Search

Lung cancer is a prevalent malignancy and the leading cause of cancer-related deaths, posing a significant threat to human health. Despite advancements in treatment, the prognosis for lung cancer patients remains poor due to late diagnosis, cancer recurrence, and drug resistance. Epigenetic research, particularly in microRNAs, has introduced a new avenue for cancer prevention and treatment. MicroRNAs, including miR-137, play a vital role in tumor development by regulating various cellular processes. MiR-137 has garnered attention for its tumor-suppressive properties, with studies showing its potential in inhibiting cancer progression. In lung cancer, miR-137 is of particular interest, with numerous reports exploring its role and mechanisms. A comprehensive review is necessary to consolidate current evidence. This review highlights recent studies on miR-137 in lung cancer, covering cell proliferation, migration, apoptosis, drug resistance, and therapy, emphasizing its potential as a biomarker and therapeutic target for lung cancer treatment and prognosis. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases affect an increasing part of the population of modern societies, burdening healthcare systems and causing immense suffering at the personal level. The pathogenesis of several of these disorders involves dysregulation of gene expression, which depends on several molecular processes ranging from transcription to protein stability. microRNAs (miRNAs) are short non-coding RNA molecules that modulate gene expression by suppressing the translation of partially complementary mRNAs. miR-137 is a conserved, neuronally enriched miRNA that is implicated in neurodegeneration. Here, we review the current body of knowledge about the role that miR-137 plays in five prominent neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. The presented data indicate that, rather than having a general neuroprotective role, miR-137 modulates the pathology of distinct disorders differently. [ABSTRACT FROM AUTHOR]

Abstract Background Neurodevelopmental disorders (NDD), such as autism spectrum disorders (ASD) and intellectual disorders (ID), are highly debilitating childhood psychiatric conditions. Genetic factors are recognized as playing a major role in NDD, with a multitude of genes and genomic regions implicated. While the functional validation of NDD-associated genes has predominantly been carried out using mouse models, the significant differences in brain structure and gene function between mice and humans have limited the effectiveness of mouse models in exploring the underlying mechanisms of NDD. Therefore, it is important to establish alternative animal models that are more evolutionarily aligned with humans. Results In this study, we employed CRISPR/Cas9 and somatic cell nuclear transplantation technologies to successfully generate a knockout miniature pig model of the MIR137 gene, which encodes the neuropsychiatric disorder-associated microRNA miR-137. The homozygous knockout of MIR137 (MIR137 –/– ) effectively suppressed the expression of mature miR-137 and led to the birth of stillborn or short-lived piglets. Transcriptomic analysis revealed significant changes in genes associated with neurodevelopment and synaptic signaling in the brains of MIR137 –/– miniature pig, mirroring findings from human ASD transcriptomic data. In comparison to miR-137-deficient mouse and human induced pluripotent stem cell (hiPSC)-derived neuron models, the miniature pig model exhibited more consistent changes in critical neuronal genes relevant to humans following the loss of miR-137. Furthermore, a comparative analysis identified differentially expressed genes associated with ASD and ID risk genes in both miniature pig and hiPSC-derived neurons. Notably, human-specific miR-137 targets, such as CAMK2A, known to be linked to cognitive impairments and NDD, exhibited dysregulation in MIR137 –/– miniature pigs. These findings suggest that the loss of miR-137 in miniature pigs affects genes crucial for neurodevelopment, potentially contributing to the development of NDD. Conclusions Our study highlights the impact of miR-137 loss on critical genes involved in neurodevelopment and related disorders in MIR137 –/– miniature pigs. It establishes the miniature pig model as a valuable tool for investigating neurodevelopmental disorders, providing valuable insights for potential applications in human research.

Abstract Autism spectrum disorder (ASD) is a multifaceted neurodevelopmental disorder predominant in childhood. Despite existing treatments, the benefits are still limited. This study explored the effectiveness of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) loaded with miR-137 in enhancing autism-like behaviors and mitigating neuroinflammation. Utilizing BTBR mice as an autism model, the study demonstrated that intranasal administration of MSC-miR137-EVs ameliorates autism-like behaviors and inhibits pro-inflammatory factors via the TLR4/NF-κB pathway. In vitro evaluation of LPS-activated BV2 cells revealed that MSC-miR137-EVs target the TLR4/NF-κB pathway through miR-137 inhibits proinflammatory M1 microglia. Moreover, bioinformatics analysis identified that MSC-EVs are rich in miR-146a-5p, which targets the TRAF6/NF-κB signaling pathway. In summary, the findings suggest that the integration of MSC-EVs with miR-137 may be a promising therapeutic strategy for ASD, which is worthy of clinical adoption.

Background: Neurodevelopmental disorders (NDD), such as autism spectrum disorders (ASD) and intellectual disorders (ID), are highly debilitating childhood psychiatric conditions. Genetic factors are recognized as playing a major role in NDD, with a multitude of genes and genomic regions implicated. While the functional validation of NDD-associated genes has predominantly been carried out using mouse models, the significant differences in brain structure and gene function between mice and humans have limited the effectiveness of mouse models in exploring the underlying mechanisms of NDD. Therefore, it is important to establish alternative animal models that are more evolutionarily aligned with humans. Results: In this study, we employed CRISPR/Cas9 and somatic cell nuclear transplantation technologies to successfully generate a knockout miniature pig model of the MIR137 gene, which encodes the neuropsychiatric disorder-associated microRNA miR-137. The homozygous knockout of MIR137 (MIR137–/–) effectively suppressed the expression of mature miR-137 and led to the birth of stillborn or short-lived piglets. Transcriptomic analysis revealed significant changes in genes associated with neurodevelopment and synaptic signaling in the brains of MIR137–/– miniature pig, mirroring findings from human ASD transcriptomic data. In comparison to miR-137-deficient mouse and human induced pluripotent stem cell (hiPSC)-derived neuron models, the miniature pig model exhibited more consistent changes in critical neuronal genes relevant to humans following the loss of miR-137. Furthermore, a comparative analysis identified differentially expressed genes associated with ASD and ID risk genes in both miniature pig and hiPSC-derived neurons. Notably, human-specific miR-137 targets, such as CAMK2A, known to be linked to cognitive impairments and NDD, exhibited dysregulation in MIR137–/– miniature pigs. These findings suggest that the loss of miR-137 in miniature pigs affects genes crucial for neurodevelopment, potentially contributing to the development of NDD. Conclusions: Our study highlights the impact of miR-137 loss on critical genes involved in neurodevelopment and related disorders in MIR137–/– miniature pigs. It establishes the miniature pig model as a valuable tool for investigating neurodevelopmental disorders, providing valuable insights for potential applications in human research. [ABSTRACT FROM AUTHOR]

The neural plate border (NPB) of vertebrate embryos is segregated from the neural plate (NP) and epidermal regions, and comprises an intermingled group of progenitors with multiple fate potential. Recent studies have shown that, during the gastrula stage, TFAP2A acts as a pioneer factor in remodeling the epigenetic landscape required to activate components of the NPB induction program. Here, we show that chick Tfap2a has two highly conserved binding sites for miR-137, and both display a reciprocal expression pattern at the NPB and NP, respectively. In addition, ectopic miR-137 expression reduced TFAP2A, whereas its functional inhibition expanded their territorial distribution overlapping with PAX7. Furthermore, we demonstrate that loss of the de novo DNA methyltransferase DNMT3A expanded miR-137 expression to the NPB. Bisulfite sequencing revealed a markedly elevated presence of non-canonical CpH methylation within the miR-137 promoter region when comparing NPB and NP samples. Our findings show that miR-137 contributes to the robustness of NPB territorial restriction in vertebrate development. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a multifaceted neurodevelopmental disorder predominant in childhood. Despite existing treatments, the benefits are still limited. This study explored the effectiveness of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) loaded with miR-137 in enhancing autism-like behaviors and mitigating neuroinflammation. Utilizing BTBR mice as an autism model, the study demonstrated that intranasal administration of MSC-miR137-EVs ameliorates autism-like behaviors and inhibits pro-inflammatory factors via the TLR4/NF-κB pathway. In vitro evaluation of LPS-activated BV2 cells revealed that MSC-miR137-EVs target the TLR4/NF-κB pathway through miR-137 inhibits proinflammatory M1 microglia. Moreover, bioinformatics analysis identified that MSC-EVs are rich in miR-146a-5p, which targets the TRAF6/NF-κB signaling pathway. In summary, the findings suggest that the integration of MSC-EVs with miR-137 may be a promising therapeutic strategy for ASD, which is worthy of clinical adoption. [ABSTRACT FROM AUTHOR]

Oxidative stress is one of the most important environmental exposures associated with psychiatric disorders, but the underlying molecular mechanisms remain to be elucidated. In a previous study, we observed a substantial alteration of the gene expression landscape in neuron-like cells that were differentiated from SH-SY5Y cells after or during exposure to oxidative stress, with a subset of dysregulated genes being enriched for neurodevelopmental processes. To further explore the regulatory mechanisms that might account for such profound perturbations, we have now applied small RNA-sequencing to investigate changes in the expression of miRNAs. These molecules are known to play crucial roles in brain development and response to stress through their capacity to suppress gene expression and influence complex biological networks. Through these analyses, we observed more than a hundred differentially expressed miRNAs, including 80 previously reported to be dysregulated in psychiatric disorders. The seven most influential miRNAs associated with pre-treatment exposure, including miR-138-5p, miR-96-5p, miR-34c-5p, miR-1287-5p, miR-497-5p, miR-195-5p, and miR-16-5p, supported by at least 10 negatively correlated mRNA connections, formed hubs in the interaction network with 134 genes enriched with neurobiological function, whereas in the co-treatment condition, miRNA-mRNA interaction pairs were enriched in cardiovascular and immunity-related disease ontologies. Interestingly, 12 differentially expressed miRNAs originated from the DLK1-DIO3 location, which encodes a schizophrenia-associated miRNA signature. Collectively, our findings suggest that early exposure to oxidative stress, before and during prenatal neuronal differentiation, might increase the risk of mental illnesses in adulthood by disturbing the expression of miRNAs that regulate neurodevelopmentally significant genes and networks. [ABSTRACT FROM AUTHOR]

The enteric nervous system (ENS) is an essential network of neurons and glia in the bowel wall. Defects in ENS development can result in Hirschsprung disease (HSCR), a life-threatening condition characterized by severe constipation, abdominal distention, bilious vomiting, and failure to thrive. A growing body of literature connects HSCR to alterations in miRNA expression, but there are limited data on the normal miRNA landscape in the developing ENS. We sequenced small RNAs (smRNA-seq) and messenger RNAs (mRNA-seq) from ENS precursor cells of mid-gestation Ednrb-EGFP mice and compared them to aggregated RNA from all other cells in the developing bowel. Our smRNA-seq results identified 73 miRNAs that were significantly enriched and highly expressed in the developing ENS, with miR-9, miR-27b, miR-124, miR-137, and miR-488 as our top 5 miRNAs that are conserved in humans. However, contrary to prior reports, our follow-up analyses of miR-137 showed that loss of Mir137 in Nestin-cre, Wnt1-cre, Sox10-cre, or Baf53b-cre lineage cells had no effect on mouse survival or ENS development. Our data provide important context for future studies of miRNAs in HSCR and other ENS diseases and highlight open questions about facility-specific factors in development. [ABSTRACT FROM AUTHOR]

The MIR137 gene encodes microRNA-137 (miR-137), which is a brain-enriched miR that is highly expressed in various brain regions. miR-137 has been identified as a modulator of processes involved in the pathogenesis of neuropsychiatric disorders. Functional polymorphism of variable number of tandem repeats (VNTR) rs58335419 was found in the regulatory region of the MIR137 gene. It is associated with a change in the expression of miR-137 and, as a result, with an increased risk of developing psychopathologies, including schizophrenia. In this study, we for the first time have analyzed the distribution of frequencies of alleles and genotypes of MIR137 VNTR in a large sample from the Russian population. The association of VNTR with the risk of schizophrenia has been studied. It was found that the presence of VNTR alleles with more than three repeats, as well as a genotype homozygous for such alleles, is associated with an increased risk of developing schizophrenia (OR = 1.4, 95% CI: 1.01–1.95). [ABSTRACT FROM AUTHOR]

miR-137 is a highly conserved brain-enriched microRNA (miRNA) that has been associated with neuronal function and proliferation. Here, we show that Drosophila miR-137 null mutants display increased body weight with enhanced triglyceride content and decreased locomotor activity. In addition, when challenged by nutrient deprivation, miR-137 mutants exhibit reduced motivation to feed and prolonged survival. We show through genetic epistasis and rescue experiments that this starvation resistance is due to a disruption in insulin signaling. Our studies further show that miR-137 null mutants exhibit a drastic reduction in levels of the phosphorylated/activated insulin receptor, InR (InR-P). We investigated if this is due to the predicted miR-137 target, Protein Tyrosine Phosphatase 61F (PTP61F), ortholog of mammalian TC-PTP/PTP1B, which are known to dephosphorylate InR-P. Indeed, levels of an endogenously tagged GFP-PTP61F are significantly elevated in miR-137 null mutants, and we show that overexpression of PTP61F alone is sufficient to mimic many of the metabolic phenotypes of miR-137 mutants. Finally, we knocked-down elevated levels of PTP61F in the miR-137 null mutant background and show that this rescues levels of InR-P, restores normal body weight and triglyceride content, starvation sensitivity, as well as attenuates locomotor and starvation-induced feeding defects. Our study supports a model in which miR-137 is critical for dampening levels of PTP61F, thereby maintaining normal insulin signaling and energy homeostasis. [ABSTRACT FROM AUTHOR]

As miR-137 is a regulator of aquaporin (AQP)2 expression and tumor necrosis factor (TNF) inhibits the expression of several extrarenal AQPs, we tested the hypothesis that TNF inhibits AQP2 in the kidney via a miR-137-dependent mechanism. AQP2 mRNA and protein expression decreased ~70% and 53%, respectively, in primary renal inner medullary collecting duct (IMCD) cells transfected with a miRNA mimic of mmu-miR-137, suggesting that miR-137 directly targets AQP2 mRNA in these cells. Exposure of IMCD cells for 2 h to 400 mosmol/kgH2O medium increased mmu-miR-137 mRNA expression about twofold, conditions that also increased TNF production approximately fourfold. To determine if the increase in mmu-miR-137 mRNA expression was related to the concomitant increase in TNF, IMCD cells were transfected with a lentivirus construct to silence TNF. This construct decreased mmu-miR-137 mRNA expression by ~63%, suggesting that TNF upregulates the expression of miR-137. Levels of miR-137 also increased approximately twofold in IMCD tubules isolated from male mice given 1% NaCl in the drinking water for 3 days. Intrarenal lentivirus silencing of TNF increased AQP2 mRNA levels and protein expression concomitant with a decrease in miR-137 levels in tubules isolated from mice given NaCl. The changes in AQP2 expression levels affected the diluting ability of the kidney, which was assessed by measuring urine osmolality and urine volume, as the decrease in these parameters after renal silencing of TNF was prevented on intrarenal administration of miR-137. The study reveals a novel TNF function via a miR-137-dependent mechanism that regulates AQP2 expression and function. [ABSTRACT FROM AUTHOR]

Long-term isoflurane inhalation has been reported to induce hippocampal apoptosis in young animals, whereas dexmedetomidine (DEX) can reduce isoflurane-induced neuronal apoptosis. The neuroprotective effect of miR-137 has been reported before, however, the effect of on isoflurane triggered neuronal apoptosis, and whether miR-137 is involved in the neuroprotection of DEX remain unclear. To investigate these doubts, we established an isoflurane exposure model in postnatal day 7 (P7) Sprague‒Dawley rats and the PC12 cells, containing a control group (CON), isoflurane group (ISO), DEX group (DEX) and DEX pretreatment group (DEX + ISO). We first confirmed that DEX attenuates isoflurane-induced hippocampal apoptosis. And we found DEX increased miR-137 and attenuated GSK-3β levels in the DEX and DEX + ISO groups in the hippocampus and PC12 cells. In addition, the regulative relationship of miR-137 and GSK-3β was confirmed using the TargetScan tool and dual-luciferase reporter assay. Moreover, miR-137 overexpression inhibited GSK-3β and increased its downstream gene β-catenin, whereas knockdown of miR-137 changed the GSK-3β and β-catenin expression oppositely. Upregulation of miR-137 increased the apoptosis-related genes and decreased the anti-apoptosis gene; however, knockdown of miR-137 produced the opposite results. This study suggested that DEX attenuated isoflurane-induced neuroapoptosis by upregulating the miR-137 mediated GSK-3β/β-catenin pathway in the developing rat hippocampus.

Traumatic brain injury (TBI) is a significant risk factor for neurodegenerative disorders, and patients often experience varying degrees of motor impairment. MiR-137, a broadly conserved and brain-enriched miRNA, is a key regulator in neural development and in various neurological diseases. Following TBI, the expression of miR-137 is dramatically downregulated. However, whether miR-137 is a therapeutic target for TBI still remains unknown. Here, for the first time, we demonstrate that intranasal administration of miR-137 agomir (a mimic) in the early stage (0–7 days) of TBI effectively inhibits glial scar formation and improves neuronal survival, while early-stage administration of miR-137 antagomir (an inhibitor) deteriorates motor impairment. This study elucidates the therapeutic potential of miR-137 mimics in improving locomotor recovery following motor cortex injury. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases affect an increasing part of the population of modern societies, burdening healthcare systems and causing immense suffering at the personal level. The pathogenesis of several of these disorders involves dysregulation of gene expression, which depends on several molecular processes ranging from transcription to protein stability. microRNAs (miRNAs) are short non-coding RNA molecules that modulate gene expression by suppressing the translation of partially complementary mRNAs. miR-137 is a conserved, neuronally enriched miRNA that is implicated in neurodegeneration. Here, we review the current body of knowledge about the role that miR-137 plays in five prominent neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and multiple sclerosis. The presented data indicate that, rather than having a general neuroprotective role, miR-137 modulates the pathology of distinct disorders differently.

Oxidative stress is one of the most important environmental exposures associated with psychiatric disorders, but the underlying molecular mechanisms remain to be elucidated. In a previous study, we observed a substantial alteration of the gene expression landscape in neuron-like cells that were differentiated from SH-SY5Y cells after or during exposure to oxidative stress, with a subset of dysregulated genes being enriched for neurodevelopmental processes. To further explore the regulatory mechanisms that might account for such profound perturbations, we have now applied small RNA-sequencing to investigate changes in the expression of miRNAs. These molecules are known to play crucial roles in brain development and response to stress through their capacity to suppress gene expression and influence complex biological networks. Through these analyses, we observed more than a hundred differentially expressed miRNAs, including 80 previously reported to be dysregulated in psychiatric disorders. The seven most influential miRNAs associated with pre-treatment exposure, including miR-138-5p, miR-96-5p, miR-34c-5p, miR-1287-5p, miR-497-5p, miR-195-5p, and miR-16-5p, supported by at least 10 negatively correlated mRNA connections, formed hubs in the interaction network with 134 genes enriched with neurobiological function, whereas in the co-treatment condition, miRNA-mRNA interaction pairs were enriched in cardiovascular and immunity-related disease ontologies. Interestingly, 12 differentially expressed miRNAs originated from the DLK1-DIO3 location, which encodes a schizophrenia-associated miRNA signature. Collectively, our findings suggest that early exposure to oxidative stress, before and during prenatal neuronal differentiation, might increase the risk of mental illnesses in adulthood by disturbing the expression of miRNAs that regulate neurodevelopmentally significant genes and networks.

Abstract Purpose As the global population ages rapidly, osteoporotic fractures have become an important public health problem. Previous studies have suggested that miR-137 is involved in the regulation of bone formation, but its specific regulatory mechanism remains unclear. In this study, we aimed to explore the expression, role, and regulatory mechanism of miR-137 in the osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs). Methods hBMSCs were induced into osteoblasts at first, and the expression level of miR-137 at different time points was detected. After knockdown and overexpression of miR-137, the effect of miR-137 on the osteogenic differentiation of hBMSCs was examined through alkaline phosphatase (ALP) staining and Alizarin Red staining. Western blotting was performed to detect the expression of runt-related transcription factor 2 (Runx2), osteocalcin (OCN), and toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway. Bioinformatics websites were used to predict the target binding sites for miR-137 and KDM4A, and the results were validated using luciferase reporter gene experiments. Moreover, the ALP activity, calcium nodule formation, and activation of Runx2, OCN, and TLR4/NF-κB pathways were observed after knockdown of KDM4A. Results The expression of miR-137 decreased during osteogenic differentiation. Knockdown of miR-137 expression increased the osteogenic ability of hBMSCs, while overexpression of it weakened the ability. Through the activation of the TLR4/NF-κB pathway, miR-137 inhibited osteogenic differentiation. KDM4A was identified as a predicted target gene of miR-137. After knocking down KDM4A expression, the osteogenic ability of hBMSCs was diminished, and the TLR4/NF-κB pathway was activated. Furthermore, the osteogenic ability of hBMSCs was partially restored and the activation level of TLR4/NF-κB was reduced after miR-137 knockdown. Conclusion MiR-137 enhances the activity of the TLR4/NF-κB pathway by targeting KDM4A, thereby inhibiting the osteogenic differentiation of hBMSCs and exacerbating osteoporosis.

Abstract Tanshinone IIA (Tan IIA) has an important role in treatment of cardiovascular diseases, including atherosclerosis. The vascular smooth muscle cells (VSMCs) are a major part of the atherosclerotic plaque. However, the biological functions of Tan IIA in regulating VSMCs function remain mostly unclear. This research aimed at identifying the explicit molecular mechanism that Tan IIA regulates oxidized low‐density lipoprotein (ox‐LDL)‐mediated VSMC proliferation and migration. VSMCs challenged by ox‐LDL were adopted as cellular model of atherosclerosis, and suffered from Tan IIA treatment. After that, cells proliferation, apoptosis or migration were measured. The expression levels of microRNA (miR)‐137, transient receptor potential cation channel subfamily C member 3 (TRPC3) and proliferating cell nuclear antigen (PCNA) were measured. The targeting relationship between miR‐137 and TRPC3 was determined. It was found that Tan IIA blunted VSMC proliferation, PCNA expression and migration mediated by ox‐LDL. Tan IIA promoted miR‐137 level, and miR‐137 knockdown reversed the influences of Tan IIA on VSMC proliferation, PCNA expression and migration in the presence of ox‐LDL. TRPC3 was verified to be targeted by miR‐137. Moreover, TRPC3 silencing exacerbated the influences of Tan IIA on VSMC proliferation, apoptosis and migration, and it mitigated the inhibitive effects of miR‐137 knockdown on function of Tan IIA. We confirmed for the first time that Tan IIA constrained ox‐LDL‐stimulated VSMC proliferation and migration via regulating the miR‐137/TRPC3 axis, which provided a theoretical basis for the research and promotion of Tan IIA as a therapeutic drug.

Background The function of long non-coding RNA (lncRNA) MALAT1 in regulating triple-negative breast cancer (TNBC) stemness and tumorigenesis was investigated. Methods Sphere formation and colony formation assays coupled with flow cytometry were employed to evaluate the percentage of CD44high/CD44low cells, and ALDH+ cells were performed to evaluate the stemness. Bisulfite sequencing PCR (BSP) was employed to detect the methylation level of MALAT1. Tumor xenograft experiment was performed to evaluate tumorigenesis in vivo. Finally, dual-luciferase reporter and RIP assays were employed to verify the binding relationship between MALAT1 and miR-137. Results Our results revealed that MALAT1 and BCL11A were highly expressed in TNBC, while miR-137 and DNMT1 were lowly expressed. Our results proved that MALAT1 positively regulated BCL11A expression through targeting miR-137. Functional experiments revealed that MALAT1 inhibited DNMT1 expression through acting on the miR-137/BCL11A pathway to enhance TNBC stemness and tumorigenesis. We also found that high MALAT1 expression in TNBC was related to the DNMT1-mediated hypomethylation of MALAT1. As expected, DNMT1 overexpression could remarkably inhibit TNBC stemness and tumorigenesis, which was eliminated by MALAT1 overexpression. Conclusion MALAT1 downregulated DNMT1 by miR-137/BCL11A pathway to enhance TNBC stemness and tumorigenesis; meanwhile, DNMT1/MALAT1 formed a positive feedback loop to continuously promote TNBC malignant behaviors.

Background: Schizophrenia (SCZ) is a serious chronic mental disorder. Our previous case--control genetic association study has shown that microRNA-137 (miR-137) may only protect females against SCZ. Since estrogen, an important female sex hormone, exerts neuroprotective effects, the relationship between estrogen and miR-137 in the pathophysiology of SCZ was further studied in this study. Methods: Genotyping of single-nucleotide polymorphism rs1625579 of miR-137 gene in 1,004 SCZ patients and 896 healthy controls was conducted using the iMLDR assay. The effect of estradiol (E2) on the miR-137 expression was evaluated on the human mammary adenocarcinoma cell line (MCF-7) and the mouse hippocampal neuron cell line (HT22). The relationships between serumE2, prolactin (PRL), and peripheral bloodmiR-137 were investigated in 41 SCZ patients and 43 healthy controls. The miR-137 and other reference miRNAs were detected by real-time fluorescent quantitative reverse transcription-PCR. Results: Based on the well-known SNP rs1625579, the distributions of protective genotypes and alleles of the miR-137 gene were not different between patients and healthy controls but were marginally significantly lower in female patients. E2 upregulated the expression of miR-137 to 2.83 and 1.81 times in MCF-7 and HT22 cells, respectively. Both serum E2 and blood miR-137 were significantly decreased or downregulated in SCZ patients, but they lacked expected positive correlations with each other in both patients and controls. When stratified by sex, bloodmiR-137 was negatively correlated with serumE2 in female patients. On the other hand, serum PRL was significantly increased in SCZ patients, and the female patients had the highest serumPRL level and a negative correlation between serum PRL and blood miR-137. Conclusion: The plausible SCZ-protective effect of miR-137 may be female specific, of which the underlying mechanism may be that E2 upregulates the expression of miR-137. This protective mechanism may also be abrogated by elevated PRL in female patients. These preliminary findings suggest a new genetic/environmental interaction mechanism for E2/miR-137 to protect normal females against SCZ and a novel E2/PRL/miR-137-related pathophysiology of female SCZ, implying some new antipsychotic ways for female patients in future. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Modern Laboratory Medicine is the property of Journal of Modern Laboratory Medicine Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background & Aims: Despite limited sensitivity, the gold standard for the diagnosis of malignant cells in ascites is still cytology. The aim of this prospective proof-of-principle study was to evaluate DNA methylation as a molecular tool for the differential diagnosis of benign and malignant ascites. Methods: A cohort of 79 patients with malignant and non-malignant ascites was prospectively enrolled. Ascites was assessed by cytopathological and laboratory examination. Cell pellets obtained by centrifugation were analyzed for differences in DNA methylation of long interspersed nuclear element-1 (LINE-1) and microRNA-137. Quantitative determination of methylation in bisulfite-converted DNA was performed by pyrosequencing. In a subsequent stage, we compared our data to previously published data in the field following systematic review of the literature. Results: Methylation status of studied LINE-1 and microRNA-137 could be reliably detected in all samples. Systematic evaluation revealed reliable reproducibility with satisfactory short- and long-term stability against degradation. Ascites from patients with a malignancy had a significantly higher methylation level of microRNA-137 compared with patients without tumor disease, whereas patients with peritonitis had significantly decreased methylation of microRNA-137. In contrast, differences in the measurement of the methylation status of LINE-1 could only be detected between patients with portal hypertension and a combination of malignant and infectious ascites. Inflammatory cells reflecting peritonitis correlated to DNA methylation changes. Conclusions: Analysis of DNA methylation in ascites is technically feasible, well reproducible and may lead to identification of potential biomarkers for peritoneal carcinomatosis and other conditions. Inflammatory cells due to peritonitis may also be associated with DNA methylation changes and need to be considered in future studies. Profiling studied under standardized conditions will be needed to identify the appropriate biomarkers for differential diagnosis of ascites. [ABSTRACT FROM AUTHOR]

Tanshinone IIA (Tan IIA) has an important role in treatment of cardiovascular diseases, including atherosclerosis. The vascular smooth muscle cells (VSMCs) are a major part of the atherosclerotic plaque. However, the biological functions of Tan IIA in regulating VSMCs function remain mostly unclear. This research aimed at identifying the explicit molecular mechanism that Tan IIA regulates oxidized low‐density lipoprotein (ox‐LDL)‐mediated VSMC proliferation and migration. VSMCs challenged by ox‐LDL were adopted as cellular model of atherosclerosis, and suffered from Tan IIA treatment. After that, cells proliferation, apoptosis or migration were measured. The expression levels of microRNA (miR)‐137, transient receptor potential cation channel subfamily C member 3 (TRPC3) and proliferating cell nuclear antigen (PCNA) were measured. The targeting relationship between miR‐137 and TRPC3 was determined. It was found that Tan IIA blunted VSMC proliferation, PCNA expression and migration mediated by ox‐LDL. Tan IIA promoted miR‐137 level, and miR‐137 knockdown reversed the influences of Tan IIA on VSMC proliferation, PCNA expression and migration in the presence of ox‐LDL. TRPC3 was verified to be targeted by miR‐137. Moreover, TRPC3 silencing exacerbated the influences of Tan IIA on VSMC proliferation, apoptosis and migration, and it mitigated the inhibitive effects of miR‐137 knockdown on function of Tan IIA. We confirmed for the first time that Tan IIA constrained ox‐LDL‐stimulated VSMC proliferation and migration via regulating the miR‐137/TRPC3 axis, which provided a theoretical basis for the research and promotion of Tan IIA as a therapeutic drug. [ABSTRACT FROM AUTHOR]

Abstinence from prolonged psychostimulant use prompts stimulant withdrawal syndrome. Molecular adaptations within the dorsal striatum have been considered the main hallmark of stimulant abstinence. Here we explored striatal miRNA–target interaction and its impact on circulating miRNA marker as well as behavioral dysfunctions in methamphetamine (MA) abstinence. We conducted miRNA sequencing and profiling in the nonhuman primate model of MA abstinence, followed by miRNA qPCR, LC–MS/MS proteomics, immunoassays, and behavior tests in mice. In nonhuman primates, MA abstinence triggered a lasting upregulation of miR-137 in the dorsal striatum but a simultaneous downregulation of circulating miR-137. In mice, aberrant increase in striatal miR-137-dependent inhibition of SYNCRIP essentially mediated the MA abstinence-induced reduction of circulating miR-137. Pathway modeling through experimental deduction illustrated that the MA abstinence-mediated downregulation of circulating miR-137 was caused by reduction of SYNCRIP-dependent miRNA sorting into the exosomes in the dorsal striatum. Furthermore, diminished SYNCRIP in the dorsal striatum was necessary for MA abstinence-induced behavioral bias towards egocentric spatial learning. Taken together, our data revealed circulating miR-137 as a potential blood-based marker that could reflect MA abstinence-dependent changes in striatal miR-137/SYNCRIP axis, and striatal SYNCRIP as a potential therapeutic target for striatum-associated cognitive dysfunction by MA withdrawal syndrome.

Purpose: The present work focused on exploring the role of circRNA3616 in neuronal inflammation and apoptosis in spinal cord injury (SCI). Methods: The SCI mouse model and circRNA3616 knockdown SCI mouse model were established. This work focused on assessing the mouse locomotor function using Basso Mouse Scale (BMS) and BMS subscore. Hematoxylin–eosin (HE) staining and Tunel staining were conducted, while myeloperoxidase (MPO) activity was also detected on spinal cord tissues. We also knocked down circRNA3616 expression in NSC-34 cells. Meanwhile, the SCI cell model was established by oxygen glucose deprivation (OGD) in NSC-34 cells. Moreover, we conducted dual-luciferase reporter gene assay. Flow cytometry (FCM) was conducted to detect SCI cell apoptosis, whereas cell counting kit-8 (CCK-8) assay was performed to analyze cell viability. This study also implemented enzyme-linked immunosorbent assay to detect inflammatory factors in spinal cord tissues, serum, and cells. Results: CircRNA3616 knockdown reduced the damage, inflammatory response, apoptosis, and MPO activity in SCI mouse serum and spinal cord tissues. CircRNA3616 knockdown increased BMS and BMS subscore of SCI mice. CircRNA3616 up-regulated TLR4 expression by sponging miR-137. CircRNA3616 knockdown inhibited the TLR4, p-IkBα, p-p65/p65 protein expression, while promoting IkBα protein expression within SCI mouse spinal cord. TLR4 reversed circRNA3616 knockdown-induced inhibition on NF-κB pathway activity in SCI cells. CircRNA3616 knockdown attenuated neuronal cell inflammation and apoptosis via TLR4/NF-κB pathway after SCI. Conclusion: CircRNA3616 silencing attenuates inflammation and apoptosis in SCI by inhibiting TLR4/NF-κB activity via sponging miR-137. CircRNA3616 is the possible anti-SCI therapeutic target. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a significant risk factor for neurodegenerative disorders, and patients often experience varying degrees of motor impairment. MiR-137, a broadly conserved and brain-enriched miRNA, is a key regulator in neural development and in various neurological diseases. Following TBI, the expression of miR-137 is dramatically downregulated. However, whether miR-137 is a therapeutic target for TBI still remains unknown. Here, for the first time, we demonstrate that intranasal administration of miR-137 agomir (a mimic) in the early stage (0–7 days) of TBI effectively inhibits glial scar formation and improves neuronal survival, while early-stage administration of miR-137 antagomir (an inhibitor) deteriorates motor impairment. This study elucidates the therapeutic potential of miR-137 mimics in improving locomotor recovery following motor cortex injury.

The enteric nervous system (ENS) is an essential network of neurons and glia in the bowel wall. Defects in ENS development can result in Hirschsprung disease (HSCR), a life-threatening condition characterized by severe constipation, abdominal distention, bilious vomiting, and failure to thrive. A growing body of literature connects HSCR to alterations in miRNA expression, but there are limited data on the normal miRNA landscape in the developing ENS. We sequenced small RNAs (smRNA-seq) and messenger RNAs (mRNA-seq) from ENS precursor cells of mid-gestation Ednrb-EGFP mice and compared them to aggregated RNA from all other cells in the developing bowel. Our smRNA-seq results identified 73 miRNAs that were significantly enriched and highly expressed in the developing ENS, with miR-9, miR-27b, miR-124, miR-137, and miR-488 as our top 5 miRNAs that are conserved in humans. However, contrary to prior reports, our follow-up analyses of miR-137 showed that loss of Mir137 in Nestin-cre, Wnt1-cre, Sox10-cre, or Baf53b-cre lineage cells had no effect on mouse survival or ENS development. Our data provide important context for future studies of miRNAs in HSCR and other ENS diseases and highlight open questions about facility-specific factors in development.

Abstract Background Conventionally, breast cancer (BC) prognosis and prediction of response to therapy are based on TNM staging, histological and molecular subtype, as well as genetic alterations. The role of various epigenetic factors has been elucidated in carcinogenesis. However, it is still unknown to what extent miRNAs affect the response to neoadjuvant chemotherapy (NACT). This pilot study is focused on evaluating the role of miR-34a, miR-124a, miR-155, miR-137 and miR-373 in response to NACT. Methods That was a prospective study enrolling 34 patients with histologically confirmed BC of II-III stages. The median age of patients was 53 (47–59.8) years old, 70.6% of whom were HR-positive. MiRs levels were measured in the primary tumor before and after NACT. The response to therapy was assessed after surgery using the Miller-Payne scoring system. To establish the role of miRs in modulating response to NACT the Cox model was applied for analysis. Results BC demonstrated a great variability of miRs expression before and after NACT with no strong links to tumor stage and molecular subtype. Only miR-124a and miR-373 demonstrated differential expression between malignant and normal breast tissues before and after therapy though these distinctions did not impact response to NACT. Besides miR-124a and miR-137 levels after NACT were found to be dependent on HR status. While miR-124a levels increased (p = 0.021) in the tumor tissue, the expression of miR-137 was downregulated (p = 0.041) after NACT in HR positive BC. Conclusions The study revealed differences in miR-124a and miR-373 expression after NACT in primary BC tissues. Although miRs levels did not impact the response to NACT, we found miR-124a and miR-137 levels to be related to hormonal sensitivity of BC.

Objective: To investigate the relationship between serum microribonucleic acid (miR)-137 and miR-138 expression and cognitive impairment and phosphatidylinositol 3 kinase/protein kinase (PI3K/Akt) signaling pathway in peripheral blood lymphocytes in patients with Alzheimer's disease (AD). From January 2020 to May 2022, 95 patients wth AD (AD group) who were admitted to the Department of Internal Medicine Neurology of the Affiliated Hospital of Qingdao University were selected. According to the clinical dementia rating scale (CDR) score, the patients were divided into mild group (1 scores, 35 cases), moderate group (2 scores, 42 cases), severe group (3 scores, 18 cases), and 63 healthy volunteers were selected as the control group. The levels of serum miR-137, miR-138 expression and the expression of PI3K/Akt signal pathway related proteins in peripheral blood lymphocytes of AD group and control group were detected. The cognitive function was evaluated with the Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment Scale (MoCA). The correlation between serum miR-137, miR-138 and MMSE, MoCA score, as well as the expression of PI3K, Akt, B lymphomatoma-2 gene (Bcl-2), Bcl-2 related X protein gene (Bax) in peripheral blood lymphocytes were analyzed. The levels of serum miR-137 and PI3K, Akt and Bcl-2 protein expression in peripheral blood lymphocytes, MMSE and MoCA scores in the AD group were lower than those in the control group (P＜0.05), while the levels of serum miR-138 and Bax protein expression in peripheral blood lymphocytes were higher than those in the control group (P＜0.05). The levels of serum miR-137 and PI3K, Akt and Bcl-2 protein expression in peripheral blood lymphocytes, and the scores of MMSE and MoCA in the severe group were lower than those in the moderate group and mild group (P＜0.05), and the moderate group was lower than the mild group (P＜0.05). The levels of miR-138 and Bax protein expression in peripheral blood lymphocytes were higher than those in the moderate group and mild group (P＜0.05), and the moderate group was higher than the mild group (P＜0.05). Serum miR-137 level in patients wth AD was positively correlated with MMSE, MoCA score, PI3K, Akt and Bcl-2 protein expression in peripheral blood lymphocytes (P＜0.05), and negatively correlated with Bax protein expression in peripheral blood lymphocytes (P＜0.05). Serum miR-138 level in patients wth AD was negatively correlated with MMSE, MoCA score, PI3K, Akt and Bcl-2 protein expression in peripheral blood lymphocytes (P＜ 0.05), and positively correlated with Bax protein expression in peripheral blood lymphocytes (P＜0.05). The serum miR-137 expression is decreased and miR-138 is increased in the patients wth AD, which is related to cognitive dysfunction. miR-137 and miR-138 may be involved in the pathogenesis of AD by regulating PI3K/Akt signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Circular RNAs (circRNAs) play an important regulatory role in human diseases, including diabetic nephropathy (DN). The purpose of this study was to investigate the role and mechanism of circHOMER1 action in DN. Methods: Human mesangial cells (HMCs) were tested with high glucose (HG) to mimic DN cell models. Quantitative real‐time PCR was performed to determine circHOMER1, microRNA (miR)‐137 and SRY‐box transcription factor 6 (SOX6) expression. SOD activity and MDA level were detected to evaluate cell oxidative stress. ELISA assay was used to analyse the levels of inflammation factors. The protein levels of extracellular matrix (ECM) deposition‐related markers and SOX6 were assessed by western blot analysis. The interaction between miR‐137 and circHOMER1 or SOX6 was analysed by dual‐luciferase reporter assay and RNA pull‐down assay. Results: CircHOMER1 was highly expressed in HG‐induced HMCs and DN patients. Downregulation of circHOMER1 suppressed oxidative stress, inflammation and ECM deposition in HMCs induced by HG. In terms of mechanism, circHOMER1 could sponge miR‐137 to regulate SOX6. Function assays showed that miR‐137 inhibitor or SOX6 overexpression revoked the negative regulation of circHOMER1 knockdown on HG‐induced HMCs injury. In addition, miR‐137 expression was negatively correlated with circHOMER1 and SOX6 expression in DN patients. Conclusion: CircHOMER1 promoted HG‐induced HMCs oxidative stress, inflammation and ECM accumulation via the miR‐137/SOX6 axis, suggesting that circHOMER1 might be a target for DN treatment. Summary at a glance: CircHOMER1 knockdown alleviates high glucose‐induced human mesangial cells injury. Mechanistically circHOMER1 upregulates SOX6 by acting as a sponge for miR‐137. [ABSTRACT FROM AUTHOR]

Noncoding RNAs, such as long noncoding RNAs (lncRNAs), are abundant in livestock. Many lncRNAs that affect the growth rate of livestock have been identified in muscles. However, some of their physiological functions and regulatory mechanisms remain unclear. In this study, we identified a new lncRNA (lncPRRX1) and investigated its effect on the proliferation of bovine myoblasts. LncPRRX1 was highly expressed in muscle tissue, and interference with lncPRRX1 inhibited the proliferation of bovine myoblasts in vitro. The RNA molecules of lncPRRX1 act on miR-137 as competitive endogenous RNAs (ceRNAs). Overexpression of miR-137 suppressed the proliferation of myoblasts, while inhibition of miR-137 had the opposite effect. In addition, the predicted target genes of miR-137 were significantly enriched in the mitogen-activated protein kinase (MAPK) signaling pathway, in which Cell Division Cycle 42 (CDC42) was shown to be the direct target gene of miR-137, and interference with CDC42 inhibited myoblast proliferation. Furthermore, interference with lncPRRX1 repaired the defects in CDC42 protein levels and cell proliferation caused by miR-137 inhibitors. Our results suggested that lncPRRX1 promoted bovine myoblast proliferation by regulating the miRNA-137/CDC42 axis. [ABSTRACT FROM AUTHOR]

Abstract Parkinson's disease (PD) is a leading cause of disability. Long noncoding RNA (LncRNA) OIP5‐AS1 alleviates the accumulation and toxicity of 1‐methyl‐4‐phenylpyridine (MPP+)/‐induced α‐synuclein in human neuroblastoma SH‐SY5Y cells, which may be involved in the pathological process of PD. This study explored the neuroprotective effect of lncRNA OIP5‐AS1 on MPP+/‐induced SH‐SY5Y cell model of PD, so as to provide a theoretical basis for PD treatment. The PD cell model was established (MPP+ group). The overexpression vector oe‐OIP5‐AS1 was constructed and transfected into MPP+/‐induced SH‐SY5Y cells, which were further transfected with miR‐137 mimic or si‐NIX plasmids. The localization of OIP5‐AS1 and its binding sites with miR‐137 were predicted by subcellular isolation and fluorescence in situ hybridization analysis. The targeting relationships between OIP5‐AS1 and miR‐137, and miR‐137 and NIX were detected by dual‐luciferase reporter assays. The mitochondrial membrane potential (Δψm) and total reactive oxygen species (ROS) levels, and expressions of α‐synuclein, inflammatory cytokines, and microglia‐activated chemokines, cell activity, and apoptosis were assessed. OIP5‐AS1 was downregulated in MPP+ cells. After OIP5‐AS1 overexpression, miR‐137 was downregulated and NIX was upregulated in MPP+ cells, inflammatory factors and chemokines were downregulated. There were target relationships between OIP5‐AS1 and miR‐137, and miR‐137 and NIX. After OIP5‐AS1 overexpression, miR‐137 overexpression or NIX downregulation inhibited mitochondrial autophagy and ROS levels and aggravated mitochondrial vacuolation; and partially reversed the effect of OIP5‐AS1 overexpression on promoting mitochondrial autophagy and protection on MPP+ cells. Collectively, lncRNA OIP5‐AS1 promoted NIX expression through competitively binding to miR‐137, and promoted mitochondrial autophagy, thus protecting neurons from degeneration which might be seen in patients with PD.

Circular RNAs (circRNAs) regulate the tumorigenesis of non-small-cell lung cancer (NSCLC). CircPDSS1 (hsa_circ_0017998) has been newly discovered, and its role in NSCLC remains elusive. We aimed to investigate the functional roles and downstream targets of circPDSS1 in NSCLC cells. Cellular viabilities were measured through the Cell Counting Kit-8 (CCK-8) assay, whereas cell death was assessed through flow cytometry. The lactate dehydrogenase activity, malondialdehyde levels, ferrous iron, and reactive oxygen species were measured using commercial assay kits. The interaction between circPDSSA/ microRNA-137 (miR-137) and miR-137/solute carrier family 7 member 11 (SLC7A11) was assayed through a dual luciferase activity assay. Finally, the mRNA and protein levels were measured using real-time reverse transcriptase-polymerase chain reaction and western blots, respectively. CircPDSS1 expression was upregulated in NSCLC cells, compared with healthy lung cells. CircPDSS1 silencing suppressed the viability of NSCLC cells. Additionally, circPDSS1 knockdown induced ferroptosis rather than other types of cell death in NSCLC cells. Mechanically, circPDSS1 functions as a "sponge" to inversely control miR-137 expression, which directly targets SLC7A11. Moreover, circPDSS1 silencing causes the downregulation of glutathione peroxidase 4 (GPX4) and glutamate-cysteine ligase catalytic subunit (GCLC). Targeting the circPDSS1/miR-137/SLC7A11/GPX4/GCLC axis may be a promising strategy to kill NSCLC cells. • Knockdown of circPDSS1 induces ferroptosis in NSCLC cells.CircPDSS1 functions as a "sponge" to inversely control the miR-137 expression, which directly targets the SLC7A11. • Silencing of circPDSS1 also leads to the downregulation of GPX4 and GCLC. [ABSTRACT FROM AUTHOR]

Obesity-induced hypogonadism (OIH) is a prevalent, but often neglected condition in men, which aggravates the metabolic complications of overweight. While hypothalamic suppression of Kiss1 -encoded kisspeptin has been suggested to contribute to OIH, the molecular mechanisms for such repression in obesity, and the therapeutic implications thereof, remain unknown. A combination of bioinformatic, expression and functional analyses was implemented, assessing the role of the evolutionary-conserved miRNAs, miR-137 and miR-325, in mediating obesity-induced suppression of hypothalamic kisspeptin, as putative mechanism of central hypogonadism and metabolic comorbidities. The implications of such miR-137/325-kisspeptin interplay for therapeutic intervention in obesity were also explored using preclinical OIH models. MiR-137/325 repressed human KISS1 3'-UTR in-vitro and inhibited hypothalamic kisspeptin content in male rats, while miR-137/325 expression was up-regulated, and Kiss1 /kisspeptin decreased, in the medio-basal hypothalamus of obese rats. Selective over-expression of miR-137 in Kiss1 neurons reduced Kiss1 / kisspeptin and partially replicated reproductive and metabolic alterations of OIH in lean mice. Conversely, interference of the repressive actions of miR-137/325 selectively on Kiss1 3'-UTR in vivo, using target-site blockers (TSB), enhanced kisspeptin content and reversed central hypogonadism in obese rats, together with improvement of glucose intolerance, insulin resistance and cardiovascular and inflammatory markers, despite persistent exposure to obesogenic diet. Reversal of OIH by TSB miR-137/325 was more effective than chronic kisspeptin or testosterone treatments in obese rats. Our data disclose that the miR-137/325 - Kisspeptin repressive interaction is a major player in the pathogenesis of obesity-induced hypogonadism and a putative druggable target for improved management of this condition and its metabolic comorbidities in men suffering obesity. Up to half of the men suffering obesity display also central hypogonadism, an often neglected complication of overweight that can aggravate the clinical course of obesity and its complications. The mechanisms for such obesity-induced hypogonadism remain poorly defined. We show here that the evolutionary conserved miR137/miR325 tandem centrally mediates obesity-induced hypogonadism via repression of the reproductive-stimulatory signal, kisspeptin; this may represent an amenable druggable target for improved management of hypogonadism and other metabolic complications of obesity. • Central hypogonadism is a prevalent condition in men with obesity, of as yet unknown mechanisms • Long-term obesity has been suggested to suppress Kiss1 neurons in the ARC of male rodents, via ill-defined molecular mechanisms • Hypothalamic miR-137/miR-325 are upregulated in obese male rats and repress Kiss1/kisspeptin • Blockade of this repressive interaction reverses central hypogonadism and metabolic comorbidities • This reversal is more effective than those induced by treatments with testosterone or kisspeptin [ABSTRACT FROM AUTHOR]

Abstinence from prolonged psychostimulant use prompts stimulant withdrawal syndrome. Molecular adaptations within the dorsal striatum have been considered the main hallmark of stimulant abstinence. Here we explored striatal miRNA–target interaction and its impact on circulating miRNA marker as well as behavioral dysfunctions in methamphetamine (MA) abstinence. We conducted miRNA sequencing and profiling in the nonhuman primate model of MA abstinence, followed by miRNA qPCR, LC–MS/MS proteomics, immunoassays, and behavior tests in mice. In nonhuman primates, MA abstinence triggered a lasting upregulation of miR-137 in the dorsal striatum but a simultaneous downregulation of circulating miR-137. In mice, aberrant increase in striatal miR-137-dependent inhibition of SYNCRIP essentially mediated the MA abstinence-induced reduction of circulating miR-137. Pathway modeling through experimental deduction illustrated that the MA abstinence-mediated downregulation of circulating miR-137 was caused by reduction of SYNCRIP-dependent miRNA sorting into the exosomes in the dorsal striatum. Furthermore, diminished SYNCRIP in the dorsal striatum was necessary for MA abstinence-induced behavioral bias towards egocentric spatial learning. Taken together, our data revealed circulating miR-137 as a potential blood-based marker that could reflect MA abstinence-dependent changes in striatal miR-137/SYNCRIP axis, and striatal SYNCRIP as a potential therapeutic target for striatum-associated cognitive dysfunction by MA withdrawal syndrome. Methamphetamine abstinence persistently enhances the psychiatric risk gene miR-137 in the dorsal striatum, which then suppresses the expression of SYNCRIP to aberrantly diminish circulating miR-137 and promote egocentric spatial learning. [Display omitted] [ABSTRACT FROM AUTHOR]

Increasing evidence demonstrates that many long noncoding RNAs (lncRNAs) are implicated with the development of laryngeal squamous cell carcinoma (LSCC). As shown by bioinformatics analysis, lncRNA non-catalytic region of tyrosine kinase adaptor protein 1-antisense 1 (NCK1-AS1) is upregulated in tissues of head and neck squamous cell carcinoma. The study aimed to explore the role and mechanism of NCK1-AS1 in LSCC. NCK1-AS1 expression in LSCC cells was evaluated by reverse transcription qPCR. The viability, proliferation, invasion, migration, and apoptosis of LSCC cells with indicated transfection were evaluated by CCK-8 assays, Ethynyl deoxyuridine incorporation assays, Transwell assays, wound healing assays, and TUNEL assays, respectively. Subcellular fractionation assays were performed to evaluate the cellular distribution of NCK1-AS1 and NCK1. NCK1 protein level in LSCC cells with indicated transfection was quantified by western blotting. The binding relation between miR-137 and NCK1-AS1 (or NCK1) were determined using RNA immunoprecipitation assays and luciferase reporter assays. NCK1-AS1 was highly expressed in LSCC cell lines. NCK1-AS1 depletion suppressed LSCC cell viability, proliferation, invasion, and migration while enhancing cell apoptosis. NCK1, an adjacent gene of NCK1-AS1, is also highly expressed in LSCC cells and was positively regulated by NCK1-AS1. Moreover, NCK1-AS1 interact with miR-137 to upregulate NCK1 expression. NCK1 was the downstream target of miR-137 and was negatively correlated to miR-137. In addition, overexpressed NCK1 reversed the suppressive impact of NCK1-AS1 depletion on malignant behaviors of LSCC cells. NCK1-AS1 contributes to LSCC cellular behaviors by upregulating NCK1 via interaction with miR-137. [ABSTRACT FROM AUTHOR]

Lung cancer is a prevalent malignancy and the leading cause of cancer-related deaths, posing a significant threat to human health. Despite advancements in treatment, the prognosis for lung cancer patients remains poor due to late diagnosis, cancer recurrence, and drug resistance. Epigenetic research, particularly in microRNAs, has introduced a new avenue for cancer prevention and treatment. MicroRNAs, including miR-137, play a vital role in tumor development by regulating various cellular processes. MiR-137 has garnered attention for its tumor-suppressive properties, with studies showing its potential in inhibiting cancer progression. In lung cancer, miR-137 is of particular interest, with numerous reports exploring its role and mechanisms. A comprehensive review is necessary to consolidate current evidence. This review highlights recent studies on miR-137 in lung cancer, covering cell proliferation, migration, apoptosis, drug resistance, and therapy, emphasizing its potential as a biomarker and therapeutic target for lung cancer treatment and prognosis., 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 © 2024 Liu, Ruan, Chen, He and Chen.)

lncRNA DSCR8 (Down syndrome critical region 8) is involved in progression of many cancers, but its specific role in gastric cancer (GC) is still unclear. Here, qRT-PCR detected upregulated expression of DSCR8 and Cdc42 and downregulated expression of miR-137 in GC. The protein expression level of Cdc42 in GC was upregulated as tested by western blot. Statistical analysis showed that DSCR8 was closely associated with some malignant clinicopathological features (such as tumor size, metastasis, and stage) in GC patients. Fluorescence in situ hybridization showed that DSCR8 was localized in the nucleus and cytoplasm. Dual-luciferase reporter gene, RNA immunoprecipitation, and biotin pull-down assays showed that DSCR8 could bind to miR-137 could bind to Cdc42. In vitro and in vivo assays showed that DSCR8 could promote proliferation, invasion, and the cycle of GC cells and inhibit cell apoptosis. In addition, a rescue experiment showed that DSCR8 regulated progression of GC cells via miR-137. Furthermore, DSCR8 regulated Cdc42 in GC cells by inhibiting miR-137. Taken together, these data indicated that DSCR8 could adsorb miR-137 to reduce its inhibitory effect on Cdc42 expression, thereby promoting the progression of GC cells and regulating the cell cycle. These results provide a novel direction for DSCR8 as a target of GC.

Long noncoding RNA (lncRNA) highly upregulated in liver cancer (HULC) has been reported to be implicated in chemoresistance. However, the potential mechanism of HULC in paclitaxel (PTX)-resistant ovarian cancer (OC) remains undefined. The expression of RNAs and proteins was measured by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and Western blot assay. The PTX resistance and apoptotic rate were assessed via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry, respectively. Furthermore, the interaction between miR-137 and HULC or integrin beta-8 (ITGB8) was predicted by miRcode and starBase v2.0 and then verified by dual luciferase reporter and RNA pull-down assays. In addition, the xenograft mice model was established to explore the effects of HULC in vivo. HULC was significantly upregulated and miR-137 was downregulated in PTX-resistant OC tissues and cells. Also, the HULC depletion suppressed tumor growth and PTX resistance in PTX-treated mice. miR-137 was verified as a target of HULC and directly targeted ITGB8. And HULC knockdown downregulated ITGB8 expression by targeting miR-137. miR-137 inhibitor or ITGB8 overexpression mitigated the suppressive impacts of HULC knockdown on PTX resistance. Collectively, HULC modulated ITGB8 expression to promote PTX resistance of OC by sponging miR-137.

Abstract Background Rheumatic arthritis (RA) is an autoimmune disease with bad effects. Recent researches have shown that circular RNAs (circRNAs) could affect the progress of RA, but the mechanism still indistinct. In this work, we explored the roles of circ_0025908 in RA. Methods The levels of circ_0025908, microRNA-137 (miR-137), and mRNA of homeodomain-interacting protein kinase 2 (HIPK2) were detected by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) in RA tissues. Meanwhile, the level of HIPK2 was quantified by Western blot analysis. Besides, the cell functions were examined by CCK8 assay, EdU assay, flow cytometry assay, ELISA, and Western blot. Furthermore, the interplay between miR-137 and circ_0025908 or HIPK2 was detected by dual-luciferase reporter assay. Results The levels of circ_0025908 and HIPK2 were upregulated, and the miR-137 level was decreased in RA tissues in contrast to that in normal tissues. For functional analysis, circ_0025908 deficiency inhibited cell vitality, cell mitotic cycle, cell proliferation, and immunoreaction in RA cells, whereas promoted cell apoptosis. Moreover, miR-137 was confirmed to repress the progression of RA cells by suppressing HIPK2. In mechanism, circ_0025908 acted as a miR-137 sponge to regulate the level of HIPK2. Conclusion Circ_0025908 facilitates the development of RA through increasing HIPK2 expression by regulating miR-137, which also offered an underlying targeted therapy for RA treatment.

Background: Glioblastoma (GBM) is the most common primary malignant brain tumor in adults exhibiting infiltration into surrounding tissues, recurrence, and resistance to therapy. GBM infiltration is accomplished by many deregulated factors such as cell adhesion molecules (CAMs), which are membrane proteins that participate in cell-cell and cell-ECM interactions to regulate survival, proliferation, migration, and stemness. Methods: A comprehensive bioinformatics analysis of CAMs (n = 518) in multiple available datasets revealed genetic and epigenetic alterations among CAMs in GBM. Univariate Cox regression analysis using TCGA dataset identified 127 CAMs to be significantly correlated with survival. The poor prognostic indicator PTGFRN was chosen to study its role in glioma. Silencing of PTGFRN in glioma cell lines was achieved by the stable expression of short hairpin RNA (shRNA) against the PTGFRN gene. PTGFRN was silenced and performed cell growth, migration, invasion, cell cycle, and apoptosis assays. Neurosphere and limiting dilution assays were also performed after silencing of PTGFRN in GSCs. Results: Among the differentially regulated CAMs (n = 181, 34.9%), major proportion of them were found to be regulated by miRNAs (n = 95, 49.7%) followed by DNA methylation (n = 32, 16.7%), and gene copy number variation (n = 12, 6.2%). We found that PTGFRN to be upregulated in GBM tumor samples and cell lines with a significant poor prognostic correlation with patient survival. Silencing PTGFRN diminished cell growth, colony formation, anchorage-independent growth, migration, and invasion and led to cell cycle arrest and induction of apoptosis. At the mechanistic level, silencing of PTGFRN reduced pro-proliferative and promigratory signaling pathways such as ERK, AKT, and mTOR. PTGFRN upregulation was found to be due to the loss of its promoter methylation and downregulation of miR-137 in GBM. PTGFRN was also found to be higher in glioma stem-like cells (GSCs) than the matched differentiated glioma cells (DGCs) and is required for GSC growth and survival. Silencing of PTGFRN in GSCs reduced transcript levels of reprogramming factors (Olig2, Pou3f2, Sall2, and Sox2). Conclusion: In this study, we provide a comprehensive overview of the differential regulation of CAMs and the probable causes for their deregulation in GBM. We also establish an oncogenic role of PTGFRN and its regulation by miR-137 in GBM, thus signifying it as a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Epithelial-mesenchymal transition (EMT) promotes tumorigenesis and metastasis and increases tumor tolerance to treatment intervention. Abnormal activation of transforming growth factor β (TGF-β) and Wnt pathway induces EMT. Long non-coding RNAs (lncRNAs) significantly influence EMT regulation. Herein, we show that MIR210HG is overexpressed in endometrial cancer tissues, which is associated with poor prognosis. MIR210HG silencing significantly inhibited proliferation, migration, invasion, and EMT phenotype formation in vitro as well as tumorigenesis in vivo. Mechanistically, bioinformatics analyses, RNA binding protein immunoprecipitation (RIP) assays, and luciferase assays showed that MIR210HG acts as a molecular sponge of miR-337-3p and miR-137 to regulate the expression of HMGA2. Additionally, MIR210HG overexpression significantly enriched the Wnt/β-catenin and TGF-β/Smad3 signaling pathway genes, while MIR210HG or HMGA2 knockdown suppressed the Wnt/β-catenin and TGF-β/Smad3 signaling pathway. Our findings on the MIR210HG-miR-337-3p/137-HMGA2 axis illustrate its potential as a target for endometrial cancer therapeutic development.

Abstract Backgrounds Gastric cancer (GC) is general disease in human digestive system with malignancy. Emerging findings indicated that hsa_circ_0031452 (circHECTD1) was strictly associated with carcinogenesis. Nevertheless, the role of circHECTD1 in drug-resistance still needed to be explained. Methods Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to examine the expression profiles of circHECTD1, microRNA (miR)-137, and pre-leukemia transcription factor 3 (PBX3). The function of circHECTD1 in tumorigenesis was evaluated via xenograft tumor model. The IC50 of Diosbulbin-B (DB) was detected using Cell Counting Kit-8 (CCK8). Cell-cycle and apoptosis were reckoned by flow cytometry. Besides, western blot was administrated to reckon the levels of PBX3 and cell apoptotic indicators. Moreover, the interrelation between miR-137 and circHECTD1 or PBX3 was expounded by dual-luciferase reporter, RNA immunoprecipitation (RIP) and RNA pull down assays. Results We uncovered that circHECTD1 was ectopically up-regulated in GC tissues and cells. CircHECTD1 deficiency sensitized DB-treatment in DB-evoked AGS and HGC-27 cells. In vivo assay, circHECTD1 silencing led to the tumor reduction. Also, circHECTD1 served as miR-137 sponge in a sequence-complementary manner. Furthermore, transfection of miR-137 inhibitor markedly eliminated circHECTD1 absence-mediated promotion of DB-sensitivity in GC cells. Moreover, PBX3, a target of miR-137, play a DB-resistant role in GC cells. Fascinatingly, the deletion of PBX3 reversed the impact of miR-137 repression and circHECTD1 knockdown on DB-sensitivity in vitro. Conclusions CircHECTD1 served as an oncogene by a novel miR-137/PBX3 axis, which might supply an underlying biomarker for the diagnosis and prognosis of GC management.

Abstract Background Esophageal squamous cell carcinoma (ESCC) is one of the most malignant tumors in gastrointestinal system. MicroRNAs (miRNAs) have been reported to be implicated in cancer development. However, the role of miR-137 has not been fully revealed in ESCC. Methods Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analyses were separately used to examine RNA level and protein level. 5-ethynyl-2′-deoxyuridine (EdU) assay, transwell assays and flow cytometry analyses were conducted to assess biological behaviors of ESCC cells. Additionally, the interaction between genes were analyzed via Chromatin Immunoprecipitation (ChIP) assay, RNA Binding Protein Immunoprecipitation (RIP) assay, RNA pull down assay and luciferase reporter assay. Results MiR-137 was down-regulated in ESCC cells. Upregulation of miR-137 hindered ESCC cell proliferation, migration, invasion and epithelial mesenchymal transition (EMT). Besides, miR-137 enhanced the sensitivity of ESCC cells to irradiation. Moreover, CCCTC-binding factor (CTCF) inactivated miR-137 transcription in ESCC cells. Furthermore, we revealed enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) and paxillin (PXN) as the downstream targets of miR-137. In turn, EZH2 was recruited by CTCF and induced methylation in miR-137 promoter. Conclusion CTCF/Suz12/EZH2 complex-silenced miR-137 facilitates ESCC progression and radioresistance by targeting EZH2 and PXN.

Abstract Background CircRNAs play crucial roles in multiple tumours. However, the functions of most circRNAs in cervical cancer remain unclear. Methods This study collected GSE113696 data from the GEO database to search for differentially expressed circRNAs in cervical cancer. Quantitative reverse transcription PCR was used to detect the expression level of circNEIL3 in cervical cancer cells and tissues. Then, functional experiments in vitro and in vivo were performed to evaluate the effects of circNEIL3 in cervical cancer. Results CircNEIL3 was highly expressed in cervical cancer. In vivo and in vitro experiments verified that circNEIL3 enhanced the proliferation capacity of cervical cancer cells. RNA immunoprecipitation, luciferase reporter assay, pull-down assay, and fluorescent in situ hybridization confirmed the interaction between circNEIL3 and miR-137 in cervical cancer. A luciferase reporter assay showed that circNEIL3 adsorbed miR-137 and upregulated KLF12 to regulate the proliferation of cervical cancer cells. Conclusions CircNEIL3 is an oncogene in cervical cancer and might serve as a ceRNA that competitively binds to miR-137, thereby indirectly upregulating the expression of KLF12 and promoting the proliferation of cervical cancer cells.

Jiachen Wang, Zhao Wang, Jiaxiang Yuan, Qun Wang, Xinsheng Shen Department of Minimally Invasive Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, People’s Republic of ChinaCorrespondence: Jiachen WangDepartment Of Minimally Invasive Surgery, The First Affiliated Hospital of Zhengzhou University, &Ngr;o. 1 Jianshe East Road, Zhengzhou 450052, Henan, People’s Republic of ChinaTel +86037167967387Email wangjiachen82@126.comBackground: Downregulation of miR-137 regulates tumor growth in hepatocellular carcinoma (HCC). Yet, the underlying molecular mechanisms stay unclear.Materials and Methods: miR-137 and DNA methyltransferase 3a (DNMT3a) expression levels were detected by Western blot, immunohistochemistry and qRT-PCR assays. Luciferase reporter and Western blot assays were also carried out to explore the correlation of miR-137 and DNMT3a. Flow cytometry assay, MTT analysis, transwell and wound healing assay were used to evaluate cell apoptosis, proliferation, as well as invasive and migratory abilities. Western blot was used to examine the caspase-3, cleaved caspase-3, PCNA, MMP-2, and MMP-7 protein levels, as well as PTEN/Akt signaling alternations. Methylation-specific PCR was applied to detect the PTEN promoter methylation status. Xenograft tumor assay, Western blot and immunohistochemistry analyses were taken to confirm the miR-137 regulation in vivo.Results: Downregulation of miR-137, upregulation of DNMT3a, as well as an inverse correlation between them were observed in HCC clinical samples and cells. Moreover, miR-137 targeted directly and inhibited DNMT3a in HCC cells, which further retarded cell proliferative, migratory and invasive capabilities, while promoted apoptotic ones. Additionally, miR-137 overexpression inactivated the PTEN/Akt pathway in HCC cell by decreasing DNMT3a expression. Furthermore, miR-137 overexpression inhibited tumor growth in vivo in HCC via interacting with DNMT3a through inhibiting the PTEN/Akt cascades.Conclusion: Our findings suggested that miR-137 inhibited HCC tumor growth and progression via interacting with DNMT3a and suppressing the PTEN/Akt signaling in vitro and in vivo.Keywords: miR-137, DNMT3a, DNA methylation, hepatocellular carcinoma, the PTEN/Akt pathway

Objective: Stimulant use instigates abstinence syndrome in humans. miRNAs are a critical component for the pathophysiology of stimulant abstinence. Here we sought to identify a miRNA marker of methamphetamine abstinence in the circulating extracellular vesicles (cEVs). Methods: miR-137 in the cEVs was quantified by qPCR in thirty-seven patients under methamphetamine abstinence and thirty-five age-matched healthy controls recruited from 2014 to 2016 from the general adult population in a hospital setting, Seoul, South Korea. Diagnostic power was evaluated by area under curve in the receiver-operating characteristics curve and other multiple statistical parameters. Results: Patients under methamphetamine abstinence exhibited a significant reduction in cEV miR-137. Overall, cEV miR-137 had high potential as a blood-based marker of methamphetamine abstinence. cEV miR-137 retained the diagnostic power irrespective of the duration of methamphetamine abstinence or methamphetamine use. Interestingly, cEV miR-137 interacted with age: Control participants displayed an aging-dependent reduction of cEV miR-137, while methamphetamine-abstinent patients showed an aging-dependent increase in cEV miR-137. Accordingly, cEV miR-137 had variable diagnostic power depending on age, in which cEV miR-137 more effectively discriminated methamphetamine abstinence in the younger population. Duration of methamphetamine use or abstinence, cigarette smoking status, depressive disorder, or antidepressant treatment did not interact with the methamphetamine abstinence-induced reduction of cEV miR-137. Conclusion: Our data collectively demonstrated that miR-137 in the circulating extracellular vesicles held high potential as a stable and accurate diagnostic marker of methamphetamine abstinence syndrome. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinoma (NPC) is the most common malignant tumor of the head and neck region and is characterized by an increased risk of developing chemoresistance after treatment. The present study demonstrated that estrogen-related receptor α (ERRα) was upregulated in cisplatin- and fluorouracil-resistant NPC cells. In addition, ERRα knockdown or treatment of cells with the ERRα inverse agonist XCT-790 attenuated the chemoresistance of NPC cells. Mechanistically, the increased expression of ERRα in chemoresistant cells was associated with enhanced mRNA stability. Bioinformatics analysis for screening microRNAs (miRs) regulating the expression of ERRα revealed that miR-137 was downregulated in chemoresistant NPC cells. Additionally, transfection of cells with miR-137 mimics reduced ERRα mRNA stability and increased the chemosensitivity of NPC cells. Furthermore, ERRα knockdown reduced glucose consumption, and lactate and ATP production rates in chemoresistant cells. The aforementioned findings suggested that the miR-137/ERRα-mediated metabolic programming could be involved in the chemoresistance of NPC cells. [ABSTRACT FROM AUTHOR]