Deciphering the molecular landscape of ionising radiation-induced eye damage with the help of genomic data mining.

Even at low levels, exposure to ionising radiation can lead to eye damage. However, the underlying molecular mechanisms are not yet fully understood. We aimed to address this gap with a comprehensive in silico approach to the issue. For this purpose we relied on the Comparative Toxicogenomics Database (CTD), ToppGene Suite, Cytoscape, GeneMANIA, and Metascape to identify six key regulator genes associated with radiation-induced eye damage (ATM, CRYAB, SIRT1, TGFB1, TREX1, and YAP1), all of which have physical interactions. Some of the identified molecular functions revolve around DNA repair mechanisms, while others are involved in protein binding, enzymatic activities, metabolic processes, and post-translational protein modifications. The biological processes are mostly centred on response to DNA damage, the p53 signalling pathway in particular. We identified a significant role of several miRNAs, such as hsa-miR-183 and hsamiR-589, in the mechanisms behind ionising radiation-induced eye injuries. Our study offers a valuable method for gaining deeper insights into the adverse effects of radiation exposure.

Exploring the role of microRNAs as diagnostic and prognostic biomarkers in canine mammary tumors.

Canine mammary tumors (CMTs) represent a significant health concern in dogs, with a high incidence among intact female dogs. CMTs are a promising comparative model for human breast cancer, due to sharing several pathophysiological features. Additionally, CMTs have a strong genetic correlation with their human counterpart, including the expression of microRNAs (miRNAs). MiRNAs are a class of non-coding RNAs that play important roles in post-translational regulation of gene expression, being implicated in carcinogenesis, tumor progression, and metastasis. Moreover, miRNAs hold promise as diagnostic, prognostic, and metastatic biomarkers. Understanding the molecular mechanisms underlying CMTs is crucial for improving diagnosis, prognosis, and monitoring of treatments. Herein, we provide a comprehensive overview of the current knowledge on miRNAs in CMTs, highlighting their roles in carcinogenesis and their potential as biomarkers. Additionally, we highlight the current limitations and critically discuss the overarching challenges in this field, emphasizing the need for future research to translate miRNA findings into veterinary clinical practice.

Identification and functional prediction of miRNAs that regulate ROS levels in dielectric barrier discharge plasma-treated boar spermatozoa.

Dielectric barrier discharge (DBD) plasma regulates the levels of reactive oxygen species (ROS), which are critical for sperm quality. MicroRNAs (miRNAs) are non-coding single-stranded RNA molecules encoded by endogenous genes, which regulate post-transcriptional gene expression in animals. At present, it is unknown whether DBD plasma can regulate sperm ROS levels through miRNAs. To further understand the regulatory mechanism of DBD plasma on sperm ROS levels, miRNAs in fresh boar spermatozoa were detected using Illumina deep sequencing technology. We found that 25 known miRNAs and 50 novel miRNAs were significantly upregulated, and 14 known miRNAs and 74 novel miRNAs were significantly downregulated in DBD plasma-treated spermatozoa. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that target genes of differentially expressed miRNAs were involved in many activities and pathways associated with antioxidants. We verified that DBD plasma significantly increased boar sperm quality and reduced ROS levels. These results suggest that DBD plasma can improve sperm quality by regulating ROS levels via miRNAs. Our findings provide a potential strategy to improve sperm quality through miRNA-targeted regulation of ROS, which helps to increase male reproduction and protect cryopreserved semen in clinical practice.

Integrated transcriptome and microRNA analysis reveals molecular responses to high-temperature stress in the liver of American shad (Alosa sapidissima).

BACKGROUND: Fish reproduction, development and growth are directly affected by temperature, investigating the regulatory mechanisms behind high temperature stress is helpful to construct a finer molecular network. In this study, we systematically analyzed the transcriptome and miRNA information of American shad (Alosa sapidissima) liver tissues at different cultivation temperatures of 24 â„ƒ (Low), 27 â„ƒ (Mid) and 30 â„ƒ (High) based on a high-throughput sequencing platform. RESULTS: The results showed that there were 1594 differentially expressed genes (DEGs) and 660 differentially expressed miRNAs (DEMs) in the LowLi vs. MidLi comparison group, 473 DEGs and 84 DEMs in the MidLi vs. HighLi group, 914 DEGs and 442 DEMs in the LowLi vs. HighLi group. These included some important genes and miRNAs such as calr, hsp90b1, hsp70, ssa-miR-125a-3p, ssa-miR-92b-5p, dre-miR-15a-3p and novel-m1018-5p. The DEGs were mainly enriched in the protein folding, processing and export pathways of the endoplasmic reticulum; the target genes of the DEMs were mainly enriched in the focal adhesion pathway. Furthermore, the association analysis revealed that the key genes were mainly enriched in the metabolic pathway. Interestingly, we found a significant increase in the number of genes and miRNAs involved in the regulation of heat stress during the temperature change from 24 °C to 27 °C. In addition, we examined the tissue expression characteristics of some key genes and miRNAs by qPCR, and found that calr, hsp90b1 and dre-miR-125b-2-3p were significantly highly expressed in the liver at 27 â„ƒ, while novel-m0481-5p, ssa-miR-125a-3p, ssa-miR-92b-5p, dre-miR-15a-3p and novel-m1018-5p had the highest expression in the heart at 30℃. Finally, the quantitative expression trends of 10 randomly selected DEGs and 10 DEMs were consistent with the sequencing data, indicating the reliability of the results. CONCLUSIONS: In summary, this study provides some fundamental data for subsequent in-depth research into the molecular regulatory mechanisms of A. sapidissima response to heat stress, and for the selective breeding of high temperature tolerant varieties.

Hodgkin lymphoma and liquid biopsy: a story to be told.

Hodgkin lymphoma (HL) represents a neoplasm primarily affecting adolescents and young adults, necessitating the development of precise diagnostic and monitoring tools. Specifically, classical Hodgkin lymphoma (cHL), comprising 90% of cases, necessitating tailored treatments to minimize late toxicities. Although positron emission tomography/computed tomography (PET/CT) has enhanced response assessment, its limitations underscore the urgency for more reliable progression predictive tools. Genomic characterisation of rare Hodgkin Reed-Sternberg (HRS) cells is challenging but essential. Recent studies employ single-cell molecular analyses, mass cytometry, and Next-Generation Sequencing (NGS) to unveil mutational landscapes. The integration of liquid biopsies, particularly circulating tumor DNA (ctDNA), extracellular vesicles (EVs), miRNAs and cytokines, emerge as groundbreaking approaches. Recent studies demonstrate ctDNA's potential in assessing therapy responses and predicting relapses in HL. Despite cHL-specific ctDNA applications being relatively unexplored, studies emphasize its value in monitoring treatment outcomes. Overall, this review underscores the imperative role of liquid biopsies in advancing HL diagnosis and monitoring.

Research progress on the mechanism of exosome-mediated virus infection.

Exosomes are extracelluar vesicles that facilitate intercellular communication and are pivotal in post-transcriptional regulation within cellular gene regulatory networks, impacting pathogen dynamics. These vesicles serve as crucial regulators of immune responses, mediating cellular interactions and enabling the introduction of viral pathogenic regions into host cells. Exosomes released from virus-infected cells harbor diverse microRNAs (miRNAs), which can be transferred to recipient cells, thereby modulating virus infection. This transfer is a critical element in the molecular interplay mediated by exosomes. Additionally, the endosomal sorting complex required for transport (ESCRT) within exosomes plays a vital role in virus infection, with ESCRT components binding to viral proteins to facilitate virus budding. This review elucidates the roles of exosomes and their constituents in the invasion of host cells by viruses, aiming to shed new light on the regulation of viral transmission via exosomes.

The expression profile of brain-derived exosomal miRNAs reveals the key molecules responsible for spontaneous motor function recovery in a rat model with permanent middle cerebral artery occlusion.

The analysis of alterations in the expression and functionality of brain-derived exosomal miRNAs within ischemic stroke lesions provides significant insights into the mechanisms that contribute to disease recovery. We assessed spontaneous motor function in a rat model of permanent middle cerebral artery occlusion (pMCAO) using motor function scores and magnetic resonance imaging (MRI). Brain-derived exosomes from the infarcted brain tissue of the animal model were extracted and high-throughput sequencing of them was performed followed by bioinformatics analysis for differentially expressed miRNAs target genes. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to measure expression levels of differentially expressed miRNAs at various time points. The oxygen-glucose deprivation (OGD) model was established to investigate gene function through the assessment of cell proliferation and apoptosis using EdU proliferation and JC-1 apoptosis assay. The rat model demonstrated a spontaneous recovery of motor function and a reduction in cerebral infarction area from day 1 to day 14 post-operation. Over the course of the recovery period, miR-24-3p, miR-129-1-3p, and miR-212-5p maintained consistent expression levels, reaching their peak on the initial day following surgery. In the cell model, EdU detection indicated that miR-129-1-3p promoted cellular proliferation, while JC-1 detection revealed its suppressive impact on cellular apoptosis. The current research findings indicated the presence of spontaneous motor function restoration in a rat model of ischemic stroke. MiR-24-3p, miR-129-1-3p, and miR-212-5p were identified as pivotal genes in this recovery process, with miR-129-1-3p potentially influencing the restoration of spontaneous motor function in ischemic stroke through the regulation of neuronal proliferation and apoptosis.

Ultrasensitive Photoelectrochemical Biosensor for Dual-miRNAs Detection Based on Molecular Logic Gates and Methylene Blue Sensitized ZnO@CdS@Au Nanorods.

The occurrence of cancer is often closely related to multiple tumor markers, so it is important to develop multitarget detection methods. By the proper design of the input signals and logical operations of DNA logic gates, detection and diagnosis of cancer at different stages can be achieved. For example, in the early stages, specific input signals can be designed to correspond to early specific tumor markers, thereby achieving early cancer detection. In the late stage, logic gates for multitarget detection can be designed to simultaneously detect multiple biomarkers to improve diagnostic accuracy and comprehensiveness. In this work, we constructed a dual-target-triggered DNA logic gate for anchoring DNA tetrahedra, where methylene blue was embedded in the DNA tetrahedra to sensitize ZnO@CdS@Au, achieving ultrasensitive detection of the target substance. We tested the response of AND and OR logic gates to the platform. For AND logic gates, the sensing platform only responds when both miRNAs are present. In the concentration range of 10 aM to 10 nM, the photoelectric signal gradually increases with an increase of the target concentration. Subsequently, we used OR logic gates for miRNA detection. Even if only one target exists, the sensing platform exhibits excellent performance. Similarly, within the concentration range of 10 aM to 10 nM, the photoelectric signal gradually increases with an increase of the target concentration. The minimum detection limit is 1.10 aM. Whether it is the need to detect multiple targets simultaneously or only one of them, we can achieve it by selecting the appropriate logic gate. This strategy holds promising application prospects in fields such as biosensing, medical diagnosis, and environmental monitoring.

The interplay between microRNAs and Nrf2 signaling in human cancers.

MicroRNAs (miRNAs), as a class of nonprotein-coding RNAs, post-transcriptionally regulate the expression of target genes by base pairing to 3'-untranslated regions (3'-UTRs). Nuclear factor E2-related factor 2 (Nrf2) has been identified as a critical component of the antioxidant defense mechanism. Dysregulation is associated with chemoresistance and radioresistance in cancerous cells. MiRNA-mediated regulation of the Nrf2 signaling pathway has been shown to have important implications for the development of various cancers. In this article, we review the roles of miRNAs as regulators of the Nrf2 pathway in different human cancers. Ras-associated binding (Rab) proteins have an essential role regulation of vesicle transport, as well as oncogenic functions in preventing chemotherapy efficacy and cancer development. More importantly, increased evidence indicated that the interaction between miRNAs and Rabs has been determined to play critical roles in cancer therapy. However, the significant limitations in using miRNAs for therapeutic applications include cross-targeting and instability of miRNAs. The detailed aspect of the interaction of miRNAs and Rabs is not clearly understood. In the current review, we highlighted the involvement of these molecules as regulators of the Nrf2 pathway in cancer pathogenesis. Potential methods and several obstacles in developing miRNAs as an anticancer therapy are also mentioned.

Mechanistic and therapeutic perspectives of miRNA-PTEN signaling axis in cancer therapy resistance.

Cancer, being one of the most lethal illnesses, presents an escalating clinical dilemma on a global scale. Despite significant efforts and advancements in cancer treatment over recent decades, the persistent challenge of resistance to traditional chemotherapeutic agents and/or emerging targeted drugs remains a prominent issue in the field of cancer therapies. Among the frequently inactivated tumor suppressor genes in cancer, phosphatase and Tensin Homolog (PTEN) stands out, and its decreased expression may contribute to the emergence of therapeutic resistance. MicroRNAs (miRNAs), characterized by their short length of 22 nucleotides, exert regulatory control over target mRNA expression by binding to complementary sequences. Recent findings indicate that microRNAs play varied regulatory roles, encompassing promotion, suppression, and dual functions on PTEN, and their aberration is implicated in heightened resistance to anticancer therapies. Significantly, recent research has revealed that competitive endogenous RNAs (ceRNAs) play a pivotal role in influencing PTEN expression, and the regulatory network involving circRNA/lncRNA-miRNA-PTEN is intricately linked to resistance in various cancer types to anticancer therapies. Finally, our findings showcase that diverse approaches, such as herbal medicine, small molecule inhibitors, low-intensity ultrasound, and engineered exosomes, can effectively overcome drug resistance in cancer by modulating the miRNA-PTEN axis.

The Diagnosis of Intestinal Fibrosis in Crohn's Disease-Present and Future.

Crohn's disease (CD) progresses with periods of remission and exacerbations. During exacerbations, chronic inflammation leads to tissue destruction. As a result, intestinal fibrosis may develop in response to the ongoing inflammatory process. Fibrosis in CD should be considered the result of the response of the intestinal wall (over) to the presence of inflammation in the deep structures of the intestinal wall. In the absence of ideal noninvasive methods, endoscopic evaluation in combination with biopsy, histopathological analysis, stool analysis, and blood analysis remains the gold standard for assessing both inflammation and fibrosis in CD. On the contrary, the ability to identify markers of intestinal fibrosis would help to develop new diagnostic and therapeutic methods to detect early stages of fibrosis. It is speculated that miRNAs may, in the future, become biomarkers for early noninvasive diagnosis in the treatment of intestinal fibrosis. The purpose of this review is to summarise existing diagnostic methods for Crohn's disease and present recent scientific reports on molecular testing.

Unveiling the Cutting-Edge Impact of Polarized Macrophage-Derived Extracellular Vesicles and MiRNA Signatures on TGF-ß Regulation within Lung Fibroblasts.

Depending on local cues, macrophages can polarize into classically activated (M1) or alternatively activated (M2) phenotypes. This study investigates the impact of polarized macrophage-derived Extracellular Vesicles (EVs) (M1 and M2) and their cargo of miRNA-19a-3p and miRNA-425-5p on TGF-ß production in lung fibroblasts. EVs were isolated from supernatants of M0, M1, and M2 macrophages and quantified using nanoscale flow cytometry prior to fibroblast stimulation. The concentration of TGF-ß in fibroblast supernatants was measured using ELISA assays. The expression levels of miRNA-19a-3p and miRNA-425-5p were assessed via TaqMan-qPCR. TGF-ß production after stimulation with M0-derived EVs and with M1-derived EVs increased significantly compared to untreated fibroblasts. miRNA-425-5p, but not miRNA-19a-3p, was significantly upregulated in M2-derived EVs compared to M0- and M1-derived EVs. This study demonstrates that EVs derived from both M0 and M1 polarized macrophages induce the production of TGF-ß in fibroblasts, with potential regulation by miRNA-425-5p.

Identification of miRNAs Present in Cell- and Plasma-Derived Extracellular Vesicles-Possible Biomarkers of Colorectal Cancer.

Globally, an increasing prevalence of colorectal cancer (CRC) prompts a need for the development of new methods for early tumor detection. MicroRNAs (also referred to as miRNAs) are short non-coding RNA molecules that play a pivotal role in the regulation of gene expression. MiRNAs are effectively transferred to extracellular vesicle (EVs) membrane sacs commonly released by cells. Our study aimed to examine the expression of miRNAs in four CRC cell lines and EVs derived from them (tumor EVs) in comparison to the normal colon epithelium cell line and its EVs. EVs were isolated by ultracentrifugation from the culture supernatant of SW480, SW620, SW1116, HCT116 and normal CCD841CoN cell lines and characterized according to the MISEV2023 guidelines. MiRNAs were analyzed by small RNA sequencing and validated by quantitative PCR. The performed analysis revealed 22 common miRNAs highly expressed in CRC cell lines and effectively transferred to tumor EVs, including miR-9-5p, miR-182-5p, miR-196b-5p, miR-200b-5p, miR-200c-3p, miR-425-5p and miR-429, which are associated with development, proliferation, invasion and migration of colorectal cancer cells, as well as in vesicle maturation and transport-associated pathways. In parallel, normal cells expressed miRNAs, such as miR-369 and miR-143, which play a role in proinflammatory response and tumor suppression. The analysis of selected miRNAs in plasma-derived EVs and tumor samples from CRC patients showed the similarity of miRNA expression profile between the patients' samples and CRC cell lines. Moreover, miR-182-5p, miR-196-5p, miR-425-5p and miR-429 were detected in several EV samples isolated from patients' plasma. Our results suggest that miR-182-5p, miR-196b-5p and miR-429 are differentially expressed between EVs from CRC patients and healthy donors, which might have clinical implications.

Molecular insights into programmed cell death in esophageal squamous cell carcinoma.

Background: Esophageal squamous cell carcinoma (ESCC) is a deadly type of esophageal cancer. Programmed cell death (PCD) is an important pathway of cellular self-extermination and is closely involved in cancer progression. A detailed study of its mechanism may contribute to ESCC treatment. Methods: We obtained expression profiling data of ESCC patients from public databases and genes related to 12 types of PCD from previous studies. Hub genes in ESCC were screened from PCD-related genes applying differential expression analysis, machine learning analysis, linear support vector machine (SVM), random forest and Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis. In addition, based on the HTFtarget and TargetScan databases, transcription factors (TFs) and miRNAs interacting with the hub genes were selected. The relationship between hub genes and immune cells were analyzed using the CIBERSORT algorithm. Finally, to verify the potential impact of the screened hub genes on ESCC occurrence and development, a series of in vitro cell experiments were conducted. Results: We screened 149 PCD-related DEGs, of which five DEGs (INHBA, LRRK2, HSP90AA1, HSPB8, and EIF2AK2) were identified as the hub genes of ESCC. The area under the curve (AUC) of receiver operating characteristic (ROC) curve of the integrated model developed using the hub genes reached 0.997, showing a noticeably high diagnostic accuracy. The number of TFs and miRNAs regulating hub genes was 105 and 22, respectively. INHBA, HSP90AA1 and EIF2AK2 were overexpressed in cancer tissues and cells of ESCC. Notably, INHBA knockdown suppressed ECSS cell migration and invasion and altered the expression of important apoptotic and survival proteins. Conclusion: This study identified significant molecules with promising accuracy for the diagnosis of ESCC, which may provide a new perspective and experimental basis for ESCC research.

MicroRNA-mediated metabolic regulation of immune cells in cancer: an updated review.

The study of immunometabolism, which examines how immune cells regulate their metabolism to maintain optimal performance, has become an important area of focus in cancer immunology. Recent advancements in this field have highlighted the intricate connection between metabolism and immune cell function, emphasizing the need for further research. MicroRNAs (miRNAs) have gained attention for their ability to post-transcriptionally regulate gene expression and impact various biological processes, including immune function and cancer progression. While the role of miRNAs in immunometabolism is still being explored, recent studies have demonstrated their significant influence on the metabolic activity of immune cells, such as macrophages, T cells, B cells, and dendritic cells, particularly in cancer contexts. Disrupted immune cell metabolism is a hallmark of cancer progression, and miRNAs have been linked to this process. Understanding the precise impact of miRNAs on immune cell metabolism in cancer is essential for the development of immunotherapeutic approaches. Targeting miRNAs may hold potential for creating groundbreaking cancer immunotherapies to reshape the tumor environment and improve treatment outcomes. In summary, the recognition of miRNAs as key regulators of immune cell metabolism across various cancers offers promising potential for refining cancer immunotherapies. Further investigation into how miRNAs affect immune cell metabolism could identify novel therapeutic targets and lead to the development of innovative cancer immunotherapies.

MicroRNA-138 inhibits hypoxia-inducible factor 1α expression in breast cancer cells.

BACKGROUND: Hypoxia, a critical feature during cancer development, leads to the stabilization and activation of the hypoxia-inducible factor 1-alpha (HIF-1α) to drive the expression of many target genes which in turn can promote many aspects of breast cancer biology, mainly metastasis and resistance to therapy. MicroRNAs are known to modulate the expression of many genes involved in breast cancer tumorigenesis. In this study, we examined the regulatory effect of miRNAs on HIF1α expression. METHODS: MCF-7 and MDA-MB-231 were cultivated under normoxia or hypoxia conditions. TaqMan-Low Density Array (TLDA) was used to characterize the miRNA signatures. Wild-Type (WT) or mutated fragments of HIF-1α 3'UTR containing the miR-138 potential target site were cloned downstream of the Renilla luciferase gene in the psiCHECK-1 plasmid. Luciferase assays were then carried out. A lentiviral vector containing copGFP as a reporter gene was prepared and transduced into MCF-7 and MDA-MB-231 cells to assess the effect of identified deregulated miRNAs on HIF-1α expression. RESULTS: Under hypoxic conditions, MCF-7 cells showed deregulated expression for 12 miRNAs. In the case of MDA-MB-231 cells, 16 miRNAs were deregulated in response to hypoxia. Interestingly, miR-138 that was downregulated in both MCF-7 and MDA-MB-231 cells cultivated under hypoxic conditions appeared to have a binding site in 3'UTR of HIF-1α. Moreover, our results indicated that miR-138 could down regulate HIF-1α expression, upon binding directly to its 3'UTR. CONCLUSIONS: Interestingly, our data highlights miR-138 as a potential therapeutic target to reduce HIF-1α expression and subsequently restrain breast cancer invasion and metastasis.

Emerging role of exosomal microRNA in liver cancer in the era of precision medicine; potential and challenges.

Exosomal microRNAs (miRNAs) have great potential in the fight against hepatocellular carcinoma (HCC), the fourth most common cause of cancer-related death worldwide. In this study, we explored the various applications of these small molecules while analyzing their complex roles in tumor development, metastasis, and changes in the tumor microenvironment. We also discussed the complex interactions that exist between exosomal miRNAs and other non-coding RNAs such as circular RNAs, and show how these interactions coordinate important biochemical pathways that propel the development of HCC. The possibility of targeting exosomal miRNAs for therapeutic intervention is paramount, even beyond their mechanistic significance. We also highlighted their growing potential as cutting-edge biomarkers that could lead to tailored treatment plans by enabling early identification, precise prognosis, and real-time treatment response monitoring. This thorough analysis revealed an intricate network of exosomal miRNAs lead to HCC progression. Finally, strategies for purification and isolation of exosomes and advanced biosensing techniques for detection of exosomal miRNAs are also discussed. Overall, this comprehensive review sheds light on the complex web of exosomal miRNAs in HCC, offering valuable insights for future advancements in diagnosis, prognosis, and ultimately, improved outcomes for patients battling this deadly disease.

Comparative Assessment of miR-185-5p and miR-191-5p Expression: From Normal Endometrium to High-Grade Endometrial Cancer.

Endometrial cancer (EC) is a significant cause of cancer-related deaths in women. MicroRNAs (miRs) play a role in cancer development, acting as oncogenes or tumor suppressors. This study evaluated the diagnostic potential of hsa-miR-185-5p and hsa-miR-191-5p in EC and their correlation with clinical and histopathological features. A cross-sectional study analyzed formalin-fixed, paraffin-embedded tissue samples from 59 patients: 18 with EC, 21 with endometrial hyperplasia (EH), 17 with normal endometrium (NE), and 3 with endometrial polyps (EPs). Quantitative reverse transcription-polymerase chain reaction and TaqMan probes were used for miR expression analysis. The Shapiro-Wilk test was used to analyze the normal distribution of the data. Subsequently, parametric or non-parametric tests were used to evaluate the associations between the expression levels of each miR and clinical parameters. Both miRs were underexpressed in some precursor and malignant lesions compared to certain NE subtypes and benign lesions. Specifically, hsa-miR-185-5p showed underexpression in grade 3 EC compared to some NE and EH subtypes (FC: -57.9 to -8.5, p < 0.05), and hsa-miR-191-5p was underexpressed in EH and EC compared to secretory endometrium and EPs (FC: -4.2 to -32.8, p < 0.05). SETD1B, TJP1, and MSI1 were common predicted target genes. In conclusion, hsa-miR-185-5p and hsa-miR-191-5p are underexpressed in EC tissues, correlating with histopathological grades, highlighting their potential as diagnostic biomarkers and their role as tumor suppressors in EC.

Multi-step regulation of microRNA expression and secretion into small extracellular vesicles by insulin.

Tissues release microRNAs (miRNAs) in small extracellular vesicles (sEVs) including exosomes, which can regulate gene expression in distal cells, thus acting as modulators of local and systemic metabolism. Here, we show that insulin regulates miRNA secretion into sEVs from 3T3-L1 adipocytes and that this process is differentially regulated from cellular expression. Thus, of the 53 miRNAs upregulated and 66 miRNAs downregulated by insulin in 3T3-L1 sEVs, only 12 were regulated in parallel in cells. Insulin regulated this process in part by phosphorylating hnRNPA1, causing it to bind to AU-rich motifs in miRNAs, mediating their secretion into sEVs. Importantly, 43% of insulin-regulated sEV-miRNAs are implicated in obesity and insulin resistance. These include let-7 and miR-103, which we show regulate insulin signaling in AML12 hepatocytes. Together, these findings demonstrate an important layer to insulin's regulation of adipose biology and provide a mechanism of tissue crosstalk in obesity and other hyperinsulinemic states.