‑338. Notably, the overexpression of MEPCE recovered the inhibitory influence over the migratory and invasive abilities of hypoxia‑treated HCC cells promoted by ST8SIA6‑AS1 inhibition. In conclusion, the findings of the present study suggest that lncRNA ST8SIA6‑AS1 may promote the migration and invasion of hypoxia‑induced HCC cells via the miR‑338/MEPCE axis, indicating a potential diagnostic or therapeutic marker for HCC treatment.

Background: Aberrant levels of circulating microRNAs (miRNAs) are potential biomarkers in papillary thyroid carcinoma (PTC) diagnosis and therapy. The aim of this study was to evaluate serum exosomal miR-29a expression as a non-invasive biomarker for PTC diagnosis and prognosis., Methods: Quantitative reverse transcription polymerase chain reaction was applied to measure serum exosomal miR-29a expression levels in blood samples of 119 patients with PTC and 100 control subjects., Results: Serum exosomal miR-29a expression levels were significantly decreased in PTC cases. In addition, receiver operating characteristic (ROC) analysis revealed serum exosomal miR-29a could well differentiate PTC from normal controls. Moreover, serum exosomal miR-29a levels increased progressively and significantly 30 days and 90 days after surgery. Furthermore, PTC patients with lower serum exosomal miR-29a expression had higher risk of recurrence. Decreased serum exosomal miR-29a expression was significantly associated with worse clinical variables including tumor size, extrathyroidal extension, and TNM stage, as well as shorter survival. Finally, both univariate and multivariate identified serum exosomal miR-29a as an independent prognostic indicator for overall survival., Conclusion: These results demonstrated that serum exosomal miR-29a might serve as a potential biomarker for PTC diagnosis and prognosis., (© 2020 The Authors. Journal of Clinical Laboratory Analysis Published by Wiley Periodicals, Inc.)

MicroRNA (miRNA) is involved in the physiological and pathological processes of various malignancies. In this study, miRNA microarray analysis showed that miR-4634 levels in A549 cells increased significantly after everolimus (RAD001) treatment. Decreased expression of miR-4634 was also found in non-small-cell lung carcinoma (NSCLC) cell lines and patients' tumors by qPCR. Additionally, a combination of miR-4634 and RAD001 exerted synergistic antitumor efficacy by inhibiting cell proliferation, migration, and colony formation. High expression of miR-4634 was significantly more common in non-cancerous lung tissue than adenocarcinoma or squamous cell carcinoma tissue (72.8%, 45.7%, and 50.9%, respectively; P < 0.001). Furthermore, high expression of miR-4634 was found to be more frequent in patients without lymph node metastasis (P = 0.037) by in-situ hybridization. Importantly, through univariate and multivariate analysis, high miR-4634 expression was associated with better prognosis of NSCLC patients. In conclusion, miR-4634 may act as a tumor suppressor in NSCLC, and to augment the efficacy of RAD001, co-treatment of miR-4634 and RAD001 might be a potential mTOR-targeted cancer therapy strategy for NSCLC patients. High expression of miR-4634 could be an independent good prognostic biomarker for NSCLC.

Circular RNAs (circRNAs) play vital roles in the pathogenesis and development of multiple cancers, including hepatocellular carcinoma (HCC). Nevertheless, the regulatory mechanisms of circ-SPECC1 in HCC remain poorly understood. In our study, we found that circ-SPECC1 was apparently downregulated in H 2 O 2 -treated HCC cells. Additionally, knockdown of circ-SPECC1 inhibited cell proliferation and promoted cell apoptosis of HCC cells under H 2 O 2 treatment. Moreover, circ-SPECC1 inhibited miR-33a expression by direct interaction, and miR-33a inhibitor partially reversed the effect of circ-SPECC1 knockdown on proliferation and apoptosis of H 2 O 2 -treated HCC cells. Furthermore, TGFβ2 was demonstrated to be a target gene of miR-33a and TGFβ2 overexpression rescued the phenotypes of HCC cells attenuated by miR-33a mimics. Meanwhile, autophagy inhibition by 3-methyladenine (3-MA) abrogated the effect of miR-33a mimics on proliferation and apoptosis of H 2 O 2 -treated HCC cells. Finally, knockdown of circ-SPECC1 hindered tumor growth in vivo. In conclusion, our study demonstrated that circ-SPECC1 regulated TGFβ2 and autophagy to promote HCC tumorigenesis under oxidative stress via miR-33a. These findings might provide potential treatment strategies for patients with HCC., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Lung cancer is the leading cause of cancer-related deaths worldwide, with 50-70% of patients suffering from bone metastasis. Accumulating evidence has demonstrated that miRNAs are involved in cell proliferation, migration, and invasion in malignancy, such as lung cancer bone metastasis. In the present study, we demonstrated that reduced miR-192-5p and increased TRIM44 levels were associated with the proliferation, migration and invasion of lung cancer. Furthermore, the potential functions of miR-192-5p were explored in A549 and NCI-H1299 cells. We found that miR-192-5p upregulation suppressed tumour behaviours in lung cancer cells. To further investigate whether miR-192-5p is associated with TRIM44, we used TargetScan software to predict the binding site between miR-192-5p and TRIM44. Luciferase activity assays were performed to verify this prediction. In addition, the significant role of miR-192-5p in negatively regulating TRIM44 expression was manifested by our research group. our results suggest that miR-192-5p inhibited the proliferation, migration and invasion of lung cancer through TRIM44.

Sepsis is a life-threatening disease caused by infection. Inflammation is a key pathogenic process in sepsis. Paeonol, an active ingredient in moutan cortex (a Chinese herb), has many pharmacological activities, such as anti-inflammatory and antitumour actions. Previous studies have indicated that paeonol inhibits the expression of HMGB1 and the transcriptional activity of NF-κB. However, its underlying mechanism is still unknown. In this study, microarray assay and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) results confirmed that paeonol could significantly up-regulate the expression of miR-339-5p in RAW264.7 cells stimulated by LPS. Dual-luciferase assays indicated that miR-339-5p interacted with the 3' untranslated region (3'-UTR) of HMGB1. Western blot, immunofluorescence and enzyme-linked immunosorbent assay (ELISA) analyses indicated that miR-339-5p mimic and siHMGB1 both negatively regulated the expression and secretion of inflammatory cytokines (e.g., HMGB1, IL-1β and TNF-α) in LPS-induced RAW264.7 cells. Studies have confirmed that IKK-β is targeted by miR-339-5p, and we further found that paeonol could inhibit IKK-β expression. Positive mutual feedback between HMGB1 and IKK-β was observed when we silenced HMGB1 or IKK-β. These results indicated that paeonol could attenuate the inflammation mediated by HMGB1 and IKK-β by upregulating miR-339-5p expression. In addition, we constructed CLP model mice by cecal ligation and puncture. Paeonol was used to intervene to investigate its anti-inflammatory effect in vivo. The results showed that paeonol could improve the survival rate of sepsis mice and protect the kidney of sepsis mice.

The long noncoding RNA myocardial infarction associated transcript (MIAT) was reported to be involved in the progression of multiple cancers. However, the exact roles and molecular mechanisms of MIAT in papillary thyroid cancer (PTC) progression are still unknown. We examined the expression levels of lncRNA MIAT in 50 paired PTC tissue specimens and four PTC cell lines by real time quantitative PCR (qRT-PCR). Cell counting kit 8, colony formation, wound healing and transwell assays were performed to examine the effect of MIAT on proliferation, colony formation, migration and invasion. Tumor xenograft models were created to detect the role of MIAT in vivo tumorigenesis. The target relationships were predicted by miRcode algorithm, and confirmed by dual luciferase reporter gene assay and qRT-PCR. We found that MIAT was up-regulated in PTC tissues and cell lines. High MIAT expression was positively associated with advanced tumor-node-metastasis (TNM) stage and lymph node metastasis. Functional assays showed that knockdown of MIAT in PTC cells significantly inhibited cell proliferation, colony formation, migration and invasion in vitro, as well as impaired tumor growth in vivo. Luciferase assays further confirmed that miR-212 interacts with MIAT. Additionally, the negatively correlation of miR-212 with MIAT was verified in patients' samples. Repression of miR-212 partly abrogated the inhibitory effects of MIAT knockdown on PTC cells. Taken together, these results indicated that MIAT might be an oncogenic lncRNA that promoted PTC progression, and might be a potential therapeutic target for PTC., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Cardiac hypertrophy with maladjusted cardiac remodeling is the leading cause of heart failure. In the past decades, long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been proved to exert multiple functions in cellular biological behaviors; however, their role in cardiac hypertrophy remains largely unclear. Presently, we first obtained hypertrophic H9c2 cells by treating with angiotensin II (Ang II) and uncovered upregulation of lncRNA taurine upregulated gene 1 (TUG1) in such H9c2 cells. Then, we demonstrated that silencing TUG1 attenuated Ang II-induced cardiac hypertrophy. Besides, a strong interactivity of TUG1 with miR-29b-3p at the putative sites was validated, suggesting that TUG1 was an endogenous sponge of miR-29b-3p in H9c2 cells. Additionally, the expression of miR-29b-3p was strikingly reduced by TUG1 upregulation and also inhibited under Ang II treatment, whereas it was restored after silencing TUG1 in hypertrophic cells. Also, we proved miR-29b-3p as a negative regulator in cardiac hypertrophy. Finally, miR-29b-3p inhibition abolished the anti-hypertrophy effect of TUG1 depletion in Ang II-treated H9c2 cells. Collectively, our findings confirmed that TUG1 functioned as a positive modulator of cardiac hypertrophy via sponging miR-29b-3p, indicating that TUG1 might serve as a potential target for the treatment of cardiac hypertrophy and even heart failure.

Yin Yang 1 (YY1) is a zinc-finger protein that plays critical roles in various biological processes by interacting with DNA and numerous protein partners. YY1 has been reported to play dual biological functions as either an oncogene or tumor suppressor in the development and progression of multiple cancers, but its role in human nasopharyngeal carcinoma (NPC) has not yet been revealed. In this study, we found that YY1 overexpression significantly inhibits cell proliferation and cell-cycle progression from G 1 to S and promotes apoptosis in NPC cells. Moreover, we identified YY1 as a component of the c-Myc complex and observed that ectopic expression of YY1 inhibits c-Myc transcriptional activity, as well as the promoter activity and expression of the c-Myc target gene microRNA-141 ( miR-141 ). Furthermore, restoring miR-141 expression could at least partially reverse the inhibitory effect of YY1 on cell proliferation and tumor growth and on the expression of some critical c-Myc targets, such as PTEN/AKT pathway components both in vitro and in vivo We also found that YY1 expression is reduced in NPC tissues, negatively correlates with miR-141 expression and clinical stages in NPC patients, and positively correlates with survival prognosis. Our results reveal a previously unappreciated mechanism in which the YY1/c-Myc/ miR-141 axis plays a critical role in NPC progression and may provide some potential and valuable targets for the diagnosis and treatment of NPC., (© 2019 Li et al.)

Colorectal cancer (CRC) is the one of the most common malignant tumors worldwide. Recent years, widespread long non-coding RNAs (lncRNAs) have been discovered and are known to regulate gene expression in cancers. However, the roles and underlying mechanisms of lncRNA in CRC remain largely unclear. Here, we firstly revealed that repression of lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) inhibited cell proliferation and migration in HCT116 cells and overexpression of NEAT1 promoted cell proliferation and migration in SW480 cells using CCK8 assay and transwell assay. Then, we found that suppression of NEAT1 increased the miR-196a-5p expression in HCT116 cells, while elevation of NEAT1 decreased the miR-196a-5p expression in SW480 cells using qPCR assay. Furthermore, miR-196a-5p could bind to the predicted binding site of NEAT1. We then found that miR-196a-5p was involved in the role of NEAT1 in CRCs. In addition, we demonstrated that miR-196a-5p mimics inhibited the glial cell-derived neurotrophic factor (GDNF) expression in HCT116 cells and meanwhile, miR-196a-5p inhibitor promoted GDNF expression in SW480 cells using qPCR and western blot analysis. Then, we proved that miR-196a-5p exerted its function via regulating GDNF expression in CRCs. Ultimately, our study demonstrated that NEAT1 exerted its role via miR-196a-5p/GDNF axis in CRCs. In summary, this work provided the first evidence of a NEAT1/miR-196a-5p/GDNF regulatory pathway in CRC.

Accumulating evidence indicates that microRNAs (miRs) are important regulators in a number of types of human cancer, including non‑small cell lung cancer (NSCLC). The function of miR‑3120‑5p in NSCLC remains unclear. In the present study, it was demonstrated that miR‑3120‑5p was significantly upregulated in NSCLC tissues. Additionally, miR‑3120‑5p expression level was positively associated with NSCLC metastasis and tumor, node and metastasis stage. Furthermore, it was demonstrated that miR‑3120‑5p exhibited potential as an indicator of NSCLC for use in diagnosis. Through functional experiments, it was demonstrated that overexpression of miR‑3120‑5p promoted the proliferation, colony formation and invasion of NSCLC cells. miR‑3120‑5p overexpression significantly promoted cell cycle progression. Mechanistically, it was demonstrated that Krueppel‑like factor 4 (KLF4) was a target of miR‑3120‑5p in NSCLC cells. Overexpression of miR‑3120‑5p repressed the expression of KLF4 in A549 and H460 cells. Furthermore, it was demonstrated that KLF4 was downregulated in NSCLC tissues and cell lines. Overexpression of KLF4 significantly reversed the effects of miR‑3120‑5p on NSCLC cell proliferation and invasion. In conclusion, the present study demonstrated that miR‑3120‑5p promoted NSCLC progression by directly targeting KLF4.

BACKGROUND Growing evidence indicates that a non-coding RNA named miR-34b/c plays crucial roles in carcinogenesis, and its common polymorphism, pri-miR-34b/c rs4938723, also participates in this process and is associated with cancer susceptibility. However, this association was previously undefined and ambiguous. Therefore, we carried out an updated analysis to evaluate this relationship between rs4938723 polymorphism and cancer susceptibility. MATERIAL AND METHODS PubMed, EMbase, Web of Science and Chinese language (WanFang, CNKI and VIP) databases were searched for relevant studies until Sep 10, 2018. Odds ratios and 95% confidence interval were applied to assess this relationship. RESULTS Thirty case-control studies were retrieved. No positive association was found in either the overall study population or in the subgroups, based on ethnicity, source of group, sex, smoking, and drinking status. The main results were observed in the stratified analysis subgroups in cancer type subgroup: rs4938723 polymorphism may be a protective factor in leukemia, colorectal cancer, and esophageal cancer; however, C-allele was a risk factor in carriers for hepatocellular carcinoma. Last but not the least, poor positive results were discovered in the age subgroup. CONCLUSIONS Current meta-analysis suggested that rs4938723 polymorphism was potentially associated with hepatocellular carcinoma risk, but this polymorphism had a decreased association for susceptibility to esophageal cancer, leukemia, and colorectal cancer. Furthermore, studies with larger sample sizes and including gene-gene or gene-environment interactions should be carried out to elucidate the role of rs4938723 polymorphism in cancer risk.

Objective: Stroke remains the most common malignant cerebrovascular event in the world. The correlation between the expression of miR-544 and the degree of cerebral ischemia reperfusion (CIR) injury has not been well recognized in recent years. This study focuses on the effect of miR-544 on inflammation and apoptosis after CIR., Patients and Methods: Plasma expression of miR-544 in ischemic stroke (IS) patients and healthy controls was determined by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). The effects of miR-544 on cerebral infarction and neurological deficits were verified in vitro by tail vein injection of Ago-miR-544. Western blotting was utilized to examine protein expressions of key proteins involving in inflammation and apoptosis in mouse brain. Western blotting, immunofluorescence staining and luciferase assays were used to demonstrate whether miR-544 influences the expression of interleukin-1 receptor-associated kinase 4 (IRAK4), downstream inflammatory and apoptosis-related proteins., Results: MiR-544 was found decreased in peripheral blood of IS patients compared with healthy controls. MiR-544 has been shown to relieve neurological deficits and reduce the volume of cerebral infarction in mice. Overexpression of miR-544 ameliorated the inflammation and apoptotic responses in brain tissue after ischemia reperfusion by down-regulating the expression of IRAK4, whereas the low expression was opposite in vivo and in vitro., Conclusions: We found that miR-544 may participate in controlling inflammation and apoptosis after ischemia-reperfusion by targeting IRAK4, providing possible diagnostic indicators and therapeutic targets for IS.

miR-212 as a tumor suppressor has been reported to be downregulated in multiple cancer cells lines and tumor tissues. However, its role in thyroid cancer has nor been investigated. Therefore, the present study aimed to investigate the role of miR-212 in human thyroid cancer and the underlying mechanisms. In the present study, we demonstrated that miR-212 expression was significantly decreased in thyroid cancer specimens and cell lines compared with adjacent normal tissues and normal thyroid cell lines. In addition, we demonstrated that miR-212 downrwegulation in thyroid cancer tissues was negatively associated with lymph node metastasis and advanced clinical stage. Functionally, ectopic expression of miR-212 by transfection with miR-212 mimic significantly inhibited proliferation, colony formation, migration and invasion in TPC-1 cells. In addition, Sirtuin 1 (SIRT1) was identified as a direct target of miR-212 and its expression was inversely correlated with miR-212 expression in thyroid cancer tissues. Overexpression of SIRT1 could effectively rescue miR-212 mimic-induced suppression of cell proliferation, migration and invasion in TPC-1 cells. In vivo, miR-212 overexpression significantly inhibited tumor growth in a nude mice model. In light of these findings, miR-212 may function as a tumor suppressor in thyroid cancer by targeting SIRT1.

Purpose: The aims of this study were to test the influence of miR-217 on the proliferation, invasion, migration of thyroid cancer and the relevant mechanism., Method: miR-217 expression levels in thyroid cancer tissues and cell lines were detected by quantitative real-time PCR (qRT-PCR).Cell Counting Kit-8, flow cytometer, wound healing, transwell invasion assays were applied to evaluate the effect of miR-217 on proliferation, apoptosis, migration and invasion of thyroid cells. The luciferase reporter assay, qRT-PCR, and western blot were used to identify target of miR-217. Relative relationship of expression level between miR-217 and AKT3 was analyzed in thyroid cancer tissues. Xenograft transplantation was performed to test effect of miR-217 in vivo., Results: We found that the expression of miR-217 was significantly decreased in thyroid cancer tissues cell lines. Significantly, decreased miR-217 expression were associated with the clinical stage and lymph node metastasis. Function studies revealed that miR-217 overexpression in thyroid cancer cells inhibited proliferation, migration, and invasion in vitro, as well as suppressed tumor growth in vivo. Subsequently, AKT3 was identified as a target of miR-217 in thyroid cancer. AKT3 expression was upregulated in thyroid cancer tissues, was inversely correlated with miR-217expression. Besides, overexpression of AKT3 efficiently abrogates suppressive effect on proliferation, migration and invasion in thyroid cancer cells caused by overexpression of miR-217., Conclusion: These data demonstrated a tumor suppressor role for miR-217 in thyroid cancer development and progression by targeting AKT3, suggesting miR-217 might be a potential target for thyroid cancer., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Recent studies have suggested that interleukin 1 receptor-like 1 (ST2) plays a critical role in pathogenesis of several cardiovascular disease conditions. In this study, we examined association of 13 single nucleotide polymorphisms (SNPs) of ST2 gene with essential hypertension (EH) risk in 1151 patients with EH and 1135 controls. Our study showed that variants rs11685424, rs12999364 and rs3821204 are highly associated with an increase in risk of EH, while rs6543116 is associated with a decrease risk of EH. Notably, in silico analyses suggested the G>C change of rs3821204, which located within the 3'UTR of soluble ST2 mRNA, disrupted a putative binding site for miR202-3p. Functional analyses suggested that miR-202-3p significantly decreased soluble ST2-G mRNA stability and inhibited its endogenous expression. Furthermore, we found increased plasma-soluble ST2 (sST2) level was highly associated with CC genotype of rs3821204 in vivo. Taken together, our findings provide the first evidence that genetic variants in ST2 gene are associated with EH risk and variant rs3821204 may influence the development of EH by controlling sST2 expression., (© 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Objectives: The aims of this study were to investigate the functions of GAS5 as a tumor suppressor in cervical cancer and explore the mechanism., Methods: The expression of GAS5 and microRNA 21 (miR-21) was detected in primary cervical cancer tissue specimens, as well as in cervical cancer cell lines. We identified the interaction of GAS5 and miR-21 by quantitative polymerase chain reaction, Western blot, and dual-luciferase reporter assay. We also studied the functions of GAS5 in proliferation, apoptosis, migration, and invasion in cervical cancer cells in vitro and vivo. Finally, the impact of GAS5 on cisplatin resistance and its mechanism in cervical cancer cells was also identified., Results: The expression of GAS5 and miR-21 was detected in primary cervical cancer tissue specimens, as well as in cervical cancer cell lines. GAS5, which is a tumor suppressor playing roles in inhibiting the malignancy of cervical cancer cells, including proliferation in vivo and vitro, migration, and invasion, has a low expression in cervical cancer tissue and cervical cancer cell lines, whereas miR-21 expression is high. GAS5 significantly decreased the expression of miR-21, and there is a reciprocal repression of gene expression between GAS5 and miR-21. Besides, most importantly, we found that high expression of GAS5 and low expression of miR-21 can enhance the sensitivity of SiHa/cDDP cancer cells to cisplatin. A further experiment for identifying the mechanism of cisplatin resistance by GAS5 showed that GAS5 can not only regulate phosphatase and tensin homolog through miR-21 but also influence the phosphorylation of Akt., Conclusions: Our results indicate that GAS5 is a direct target of miR-21 and can predict the clinical staging of cervical cancer. Most importantly, GAS5 can also influence cisplatin resistance in cervical cancer via regulating the phosphorylation of Akt. All of these suggest that GAS5 may be a novel therapeutic target for treating cervical cancer.

As an important type of somatic cell, granulosa cells play a major role in deciding the fate of follicles. Therefore, analyses of granulosa cell apoptosis and follicular atresia have become hotspots of animal research. Autophagy is a cellular catabolic mechanism that protects cells from stress conditions, including starvation, hypoxia, and accumulation of misfolded proteins. However, the relationship between autophagy and apoptosis in granulosa cells is not well known. Here, we demonstrate that let-7g regulates the mouse granulosa cell autophagy signaling pathway by inhibiting insulin-like growth factor 1 receptor expression and affecting the phosphorylation of protein kinase B/mammalian target of rapamycin. Small interference-mediated knockdown of insulin-like growth factor 1 receptor significantly promoted autophagy signaling of mouse granulosa cells. In contrast, overexpression of insulin-like growth factor 1 receptor in mouse granulosa cells attenuated autophagy activity in the presence of let-7g. In addition, overexpression of let-7g increased the apoptosis rate, as indicated by an increased number of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling-positive cells. Finally, 3-methyladenine as well as the lysosomal enzyme inhibitor chloroquine partially blocked apoptosis. In summary, this study demonstrates that let-7g regulates autophagy in mouse granulosa cells by targeting insulin-like growth factor 1 receptor and downregulating protein kinase B/mammalian target of rapamycin signaling, and that mouse granulosa cell autophagy induced by let-7g participates in apoptosis., (Copyright © 2016. Published by Elsevier Ltd.)

Tuberculosis is still the widest spread infectious disease in the world, and more in-depth studies are needed on the interaction between the pathogen and the host. Due to the highest lipid components in Mycobacterium tuberculosis, the CD1 family that specifically presents antigenic lipids plays important roles in the antituberculosis immunity, especially CD1c, which functions as the intracellular Ag inspector at the full intracellular range. However, downregulation of the CD1c mRNA level has been observed in M. tuberculosis-infected cells, which is consistent with the regulatory mechanism of miRNA on gene expression. In this study, through combinatory analysis of previous miRNA transcriptomic assays and bioinformatic predictions by web-based algorithms, miR-381-3p was predicted to bind the 3'-untranslated region of CD1c gene. In vivo expression of miR-381-3p in dendritic cells (DCs) of TB patients is higher than in DCs of healthy individuals, inversely related to CD1c. Suppression of CD1c expression in bacillus Calmette-Guérin (BCG)-infected DCs was accompanied with upregulation of miR-381-3p, whereas inhibition of miR-381-3p could reverse suppression of CD1c expression and promote T cell responses against BCG infection. Further study indicated that miR-381-3p is also one of the mediators of the immune suppressor IL-10. Collectively, these results demonstrated the mechanism that suppression of CD1c by BCG infection is mediated by miR-381-3p. This finding may provide a novel approach to boost immune responses to M. tuberculosis., (Copyright © 2016 by The American Association of Immunologists, Inc.)

We previously reported that miR-1207-5p can inhibit epithelial-mesenchymal transition (EMT) induced by growth factors such as EGF and TGF-β, but the exact mechanism is unclear. Here we identified that Colony stimulating factor 1 (CSF1) is a target gene of miR-1207-5p. CSF1 controls the production, differentiation and function of macrophage and promotes the release of proinflammatory chemokines. We showed that miR-1207-5p inhibited lung cancer cell A549 proliferation, migration and invasion in vitro, and suppressed the STAT3 and AKT signalings. miR-1207-5p overexpression can increase HUVEC angiogenesis, and can modulate the M2 phenotype of macrophage. miR-1207-5p also significantly inhibited A549 cells metastasis in a nude mouse xenograft model. miR-1207-5p and CSF1 expression levels and their relationship with lung cancer survival and metastasis status were assayed by means of a lung cancer tissue microarray. Macrophage is an essential part of the tumor microenvironment, thus the miR-1207-5p-CSF1 axis maybe a new regulator of lung cancer development through modulating the tumor microenvironment., Competing Interests: The authors declare no conflicts of interest.

Bromodomain containing 7 (BRD7) was identified as a nuclear transcriptional regulatory factor. BRD7 functions as a tumor suppressor in multiple cancers, including nasopharyngeal carcinoma (NPC). In this study, we reported a novel mechanism of BRD7 in NPC progression. We demonstrated that the expression of miR-141 was remarkably increased in NPC tissues and was negatively correlated with the expression of BRD7 and the survival rate of NPC patients. Decreased expression levels of miR-141, including the primary, the precursor and the mature forms of miR-141, were found in BRD7-overexpressing HEK293, 5-8F and HNE1 cells compared the control cells, while there was no obvious effect on the expression levels of the two critical enzymes Drosha and Dicer. BRD7 can negatively regulate the promoter activity of miR-141, while no obvious binding site of BRD7 was found in the potential promoter region of miR-141. Moreover, ectopic expression of miR-141 can significantly promote cell proliferation and inhibit apoptosis in NPC, and rescuing the expression of miR-141 in BRD7-overexpressing NPC cells could partially reverse the tumor suppressive effect of BRD7 on cell proliferation and tumor growth in vitro and in vivo. Furthermore, the activation of the PTEN/AKT pathway mediated by the overexpression of BRD7 could be inhibited by rescuing the expression of miR-141, which accordingly results in the partial restoration of cell proliferation and tumor growth. Our findings demonstrate that the BRD7/miR-141/PTEN/AKT axis has critical roles in the progression of NPC and provide some promising targets for the diagnosis and treatment of NPC.

Background: Nasopharyngeal carcinoma (NPC) is prevalent in South East Asia and Southern China particularly, despite the reported 5-year survival ratio is relative higher than other deadly cancers such as liver, renal, pancreas cancer, the lethality is characterized by high metastatic potential in the early stage and high recurrence rate after radiation treatment. MicroRNA-29c was found to be down-regulated in the serum as well as in the tissue of nasopharyngeal carcinoma tissue., Methods: In this study, we found accidentally that the transfection of pre-miR-29c or miR-29c mimics significantly increases the expression level of miR-34c and miR-449a but doesn't affect that of miR-222 using real-time quantitative PCR in nasopharyngeal carcinoma cell lines. To explore the molecular mechanism of the regulatory role, the cells are treated with 5-Aza-2-deoxycytidine (5-Aza-CdR) treatment and the level of miR-34c and miR-449a but not miR-222 accumulated by the treatment. DNA methyltransferase 3a, 3b were down-regulated by the 5-Aza-CdR treatment with western blot and real-time quantitative PCR., Results: We found that pre-miR-29c or miR-29c mimics significantly increases the expression level of miR-34c and miR-449a. We further found DNA methyltransferase 3a and 3b are the target gene of miR-29c. Restoration of miR-29c in NPC cells down-regulated DNA methyltransferase 3a, 3b, but not DNA methyltransferase T1., Conclusions: The regulation of miR-29c/DNMTs/miR-34c\449a is an important molecular axis of NPC development and targeting DNMTs or restoring of miR-29c might be a promising therapy strategy for the prevention of NPC.

microRNA-126 (miR-126) has been reported to play tumor suppressor roles in various types of cancers. Although it has been reported that miR-126 expression is downregulated in papillary thyroid carcinoma (PTC), the precise role and underlying molecular mechanism of miR-126 in PTC remains unclear. Therefore, the aims of the present study were to investigate the role and potential mechanism of miR-126 in tumorigenicity of PTC in vivo and in vitro. We observed that the miR-126 expression level was significantly downregulated in PTC tissue and PTC cell lines, the aberrant expression of miR-126 was correlated with lymph node metastasis, tumor size and TNM stage. We also showed that restoration of miR-126 in PTC cells inhibited cell proliferation, colony formations, migration and invasion, promoted cell apoptosis and cell cycle arrest at G1 stage in vitro, as well as inhibited tumor growth and decreased tumor volume and weight in vivo. Furthermore, low-density lipoprotein receptor‑related protein 6 (LRP6), a regulator of the Wnt/β‑catenin signaling cascade, was identified as a crucial target gene of miR-126. Overexpression of miR-126 inhibited LP6 expression on mRNA and protein levels, and deactivate Wnt/β-catenin signaling pathway. These results suggested that miR-126 functions as a tumor-suppressive miRNA by targeting LRP6 regulating Wnt/β-catenin signaling pathway and represents a therapeutic target for PTC.

Objective: To investigate the role of miR-520a in regulation ErbB4 expression and the biological behavior of esophageal squamous cell carcinoma (ESCC)., Methods: The role of miR-520a in regulating the expression of ErbB4 was investigated by Western blotting and luciferase reporter assay system. The effect of miR-520a on the proliferation and invasion of ESCC cells was detected by MTT and Transwell invasion assay, respectively., Results: Western blotting and luciferase reporter assay revealed that miR-520a down-regulated the expression of ErbB4 in vitro. miR-520a significantly inhibited the proliferation and suppressed the invasion of ESCC cell line Eca109., Conclusion: miR-520a regulates the expression of ErbB4 and suppresses the proliferation and invasion of ESCC cells in vitro, suggesting its role as a tumor suppressor.

Background: ErbB4 expression has been noted in various tumors, but its regulatory mechanism in esophageal squamous cell carcinoma (ESCC) remains unclear. The aim of this study was to investigate whether miR-302b regulates the expression of ErbB4 at the post-transcriptional level and to determine its expression, significance, and function in ESCC., Methods: We used real-time reverse transcriptase-polymerase chain reaction to quantify the expression of miR-302b in 50 ESCC tissues and analyzed its relationship with clinicopathological factors and survival. Then, we investigated the post-transcriptional regulation of ErbB4 expression using immunoblot analysis and luciferase reporter assays. Finally, the effects of miR-302b on proliferation, apoptosis, and invasion of ESCC cells was detected using MTT, flow cytometric analysis, and transwell invasion assays, respectively., Results: miR-302b was significantly down-regulated and correlated with tumor differentiation and lymph node metastasis in ESCC. Univariate and multivariate analyses indicated that low miR-302b expression might be a poor prognostic factor. Further studies demonstrated that miR-302b post-transcriptionally down-regulated the expression of ErbB4 in vitro. Moreover, miR-302b inhibited proliferation by inducing apoptosis and repressed invasion in the ESCC cell lines., Conclusions: miR-302b is a potential molecular marker of ESCC and functions as a tumor suppressor by post-transcriptionally regulating ErbB4.

Objective: Propofol is one of the extensively and commonly used intravenous anaesthetic agents. The aims of the current study were to evaluate effects of propofol on the behavior of human epithelial ovarian cancer (EOC) cells and role of miR-let-7i in these effects., Materials and Methods: The effects of propofol on cell proliferation and apoptosis were detected by MTT assays and flow cytometry. Real-time polymerase chain reaction (PCR) was used to assess miR-let-7i expression in human EOC cells OVCAR-3 with or without propofol treatment. Finally, the authors evaluated the effect ofmiR-let-7i on propofol-induced anti-tumor activity using anti-miR-let-7i., Results: Propofol inhibited the proliferation of OVCAR-3 cells in a dose- and time-dependent manner. After exposure to propofol for 24 hours, OVCAR-3 cells showed increased apoptosis and increased expression of miR-let-7i. Finally, anti-miR-let-7i reversed the effect of propofol on cell proliferation and apoptosis., Conclusions: Propofol can effectively inhibit proliferation and induce apoptosis of EOC cells and modulation of miR-let-7i possibly contributes to the anti-tumor action of propofol.