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Gastric cancer (GC) is one of the most common and lethal gastrointestinal malignancies worldwide. Many studies have shown that development of GC and other malignancies is mainly driven by alterations of cellular signaling pathways. MicroRNAs (miRNAs) are small noncoding molecules that function as tumor-suppressors or oncogenes, playing an essential role in a variety of fundamental biological processes. In order to understand the functional relevance of miRNA dysregulation, studies analyzing their target genes are of major importance. Here, we chose to analyze two miRNAs, miR-20b and miR-451a, shown to be deregulated in many different malignancies, including GC. Deregulated expression of miR-20b and miR-451a was determined in GC cell lines and the INS-GAS mouse model. Using Western Blot and luciferase reporter assay we determined that miR-20b directly regulates expression of PTEN and TXNIP, and miR-451a: CAV1 and TSC1. Loss-of-function experiments revealed that down-regulation of miR-20b and up-regulation of miR-451a expression exhibits an anti-tumor effect in vitro (miR-20b: reduced viability, colony formation, increased apoptosis rate, and miR-451a: reduced colony forming ability). To summarize, the present study identified that expression of miR-20b and miR-451a are deregulated in vitro and in vivo and have a tumor suppressive role in GC through regulation of the PI3K/AKT/mTOR signaling pathway.

OBJECTIVE: To explore the role of miR-451a in the migration and invasion of non-small cell lung cancer (NSCLC) cells. MATERIALS AND METHODS: Quantitative Real time-polymerase chain reaction (qRT-PCR) and Western blot were performed to detect the levels of miR-451a and activating transcription factor 2 (ATF2) in NSCLC. Transwell assay was employed to analyze the migratory and invasive abilities in NSCLC cells. Dual-luciferase reporter assay was applied to confirm the binding condition of miR-451 and its target gene in NSCLC cells. RESULTS: MiR-451a was downregulated in NSCLC tissues and lung cancer cell lines A549 and NCI-H460, while ATF2 was upregulated. The mRNA level of miR-451a was negatively correlated to ATF2. Additionally, miR-451a regulated cell migration and invasion through targeting ATF2. Furthermore, ATF2 could reverse the inhibitory migration and invasion of A549 cells induced by miR-451a. CONCLUSIONS: MiR-451a inhibits the migratory and invasive abilities of NSCLC cells through ATF2 regulation. The newly identified miR-451a/ATF2 axis provides a novel insight into the pathogenesis of NSCLC. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To explore the role of miR-451a in the migration and invasion of non-small cell lung cancer (NSCLC) cells. MATERIALS AND METHODS: Quantitative Real time-polymerase chain reaction (qRT-PCR) and Western blot were performed to detect the levels of miR-451a and activating transcription factor 2 (ATF2) in NSCLC. Transwell assay was employed to analyze the migratory and invasive abilities in NSCLC cells. Dual-luciferase reporter assay was applied to confirm the binding condition of miR-451 and its target gene in NSCLC cells. RESULTS: MiR-451a was downregulated in NSCLC tissues and lung cancer cell lines A549 and NCI-H460, while ATF2 was upregulated. The mRNA level of miR-451a was negatively correlated to ATF2. Additionally, miR-451a regulated cell migration and invasion through targeting ATF2. Furthermore, ATF2 could reverse the inhibitory migration and invasion of A549 cells induced by miR-451a. CONCLUSIONS: MiR-451a inhibits the migratory and invasive abilities of NSCLC cells through ATF2 regulation. The newly identified miR-451a/ATF2 axis provides a novel insight into the pathogenesis of NSCLC. [ABSTRACT FROM AUTHOR]

Background Macrophage migration inhibitory factor is a proinflammatory cytokine that has been associated with various psychiatric disorders. MicroRNA-451a can directly target macrophage migration inhibitory factor and downregulate its expression in cells. However, the role of macrophage migration inhibitory factor and microRNA-451a in psychiatric patients treated with psychotherapeutic interventions is unknown. In this study, our aim was to investigate levels of macrophage migration inhibitory factor and its regulating microRNA-451a in patients with depression, anxiety, or stress and adjustment disorders who underwent mindfulness-based therapy or treatment as usual. Methods A total of 168 patients with psychiatric disorders were included from a randomized controlled trial that compared mindfulness-based therapy with treatment as usual. Plasma levels of macrophage migration inhibitory factor and microRNA-451a were measured at baseline and after the 8-week follow-up using Luminex assay and qPCR. Results Macrophage migration inhibitory factor levels decreased significantly in patients posttreatment, whereas microRNA-451a levels showed a nonsignificant change. Macrophage migration inhibitory factor levels were inversely associated with microRNA-451a expression levels at baseline (β=−0.04, P =.008). The change in macrophage migration inhibitory factor levels (follow-up levels minus baseline levels) was associated with the change in microRNA-451a (follow-up levels minus baseline levels) (β=−0.06, P <.0001). The change in either macrophage migration inhibitory factor or microRNA-451a was not associated with improvement in psychiatric symptoms. Conclusion We demonstrate that the levels of macrophage migration inhibitory factor decreased after psychotherapeutic interventions in patients with psychiatric disorders. However, this reduction was not associated with an improvement in psychiatric symptoms in response to the treatment. We also found an association between macrophage migration inhibitory factor and its regulating microRNA. However, this association needs to be further examined in future studies. [ABSTRACT FROM AUTHOR]

Abstract: 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. [ABSTRACT FROM AUTHOR]

The identification of aberrant microRNA (miRNA) expression during chemical-induced hepatic dysfunction will lead to a better understanding of the substantial role of miRNAs in liver diseases. 1,2-Dichloroethane (1,2-DCE), a chlorinated organic toxicant, can lead to hepatic abnormalities in occupationally exposed populations. To explore whether aberrant miRNA expression is involved in liver abnormalities mediated by 1,2-DCE exposure, we examined alterations in miRNA expression patterns in the livers of NIH Swiss mice after dynamic inhalation exposure to 350 or 700 mg m-3 1,2-DCE for 28 days. Using a microarray chip, we discovered that only mmumiR-451a was significantly upregulated in the liver tissue of mice exposed to 700 mg m-3 1,2-DCE; this finding was validated by quantitative real-time polymerase chain reaction. In vitro study revealed that it was metabolite 2-chloroacetic acid, not 1,2-DCE that resulted in the upregulation of mmu-miR-451a in the mouse AML12 cell line. Furthermore, our data showed that the upregulation of mmu-miR-451a induced by 2-chloroacetic acid could suppress the expression of glycerol kinase and lead to the inhibition of glycerol gluconeogenesis in mouse liver tissue and AML12 cells. These observations provide evidence that hepatic mmu-miR-451a responds to 1,2-DCE exposure and might induce glucose metabolism disorders by suppressing the glycerol gluconeogenesis process. [ABSTRACT FROM AUTHOR]

Microcystin-LR is a cyclic heptapeptide hepatotoxin produced by harmful cyanobacteria. A panel of microRNAs containing miR-451a were found to be significantly changed in normal human liver cells HL7702 after exposure to microcystin-LR (MC-LR) in our previous study. However, the functions of miR-451a in hepatotoxicity induced by MC-LR remained unclear. The study aimed to investigate the impacts of miR-451a in HL7702 cells following treatment with 5 or 10 μM MC-LR. The comet assay indicated that MC-LR can influence Olive tail moment (OTM) in HL7702 cells. Furthermore, increase of miR-451a significantly repressed DNA damage and the protein expression level of γ-H2AX induced by MC-LR. Moreover, over-expression of miR-451a inhibited the expression level of p-AKT1 protein in cells following treatment by MC-LR. These results showed that miR-451a may protect from MC-LR-induced DNA damage by down-regulating the expression of p-AKT1, which provides new clues for the diagnosis and therapy policies for liver damage induced by MC-LR.

In the human genome, miR-451a is encoded close to the miR-144 on chromosome region 17q11.2. Our previous study showed that both strands of pre-miR-144 acted as antitumor miRNAs and were involved in lung squamous cell carcinoma (LUSQ) pathogenesis. Here, we aimed to investigate the functional significance of miR-451a and to identify its targeting of oncogenic genes in LUSQ cells. Downregulation of miR-451a was confirmed in LUSQ clinical specimens, and low expression of miR-451a was significantly associated with poor prognosis of LUSQ patients (overall survival: p = 0.035, disease-free survival: p = 0.029). Additionally, we showed that ectopic expression of miR-451a significantly blocked cancer cell aggressiveness. In total, 15 putative oncogenic genes were shown to be regulated by miR-451a in LUSQ cells. Among these targets, high kinesin family member 2A (KIF2A) expression was significantly associated with poor prognosis (overall survival: p = 0.043, disease-free survival: p = 0.028). Multivariate analysis showed that KIF2A expression was an independent prognostic factor in patients with LUSQ (hazard ratio = 1.493, p = 0.034). Aberrant KIF2A expression promoted the malignant transformation of this disease. Analytic strategies based on antitumor miRNAs and their target oncogenes are effective tools for identification of novel molecular pathogenesis of LUSQ.

We have previously demonstrated that human microRNA-451a (miR-451a) endometriotic lesion expression is significantly higher compared to that of the corresponding eutopic endometrium. The objective of the current study was to examine the relationship between lesion and serum content of miR-451a and to determine the utility of serum miR-451a in distinguishing between women with and without visible signs of endometriosis. Eighty-one participants were enrolled in this study, 41 with confirmed endometriosis and 40 without visible signs of endometriosis at laparoscopy (n = 20) or symptoms of endometriosis (pain, infertility n = 20). Experimental endometriosis was also induced in 8 baboons. Blood, endometriotic lesions, and eutopic endometrial samples were collected from women undergoing laparoscopy for surgical removal of endometriosis. Blood was also collected from control participants with no signs and symptoms associated with the disease as well as from baboons prior to, and then 1, 3, 6, 9, and 15 months postinduction of endometriosis. MicroRNA-451a was assessed by quantitative real-time polymerase chain reaction in all samples. In humans, serum miR-451a levels positively correlated with endometriotic lesion miR-451a content, and sera levels were significantly higher in these participants compared to controls. The area under the curve (AUC) for miR-451a was 0.8599. In baboons, serum miR-451a reached statistically significant peak levels at 6 months postinduction of endometriosis. We conclude from this study that sera miR-451a levels positively correlated with endometriotic lesion content and are significantly greater compared to sera levels in women without visible signs or symptoms of endometriosis. MicroRNA-451a may serve as a serum diagnostic marker for endometriosis. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) patients are often accompanied by depressive symptoms, but its underlying mechanism remains unclear. The present study aimed to explore the potential role of microRNAs in the comorbidity of AD and depression. Methods: The miRNAs associated with AD and depression were screened from databases and literature and then confirmed in the cerebrospinal fluid (CSF) of AD patients and different ages of transgenic APP/PS1 mice. AAV9-miR-451a-GFP was injected into the medial prefrontal cortex (mPFC) of APP/PS1 mice at seven months, and four weeks later, a series of behavioral and pathological analyses were performed. Results: AD patients had low CSF levels of miR-451a, which was positively correlated with the cognitive assessment score, but negatively with their depression scale. In the mPFC of APP/PS1 transgenic mice, the miR-451a levels also decreased significantly in the neurons and microglia. Specific virus vector-induced overexpression of miR-451a in the mPFC of APP/PS1 mice ameliorated AD-related behavior deficits and pathologies, including long-term memory defects, depression-like phenotype, β-amyloid load, and neuroinflammation. Mechanistically, miR-451a decreased the expression of neuronal β-secretase 1 of neurons through inhibiting Toll-like receptor 4/Inhibitor of kappa B Kinase β/ Nuclear factor kappa-B signaling pathway and microglial activation by inhibiting activation of NOD-like receptor protein 3, respectively. Conclusion: This finding highlighted miR-451a as a potential target for diagnosing and treating AD, especially for those with coexisting symptoms of depression., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Liu, Fang, Caiyan Hu, Jin Ding, Chengbing Fu, Shuqiong Wang, and Tiantian Li. GATA-1 promotes erythroid differentiation through the upregulation of miR-451a and miR-210-3p expression in CD34 + cells in high-altitude polycythemia. High Alt Med Biol . 24:59-67, 2023. Background: The clinical manifestations of high-altitude polycythemia (HAPC) include excessive accumulation of erythrocytes, and its pathogenesis is not yet clear. Methods: Peripheral blood was collected from 10 HAPC patients (HAPC group) and normal individuals (control group) each. CD34 + cells were sorted using immunomagnetic beads and differentiated into erythroid cells for 7, 11, and 15 days. Changes in GATA-binding protein 1 (GATA-1), miR-451a , and miR-210-3p expression and their possible regulatory relationships were investigated. Results: Under hypoxia, GATA-1 expression on day 15 was about 2.4 times that on day 7 in the control group and about 1.3 times that on day 7 in the HAPC group, which was significantly lower compared with the control group. miR-451a and miR-210-3p expressions in the HAPC group were 2.6 and 1.8 times that in the control group, respectively, and were significantly increased. When GATA-1 was inhibited, miR-451a and miR-210-3p expressions were significantly decreased by 0.43 and 0.39 times, respectively, compared with those in the control group. Conclusions: Hypoxia stimulated the upregulation of GATA-1 level and accelerated the change of expression, which promoted miR-451a and miR-210-3p expressions and shortened the time taken by cells to enter end-stage differentiation, so as to enhance erythroid differentiation, which may be a pathogenetic mechanism underlying HAPC polycytosis.

This study aims to observe the effect of chlorogenic acid(CGA) on microRNA(miRNA) in the process of protecting against N-acetyl-p-aminophenol(APAP)-induced liver injury. Eighteen C57BL/6 mice were randomly assigned into a normal group, a model group(APAP, 300 mg·kg~(-1)), and a CGA(40 mg·kg~(-1)) group. Hepatotoxicity of mice was induced by intragastric administration of APAP(300 mg·kg~(-1)). The mice in the CGA group were administrated with CGA(40 mg·kg~(-1)) by gavage 1 h after APAP administration. The mice were sacrificed 6 h after APAP administration, and plasma and liver tissue samples were collected for the determination of serum alanine/aspartate aminotransferase(ALT/AST) level and observation of liver histopathology, respectively. MiRNA array combined with real-time PCR was employed to discover important miRNAs. The target genes of miRNAs were predicted via miRWalk and TargetScan 7.2, verified by real-time PCR, and then subjected to functional annotation and signaling pathway enrichment. The results showed that CGA administration lowered the serum ALT/AST level elevated by APAP and alleviate the liver injury. Nine potential miRNAs were screened out from the microarray. The expression of miR-2137 and miR-451a in the liver tissue was verified by real-time PCR. The expression of miR-2137 and miR-451a was significantly up-regulated after APAP administration, and such up-regulated expression was significantly down-regulated after CGA administration, consistent with the array results. The target genes of miR-2137 and miR-451a were predicted and verified. Eleven target genes were involved in the process of CGA protecting against APAP-induced liver injury. Gene Ontology(GO) annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment with DAVID and R language showed that the 11 target genes were enriched in Rho protein-related signal transduction, vascular patterning-related biological processes, binding to transcription factors, and Rho guanyl-nucleotide exchange factor activity. The results indicated that miR-2137 and miR-451a played an important role in the inhibition of CGA on APAP-induced hepatotoxicity.

Papillary thyroid cancer (PTC) is a common malignancy. MicroRNAs (miRNAs) may act as oncogenes or tumor suppressor genes. However, the role of miR-451a in PTC is not fully understood. Hence, the objective of the study was to research the effect and mechanism of miR-451a in PTC. Differentially expressed miRNAs between GSE113629 and GSE103996 databases were assessed by Venn diagram. miR-451a and its downstream target genes were assessed by RT-PCR and Western blot. The proliferation, invasion, and apoptosis were determined by CCK-8, EdU, transwell, and flow cytometry assays. Dual-luciferase reporter assay were used to evaluated the target of miR-451a. Xenografted tumors was used to explore the function of miR-451a in vivo. Pathological changes and related protein expression were measured by HE staining and immunohistochemistry. MiR-451a was downregulated in PTC tissues and blood, and low expression of miR-451a was related to short overall survival, serious lymph node metastasis and high TNM grade in PTC patients. Moreover, increase of miR-451a restrained the proliferation and invasion and accelerated the apoptosis. Furthermore, miR-451a repressed VEGF signaling pathway. Importantly, miR-451a was demonstrated to target DCBLD2 and AKT1. Overexpression of DCBLD2 and AKT1 could restore the effect of miR-451a on PTC cells. In addition, miR-451a reduced the growth of xenografted tumors in vivo. The data suggested that miR-451a attenuated the proliferation, invasion and promoted apoptosis in PTC cells via inhibiting DCBLD2 and AKT1. Silencing of miR-451a target to facilitate DCBLD2-and AKT1-mediated VEGF, which enhance proliferation and invasion and reduced apoptosis in PTC. [Display omitted] • MiR-451a was lowly expressed in papillary thyroid cancer tissues and cells. • Overexpression of miR-451a inhibited the viability and motility in PTC cells. • MiR-451a directly targeted DCBLD2 and AKT1. • MiR-451a suppressed the viability and motility by targeting DCBLD2 and AKT1. • MiR-451a restrained the growth of xenografted tumor. [ABSTRACT FROM AUTHOR]

Aim To investigate the effects and mechanisms of miR-451a in the tamoxifen (TAM) resistance of breast cancer cells. Materials and methods TAM sensitive cells (MCF-7) and resistant cells (LCC2) were employed in the study. The lentivirus vectors of Lv-miR-451a, Lv-miR-451a sponge, and Lv-miR-451a NC were employed to increase or decrease the expression of miR-451a, respectively. SiRNA to 14-3-3ζ was used to inhibit expression of 14-3-3ζ. MTT assay was utilized to detect breast cancer cell proliferation. AnnexinV-FITC binding assay was used to detect apoptosis. Expression of ERα, 14-3-3ζ and miR-451a were measured by qRT-PCR and Western blot analysis. Interactions between 14-3-3ζ and ERα were investigated by co-immunoprecipitation. LC3-II surface expression and intracellular autophagosomes were observed by Western blot and electron microscopy. Key findings Over-expression of miR-451a can enhance MCF-7 and LCC2 cell sensitivity to TAM. Opposite effects were elicited by knocking down miR-451a. TAM treatment can up-regulate 14-3-3ζ expression, and down-regulate ERα expression. 14-3-3ζ and ERα were shown to interact. Over-expression of miR-451a decreased 14-3-3ζ expression and increased ERα expression, suppressing cell proliferation, increasing apoptosis, and reducing activation of p-AKT and p-mTOR. R18 can significantly decrease cell proliferation and increase apoptosis. R18 and 14-3-3ζ siRNA can rescue the effects of down-regulation of ERα by knocking down miR-451a. Over-expression of miR-451a inhibits autophagy, knocking-down miR-451a stimulates autophagy. Significance MiR-451a functions as a suppressor of resistance to TAM through regulating autophagy, the expression of 14-3-3ζ and ERα. This suggests miR-451a to be a potential target for reversing resistance to TAM. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer (GC) is a deadly malignancy worldwide. In the past, it has been shown that cellular signaling pathway alterations play a crucial role in the development of GC. In particular, deregulation of the PI3K/AKT/mTOR pathway seems to affect multiple GC functions including growth, proliferation, metabolism, motility and angiogenesis. Targeting alterations in this pathway by microRNAs (miRNAs) represents a potential therapeutic strategy, especially in inhibitor-resistant tumors. The objective of this study was to evaluate the expression of 3 pre-selected miRNAs, miR-101-2, miR-125b-2 and miR-451a, in a series of primary GC tissues and matched non-GC tissues and in several GC-derived cell lines, and to subsequently evaluate the functional role of these miRNAs. Methods: Twenty-five primary GC samples, 25 matched non-GC samples and 3 GC-derived cell lines, i.e., AGS, MKN28 and MKN45, were included in this study. miRNA and target gene expression levels were assessed by quantitative RT-PCR and western blotting, respectively. Subsequently, cell viability, clone formation, cell death, migration and invasion assays were performed on AGS cells. Results: miR-101-2, miR-125b-2 and miR-451a were found to be down-regulated in the primary GC tissues and the GC-derived cell lines tested. MiRNA mimic transfections significantly reduced cell viability and colony formation, increased cell death and reduced cell migration and invasion in AGS cells. We also found that exogenous expression of miR-101-2, miR-125b-2 and miR-451a decreased the expression of their putative targets MTOR, PIK3CB and TSC1, respectively. Conclusions: Our expression analyses and in vitro functional assays suggest that miR-101-2, miR-125b-2 and miR-451a act as potential tumor suppressors in primary GCs as well as in GC-derived AGS cells. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are an important class of small, non-coding RNA molecules that regulate gene expression at the transcriptional or post-transcriptional level. They are involved in apoptosis, proliferation and migration and are known to have an important role in many types of cancer. Aberrant expression of miRNA-451a (miR-451a) has previously been reported in tumors, however its role in renal cell carcinoma (RCC) is currently unknown. The aim of the present study was to investigate the role of miR-451a in RCC. The expression of miR-451a was analyzed in 50 paired RCC and normal tissues by quantitative polymerase chain reaction. Furthermore, the effects of miR-451a on cell migration, proliferation and apoptosis were evaluated, using migration scratch, MTT and flow cytometric assays. The present study demonstrated that miR-451a was upregulated in RCC, as compared with paired normal tissues (P<0.05). Downregulation of miR-451a using a synthesized inhibitor, significantly suppressed cell migration and proliferation, and induced apoptosis of renal cancer cells in vitro, as compared with a negative control (P<0.05). In the present study, it was determined that miR-451a may have an important role as a tumor enhancer in RCC. These results imply that miR-451a may be a promising therapeutic target for the treatment of RCC. [ABSTRACT FROM AUTHOR]

[Display omitted] • It's first proved that miR-451a can promote the malignant progression of osteosarcoma cells through AKT/mTOR pathway. • It's first proved that YTHDC1 modifies the m6A methylation of PDPK1. • It's first proved that YTHDC1 can promote the malignant progression of osteosarcoma cells. Osteosarcoma is the most prevalent primary malignant bone tumor containing mesenchymal cells with poor prognosis. Being a hot spot of anti-tumor therapy researches, AKT/mammalian target of rapamycin (mTOR) signaling pathway could affect various cellular processes including transcription, protein synthesis, apoptosis, autophagy and growth. The levels of RNA and protein were detected by quantitative real-time polymerase chain reaction (q-PCR) and western blot analyses respectively. Functional assays were carried out to analyze the malignant phenotypes of osteosarcoma cells. RNA-binding protein immunoprecipitation (RIP), Co-immunoprecipitation (Co-IP), RNA pulldown, luciferase reporter and in vitro kinase assays were conducted to uncover the specific mechanism of microRNA-451a (miR-451a) in osteosarcoma cells. Functionally, miR-451a represses the malignant progression of osteosarcoma. Mechanically, miR-451a could curb the AKT/mTOR pathway via 3-phosphoinositide dependent protein kinase 1 (PDPK1)-mediated phosphorylation modification. After the certification that YTH domain containing 1 (YTHDC1) regulates the m6A phosphorylation modification of PDPK1 mRNA, we further proved that miR-451a-mediated YTHDC1 stabilizes PDPK1 mRNA via m6A-dependent regulation. This study demonstrated that miR-451a regulates YTHDC1-mediated m6A methylation to activate the AKT/mTOR pathway, stimulating the malignancy of osteosarcoma. [ABSTRACT FROM AUTHOR]

Aims: MicroRNA-451a (miR-451a) regulates Th1/Th2 cell differentiation, inflammation, and septic organ injury in several experiments. Therefore, the present study aimed to explore the inter-correlation of miR-451a with the Th1/Th2 ratio, and their association with inflammation, septic organ injury, and mortality risk in patients with sepsis., Methods: Consecutively, 117 patients with sepsis and 50 healthy controls (HCs) were enrolled. Peripheral blood mononuclear cell samples were collected to detect miR-451a expression and the Th1/Th2 ratio in all subjects., Results: MiR-451a ( p < 0.001), Th1 cells ( p = 0.014), and the Th1/Th2 ratio ( p < 0.001) increased, while Th2 cells ( p < 0.001) declined in patients with sepsis compared with HCs. It was of note that miR-451a was positively correlated with Th1 cells ( p = 0.002) and the Th1/Th2 ratio ( p = 0.001), while it was negatively related to Th2 cells ( p = 0.005) in patients with sepsis. Meanwhile, miR-451a and the Th1/Th2 ratio correlated with most of the following indexes: TNF-α, IL-1β, IL-6, C-reactive protein, sequential organ failure assessment (SOFA) score, or Acute Physiology and Chronic Health Evaluation II (APACHE II) score (most p < 0.05). Moreover, miR-451a ( p < 0.001) and the Th1/Th2 ratio ( p = 0.001) increased in deaths compared to survivors of sepsis; further ROC curve showed both miR-451a and the Th1/Th2 ratio possessed a certain value to predict mortality of patients with sepsis. Additionally, the Th1/Th2 ratio [odds ratio (OR): 2.052, p = 0.005] was independently related to 28-day mortality risk from multivariate logistic regression., Conclusion: MiR-451a correlates with the Th1/Th2 ratio, and they both relate to inflammation, septic organ injury, and mortality risk in patients with sepsis., 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 © 2022 Geng, Liu and Yu.)

Objectives: To investigate the effects of miR-451a targeting interleukin-6 (IL-6) on the proliferation and apoptosis of multiple myeloma (MM) cells and its potential mechanism via JAK2/STAT3 pathway., Methods: mRNA expression of miR-451a and IL-6R in the plasma of patients with MM and normal controls were determined by RT-qPCR. U266 cells were cultured, transfected with miR-451a mimics, the proliferative ability of U266 cells was determined by CCK-8. Potential targets of miR-451a were predicted with the biological software TargetScan, and the direct relationship between miR-451a and the target IL-6R was analyzed by a dual-luciferase reporter assay. U266 cells were stimulated with IL-6R (100 ng/ml), and the proliferative ability and apoptosis rate were determined by CCK-8 and flow cytometry after 48h., Results: In the plasma of patients with MM, miR-451a expression was low and IL-6R expression was high. miR-451a targeted and negatively regulated IL-6R. Overexpressing miR-451a inhibited the proliferation and promoted the apoptosis of U266 cells. IL-6R acting on U266 cells promoted the proliferation and inhibited the apoptosis of U266 cells. Overexpressing miR-451a inhibited the activation of JAK2/STAT3 pathway and down-regulating miR-451a promoted the activation of JAK2/STAT3 pathway., Conclusions: miR-451a targeting IL-6R activates JAK2/STAT3 pathway, thus regulates the proliferation and apoptosis in MM cells., Competing Interests: The authors have no conflict of interest.

Circulating microRNAs (miRNAs) are useful biomarkers of hemolysis. Since blood cells are the main origins of circulating miRNAs, we evaluated blood cell-related pre-analytical modification of the miRNA signatures during blood drawing and serum processing. The levels of miRNA before and after ex vivo blood drawing were analyzed with the reverse transcriptase-based polymerase chain reaction method. Furthermore, the changes of miRNA signatures caused by different time-lag between blood drawing and serum preparation by 24 h were evaluated. Finally, we compared the miRNA levels between leftover samples and samples of hemolytic diseases. Blood drawing procedure induced increments of red blood cell (RBC)-related miRNAs (miR-451a, miR-486) about 2-fold. One hour standing of blood samples before serum separation induced almost the same increases in RBC-related miRNAs. To test the clinical usefulness of miR-451a as a biomarker of hemolytic diseases, we analyzed miRNAs of samples from 10 normal subjects, 30 leftover samples in the clinical laboratory, and 20 samples from patients with hemolytic diseases. Serum miR-451a significantly increased in patients with hemolytic anemia more than the levels of pre-analytical modification. In conclusion, the pre-analytical modification of serum miRNAs did not disturb the usefulness of RBC-derived miRNAs as biomarkers of hemolytic diseases. [ABSTRACT FROM AUTHOR]

Background: Triple negative breast cancer (TNBC) is associated with poor prognosis, aggressive phenotype(s) of tumours, partial chemotherapy response, and lack of clinically proven therapies. MicroRNAs (miRNAs) can target and modulate key genes that are involved in TNBC chemotherapy. Deregulated miRNA expression is highly involved in anti-cancer drug resistance phenotype and thus, miRNAs tend to be promising candidates for prediction of chemotherapy response and recurrence., Aim: This study aimed to investigate the expression levels of selected miRNAs (miR-21, miR-27b, miR-34a, miR-182, miR-200c and miR-451a) in cancerous and normal adjacent tissues of TNBC patients and to correlate with the clinicopathological data., Methods: Forty-one (41) FFPE tissue block of histopathologically confirmed TNBC patients was collected. Total RNA from the cancerous and adjacent non-cancerous tissues were isolated, transcribed, and pre-amplified. The relative expression level of miRNAs in tumour and normal adjacent tissues of TNBC patients was analysed using qRT-PCR., Results: Out of six miRNAs studied, the relative expression of miR-27b and miR-451a were found to be significantly lower in cancerous as compared to normal adjacent tissues of TNBC patients. In addition, a significant down regulation of miR-451a was also observed in infiltrating ductal carcinoma subtype, stages I and II, in both grade II and III, premenopausal and postmenopausal as well as in those with positive axillary lymph node metastases., Conclusion: The results suggest the possible utilization of miR-27b and miR-451a expression levels as potential predictive risk markers for TNBC patients undergoing TAC chemotherapy.

[Display omitted] • miR-451a affects the morphology, phagocytosis and CD11b expression of M0 macrophage. • MiR-451a increases the proliferation of M1 and M2 activated macrophages; • MiR-451a enhances the expression of iNOS upon M1 activation. Leukemia associated macrophages (LAMs), which are different from tumor-associated macrophages as well as classical M1 and M2 macrophages, are specifically activated by leukemic microenvironment. We have reported the heterogeneity of gene expression profiles in LAMs. However, the expression profiles of microRNA (miRNA) in LAMs and their regulatory mechanisms have not been established. Here, the expression profiles of miRNA in LAMs from bone marrow and spleen of acute myeloid leukemia mice were analyzed. Then, the effects of miR-451a, which was upregulated in LAMs, on macrophages were studied by transfecting miRNA mimic to peritoneal macrophages. The results showed that overexpression of miR-451a altered the morphology, enhanced the phagocytic ability of macrophages, and promotes the expression of differentiation marker CD11b in macrophages. Furthermore, miR-451a increased the proliferation capacity of both M1- and M2-polarized macrophages, but not M0 macrophages. Moreover, miR-451a further enhanced the expression of iNOS upon M1 activation. Therefore, our results reveal the miRNA expression profiles in LAMs, and broaden the knowledge about miRNA regulation in macrophages. [ABSTRACT FROM AUTHOR]

MicroRNA-451a (miR-451a) has been implicated in the initiation and progression of multiple cancers. However, the regulatory mechanisms underlying its function in nasopharyngeal carcinoma (NPC) are poorly understood. Thus, we investigated in detail the role of the microRNA-451a/chromosome segregation 1-like (miR-45a/CSE1L) axis and its regulatory mechanism in NPC. We examined the levels of miR-451a and CSE1L in NPC, and assessed the effects of miR-451a and CSE1L on NPC by cell functional experiments. Furthermore, we elucidated the direct regulatory effect of miR-451a on CSE1L by the luciferase reporter assay, RNA pull-down assay, and RNA immunoprecipitation and validated our observations by calculating the Pearson's correlation coefficient. We found that miR-451a was down-regulated in NPC cells, and its over-expression attenuated cell proliferation, migration, and invasion, and tumor growth in 5-8 F and SUNE-1 cells and promoted apoptosis. Moreover, CSE1L was the direct gene target of miR-451a, and its over-expression abrogated miR-451a-dependent inhibition of malignancy in 5-8 F and SUNE-1 cells. The Pearson's correlation coefficient indicated a negative correlation between CSE1L and miR-451a. miR-451a serves as a tumor suppressor and targets CSE1L . miR-451a suppresses CSE1L expression, thereby reducing proliferation, invasion, and migration and increasing apoptosis of NPC cells.

During the last two decades, diverse epigenetic modifications including DNA methylation, histone modifications, RNA editing and miRNA dysregulation have been associated with psychiatric disorders. A few years ago, in a review we outlined the most common epigenetic alterations in major psychiatric disorders (e.g., aberrant DNA methylation of DTNBP1 , HTR2A , RELN , MB-COMT and PPP3CC , and increased expression of miR-34a and miR-181b). Recent follow-up studies have uncovered other DNA methylation aberrations affecting several genes in mental disorders, in addition to dysregulation of many miRNAs. Here, we provide an update on new epigenetic findings and highlight potential origin of the diversity and inconsistencies, focusing on drug effects, tissue/cell specificity of epigenetic landscape and discuss shortcomings of the current diagnostic criteria in mental disorders.

Background: The lncRNA colorectal neoplasia differentially expressed (lncRNA CRNDE) has been reported to play a pivotal role in various cancers. However, the expression and function of CRNDE in pancreatic cancer remain unclear. The objective of this study was to investigate the effects of CRNDE on pancreatic cancer and the underlying mechanisms., Methods: The expression of CRNDE in pancreatic cancer tissues and cell lines was determined by RT-qPCR. Proliferation and angiogenesis were detected by MTT, colony formation, transwell and tube formation assays in vitro and in vivo. ELISA assay was used to detect the secretion of VEGFA. IHC was performed to test the expression levels of Ki67 and CD31. The binding sites between CRNDE, CDKN2D and miR-451a were predicted by bioinformatics analysis. Dual luciferase reporter and RNA immunoprecipitation assays were conducted to confirm the interaction with each other., Results: The results showed that CRNDE was significantly up-regulated in pancreatic cancer tissues as well as cell lines. CRNDE overexpression promoted the progression and angiogenesis of pancreatic cancer cells in vitro and in vivo. Moreover, we identified that CRNDE functioned as a sponge for miR-451a and CRNDE overexpression inhibited the expression of miR-451a. Furthermore, we confirmed that miR-451a directly interacted with CDKN2D and negatively regulated CDKN2D expression. In addition, CRNDE was found to positively regulate CDKN2D expression and mediate pancreatic cancer cell proliferation and angiogenesis through miR-451a/CDKN2D axis., Conclusion: CRNDE modulates cell proliferation and angiogenesis via miR-451a/CDKN2D axis in pancreatic cancer, which provides a potential therapeutic target for pancreatic cancer treatment., Competing Interests: Declaration of Competing Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Inc.)

Extensive research has indicated that miRNAs are crucial for the occurrence and progression of cancers. miR-451a, involved in breast cancer (BC), is one of the miRNAs. This study focused on the mechanism by which miR-451a regulates BC. The levels of miR-451a in BC tissues and cell lines were examined using quantitative real-time polymerase chain reaction (qRT-PCR). Kaplan‒Meier analysis showed that this was intimately related to the patient's overall survival rate. Functional experiments revealed the negative effects of miR-451a on the abilities of BC cells to multiply (tested by Cell Counting Kit-8), migrate (tested by wound healing assay), and invade (tested by Transwell assay) and its positive effects on apoptosis (tested by flow cytometry). Western blotting indicated that the expression of tumor-related proteins was affected by miR-451a. Moreover, in vivo experiments suggested that tumor growth was clearly restrained by an miR-451a agonist in a xenograft tumor model. Bioinformatic analysis indicated that miR-451a directly targeted Cyclin D2 (CCND2), as demonstrated by the luciferase reporter assay. An opposite change in the level of CCND2 and miR-451a in BC was indicated by qRT-PCR, western blotting, and immunohistochemistry. Subsequently, functional experiments and western blotting analysis confirmed that CCND2 accelerated BC progression, which was regulated by miR-451a. Cumulatively, research on miR-451a may be valuable for BC treatment. • miR-451a suppresses the development of breast cancer. • Cyclin D2 is a target gene of miR-451a. • This study confirmed the targeting relationship between miR-451a and CCND2. [ABSTRACT FROM AUTHOR]