miR-193b-3p and miR-346 Exert Antihypertensive Effects in the Rostral Ventrolateral Medulla.

BACKGROUND: Rostral ventrolateral medulla (RVLM) neuron hyperactivity raises sympathetic outflow, causing hypertension. MicroRNAs (miRNAs) contribute to diverse biological processes, but their influence on RVLM neuronal excitability and blood pressure (BP) remains widely unexplored. METHODS AND RESULTS: The RVLM miRNA profiles in spontaneously hypertensive rats were unveiled using RNA sequencing. Potential effects of these miRNAs in reducing neuronal excitability and BP and underlying mechanisms were investigated through various experiments. Six hundred thirty-seven miRNAs were identified, and reduced levels of miR-193b-3p and miR-346 were observed in the RVLM of spontaneously hypertensive rats. Increased miR-193b-3p and miR-346 expression in RVLM lowered neuronal excitability, sympathetic outflow, and BP in spontaneously hypertensive rats. In contrast, suppressing miR-193b-3p and miR-346 expression in RVLM increased neuronal excitability, sympathetic outflow, and BP in Wistar Kyoto and Sprague-Dawley rats. Cdc42 guanine nucleotide exchange factor (Arhgef9) was recognized as a target of miR-193b-3p. Overexpressing miR-193b-3p caused an evident decrease in Arhgef9 expression, resulting in the inhibition of neuronal apoptosis. By contrast, its downregulation produced the opposite effects. Importantly, the decrease in neuronal excitability, sympathetic outflow, and BP observed in spontaneously hypertensive rats due to miR-193b-3p overexpression was greatly counteracted by Arhgef9 upregulation. CONCLUSIONS: miR-193b-3p and miR-346 are newly identified factors in RVLM that hinder hypertension progression, and the miR-193b-3p/Arhgef9/apoptosis pathway presents a potential mechanism, highlighting the potential of targeting miRNAs for hypertension prevention.

Tumor cell-derived exosomal miR-193b-3p promotes tumor-associated macrophage activation to facilitate nasopharyngeal cancer cell invasion and radioresistances.

Background: Communication between cancer cells and tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) plays a crucial role in accelerating nasopharyngeal cancer (NPC) metastasis and radioresistance. However, the mechanisms through which NPC cells regulate the properties and activation of TAMs during NPC progression are not yet fully understood. Methods: A high-metastatic NPC subclone (HMC) and a low-metastatic NPC subclone (LMC) were screened from the CNE-2 cell line and exosomes were collected from HMCs and LMCs, respectively. The effects of HMC- and LMC-derived exosomes (HMC-Exos and LMC-Exos) on the regulation of TAM activation were evaluated by assessing the levels of inflammation-related or immunosuppression-related genes. The role of miRNA-193b-3p (miR-193b) in mediating communication between NPCs and TAMs was assessed using real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR), Western blot analysis, Transwell assays, and clonogenic survival assays. Results: HMCs and HMC-Exos exhibited a greater capacity to facilitate macrophage protumorigenic activation than LMCs and LMC-Exos. miR-193b levels derived from HMC-Exos were higher than those from LMC-Exos, and miR-193b levels were higher in metastatic NPC tissue-derived TAMs than in non-metastatic NPC tissue-derived TAMs. The upregulated miR-193b was packaged into exosomes and transferred to macrophages. Functionally, miR-193b up-regulation accelerated TAM activation by directly targeting mitogen-activated protein/ERK kinase kinase 3 (MEKK3). As a result, miR-193b-overexpressed macrophages facilitated NPC cell invasion and radioresistance. Conclusions: These data revealed a critical role for exosomal miR-193b in mediating intercellular communication between NPC cells and macrophages, providing a potential target for NPC treatment.

miR-193b-5p promotes GCRV replication by inhibiting autophagy via targeting deptor in grass carp (Ctenopharyngodon idellus).

miRNAs are increasingly recognized for their crucial role in autophagy processes. Recent research has highlighted the significant function of autophagy in modulating immune responses. Within this context, specific miRNAs have been identified as indirect mediators of immune functions through their modulation of autophagy. In this study, we verified that miR-193b-5p simultaneously targeted the grass carp autophagy-related gene deptor, thereby reducing autophagy levels in CIK cells. Moreover, we found the expression levels of miR-193b-5p and deptor responding to pathogen infections in the GCRV-infected CIK cells. Notably, the overexpression of miR-193b-5p was found to induce the GCRV replication and reduce the irf3, irf7 and IFN1 expression. These findings also demonstrated that grass carp miR-193b-5p impacted the proliferation, migration, and antiapoptotic abilities of CIK cells. All the above results indicated that miR-193b-5p was linked to grass carp autophagy and played a vital role in antiviral immunity by targeting deptor. Our study may provide important insights into autophagy-related miRNAs and their roles in defense and immune mechanisms against pathogens in teleost.

Cordycepin from Cordyceps militaris ameliorates diabetic nephropathy via the miR-193b-5p/MCL-1 axis.

BACKGROUND: Diabetic nephropathy (DN) is a chronic kidney disease that develops in patients with diabetes mellitus. Cordycepin (CRD), a secondary metabolite produced by Cordyceps militaris, has a variety of bioactive properties. In this study, DN mice and high glucose (HG)-treated HK-2 were used to evaluate the diagnostic value of CRD. METHODS: Quantitative real-time PCR (qRT-PCR), western blotting, immunofluorescence analysis, and immunohistochemical staining were used to assess changes in mRNA and protein expression. Oxidative stress was evaluated by detecting the production of reactive oxygen species (ROS) and the activity of antioxidant enzymes. Cell apoptosis was detected by the TUNEL and flow cytometric methods. The interaction of miR-193b-5p and myeloid leukemia 1 (MCL-1) was examined by bioinformatics analysis and luciferase reporter assay. The protective effects of CRD on DN mice were evaluated by examining DN related biochemical indicators and renal histopathology. RESULTS: In response to HG, the level of miR-193b-5p was elevated, whilst the level of MCL-1 was downregulated, and CRD therapy reversed this behavior. MCL-1 was further identified to be miR-193b-5p target. CRD attenuated HG-induced cell damage, inflammation and abnormal energy metabolism. Mechanistic investigations on in vitro models confirmed that protective effect of CRD against HG challenge to HK-2 cells is mediated through the regulation of expression of miR-193b-5p/MCL-1 axis. By examining DN related biochemical markers and renal histopathology, the protective effects of CRD on DN mice was assessed. CONCLUSIONS: In summary, CRD decreased oxidative stress and inflammation by increasing miR-193b-5p and inactivating downstream MCL-1 in DN, hinting the pivotal values of CRD and miR-193b-5p in the management of DN.

Epigenetic Downregulation of Hsa-miR-193b-3p Increases Cyclin D1 Expression Level and Cell Proliferation in Human Meningiomas.

Meningiomas are common intracranial tumors in adults. Abnormal microRNA (miRNA) expression plays a role in their pathogenesis. Change in miRNA expression level can be caused by impaired epigenetic regulation of miRNA-encoding genes. We found the genomic region covering the MIR193B gene to be DNA hypermethylated in meningiomas based on analysis of genome-wide methylation (HumanMethylation450K Illumina arrays). Hypermethylation of MIR193B was also confirmed via bisulfite pyrosequencing. Both hsa-miR-193b-3p and hsa-miR-193b-5p are downregulated in meningiomas. Lower expression of hsa-miR-193b-3p and higher MIR193B methylation was observed in World Health Organization (WHO) grade (G) II/III tumors as compared to GI meningiomas. CCND1 mRNA was identified as a target of hsa-miR-193b-3p as further validated using luciferase reporter assay in IOMM-Lee meningioma cells. IOMM-Lee cells transfected with hsa-miR-193b-3p mimic showed a decreased cyclin D1 level and lower cell viability and proliferation, confirming the suppressive nature of this miRNA. Cyclin D1 protein expression (immunoreactivity) was higher in atypical than in benign meningiomas, accordingly to observations of lower hsa-miR-193b-3p levels in GII tumors. The commonly observed hypermethylation of MIR193B in meningiomas apparently contributes to the downregulation of hsa-miR-193b-3p. Since hsa-miR-193b-3p regulates proliferation of meningioma cells through negative regulation of cyclin D1 expression, it seems to be an important tumor suppressor in meningiomas.

Bone marrow mesenchymal stem cell-derived exosomal miR-193b-5p reduces pyroptosis after ischemic stroke by targeting AIM2.

BACKGROUND: Ischemic stroke represents a major factor causing global morbidity and death. Bone marrow mesenchymal stem cell (BMSC)-derived exosomes (Exos) have important effects on treating ischemic stroke. Here, we investigated the therapeutic mechanism by which BMSC-derived exosomal miR-193b-5p affects ischemic stroke. METHODS: luciferase assay was performed to evaluate the regulatory relationship of miR-193b-5p with absent in melanoma 2 (AIM2). Additionally, an oxygen-glucose deprivation/reperfusion (OGD/R) model was constructed for the in vitro assay, while a middle cerebral artery occlusion (MCAO) model was developed for the in vivo assay. After exosome therapy, lactate dehydrogenase and MTT assays were conducted to detect cytotoxicity and cell viability, while PCR, ELISA, western blotting assay, and immunofluorescence staining were performed to detect changes in the levels of pyroptosis-related molecules. TTC staining and TUNEL assays were performed to assess cerebral ischemia/reperfusion (I/R) injury. RESULTS: In the luciferase assay, miR-193b-5p showed direct binding to the 3'-untranslated region of AIM2. In both in vivo and in vitro assays, the injected exosomes could access the sites of ischemic injury and could be internalized. In the in vitro assay, compared to normal BMSC-Exos, miR-193b-5p-overexpressing BMSC-Exos showed greater effects on increasing cell viability and attenuating cytotoxicity; AIM2, GSDMD-N, and cleaved caspase-1 levels; and IL-1ß/IL-18 generation. In the in vivo assay, compared to normal BMSC-Exos, miR-193b-5p-overexpressing BMSC-Exos showed greater effects on decreasing the levels of these pyroptosis-related molecules and infarct volume. CONCLUSION: BMSC-Exos attenuate the cerebral I/R injury in vivo and in vitro by inhibiting AIM2 pathway-mediated pyroptosis through miR-193b-5p delivery.

Preventing occludin tight-junction disruption via inhibition of microRNA-193b-5p attenuates viral load and influenza-induced lung injury.

Virus-induced lung injury is associated with loss of pulmonary epithelial-endothelial tight junction integrity. While the alveolar-capillary membrane may be an indirect target of injury, viruses may interact directly and/or indirectly with miRs to augment their replication potential and evade the host antiviral defense system. Here, we expose how the influenza virus (H1N1) capitalizes on host-derived interferon-induced, microRNA (miR)-193b-5p to target occludin and compromise antiviral defenses. Lung biopsies from patients infected with H1N1 revealed increased miR-193b-5p levels, marked reduction in occludin protein, and disruption of the alveolar-capillary barrier. In C57BL/6 mice, the expression of miR-193b-5p increased, and occludin decreased, 5-6 days post-infection with influenza (PR8). Inhibition of miR-193b-5p in primary human bronchial, pulmonary microvascular, and nasal epithelial cells enhanced antiviral responses. miR-193b-deficient mice were resistant to PR8. Knockdown of occludin, both in vitro and in vivo, and overexpression of miR-193b-5p reconstituted susceptibility to viral infection. miR-193b-5p inhibitor mitigated loss of occludin, improved viral clearance, reduced lung edema, and augmented survival in infected mice. Our results elucidate how the innate immune system may be exploited by the influenza virus and how strategies that prevent loss of occludin and preserve tight junction function may limit susceptibility to virus-induced lung injury.

Sp1-mediated miR-193b suppresses atopic dermatitis by regulating HMGB1.

Atopic dermatitis (AD) is a chronic and recurrent inflammatory skin disease. Keratinocyte dysfunction plays a central role in AD development. MicroRNA is a novel player in many inflammatory and immune skin diseases. In this study, we investigated the potential function and regulatory mechanism of miR-193b in AD. Inflamed human keratinocytes (HaCaT) were established by tumor necrosis factor (TNF)-α/interferon (IFN)-γ stimulation. Cell viability was measured using MTT assay, while the cell cycle was analyzed using flow cytometry. The cytokine levels were examined by enzyme-linked immunosorbent assay. The interaction between Sp1, miR-193b, and HMGB1 was analyzed using dual luciferase reporter and/or chromatin immunoprecipitation (ChIP) assays. Our results revealed that miR-193b upregulation enhanced the proliferation of TNF-α/IFN-γ-treated keratinocytes and repressed inflammatory injury. miR-193b negatively regulated high mobility group box 1 (HMGB1) expression by directly targeting HMGB1. Furthermore, HMGB1 knockdown promoted keratinocyte proliferation and inhibited inflammatory injury by repressing nuclear factor kappa-B (NF-κB) activation. During AD progression, HMGB1 overexpression abrogated increase of keratinocyte proliferation and repression of inflammatory injury caused by miR-193b overexpression. Moreover, transcription factor Sp1 was identified as the biological partner of the miR-193b promoter in promoting miR-193b expression. Therefore, Sp1 upregulation promotes keratinocyte proliferation and represses inflammatory injury during AD development via promoting miR-193b expression and repressing HMGB1/NF-κB activation.

MiR-193b-3p Regulates TLR4 Expression to Inhibit Inflammation by Targeting ETS1 in Allergic Rhinitis.

INTRODUCTION: Allergic rhinitis (AR) is identified as a multifactorial disease caused by the interaction of genes and surroundings, which is difficult to cure. MicroRNAs were reported to be engaged in AR development. Here, we aimed to seek the anti-inflammatory effects and regulatory mechanism of miR-193b-3p in AR. METHODS: Mucosal tissues from AR patients and healthy volunteers were collected, and human nasal epithelial cells (HNECs) were treated with IL-13 to establish a cell model of AR. The gene expression of miR-193b-3p, ETS1, TLR4, GM-CSF, eotaxin, and MUC5AC was determined by RT-qPCR. The protein levels of ETS1 and TLR4 were examined using Western blot. Enzyme-linked immunosorbent assay was performed to measure protein concentration of GM-CSF, eotaxin, and MUC5AC in cell supernatant. Dual luciferase assay was applied to verify the interaction among miR-193b-3p, ETS1, and TLR4. RESULTS: The expression of miR-193b-3p was declined in clinical samples from AR patients and in IL-13-induced HNECs, while the mRNA and protein levels of ETS1 and TLR4 were elevated. MiR-193b-3p overexpression or ETS1 silencing notably decreased the mRNA and protein levels of GM-CSF, eotaxin, and MUC5AC in IL-13-treated HNECs. Mechanistically, miR-193b-3p directly combined with ETS1 to silence ETS1 expression. ETS1 promoted the transcriptional activity of TLR4 through interacting with TLR4 promoter. Furthermore, rescue experiments revealed that ETS1 overexpression abolished miR-193b-3p sufficiency-mediated suppression of the mRNA and protein levels of GM-CSF, eotaxin, and MUC5AC in IL-13-treated HNECs. Similarly, TLR4 overexpression compromised the inhibitory impacts of ETS1 downregulation on the mRNA and protein levels of GM-CSF, eotaxin, and MUC5AC in IL-13-induced HNECs. DISCUSSION: MiR-193b-3p repressed IL-13-induced inflammatory response in HNECs by suppressing ETS1/TLR4 axis, which indicated that miR-193b-3p might be a therapeutic target for AR treatment.

Transcriptome analysis reveals a potential regulatory mechanism of the lnc-5423.6/IGFBP5 axis in the early stages of mouse thymic involution.

Age-related thymic involution is one of the significant reasons for induced immunity decline. Recent evidence has indicated that lncRNAs are widely involved in regulating organ development. However, the lncRNA expression profiles in mouse thymic involution have not been reported. In this study, we collect mouse thymus at the ages of 1 month, 3 months, and 6 months for sequencing to observe the lncRNA and gene expression profiles in the early stages of thymic involution. Through bioinformatics analysis, a triple regulatory network of lncRNA-miRNA-mRNA that contains 29 lncRNAs, 145 miRNAs and 12 mRNAs that may be related to thymic involution is identified. Among them, IGFBP5 can reduce the viability, inhibit proliferation and promote apoptosis of mouse medullary thymic epithelial cell line 1 (MTEC1) cells through the p53 signaling pathway. In addition, miR-193b-3p can alleviate MTEC1 cell apoptosis by targeting IGFBP5. Notably, lnc-5423.6 can act as a molecular sponge of miR-193b-3p to regulate the expression of IGFBP5. In summary, lnc-5423.6 enhances the expression of IGFBP5 by adsorption of miR-193b-3p, thereby promoting MTEC1 cell apoptosis.

Pre-Diabetes-Linked miRNA miR-193b-3p Targets PPARGC1A, Disrupts Metabolic Gene Expression Profile and Increases Lipid Accumulation in Hepatocytes: Relevance for MAFLD.

Distinct plasma microRNA profiles associate with different disease features and could be used to personalize diagnostics. Elevated plasma microRNA hsa-miR-193b-3p has been reported in patients with pre-diabetes where early asymptomatic liver dysmetabolism plays a crucial role. In this study, we propose the hypothesis that elevated plasma hsa-miR-193b-3p conditions hepatocyte metabolic functions contributing to fatty liver disease. We show that hsa-miR-193b-3p specifically targets the mRNA of its predicted target PPARGC1A/PGC1α and consistently reduces its expression in both normal and hyperglycemic conditions. PPARGC1A/PGC1α is a central co-activator of transcriptional cascades that regulate several interconnected pathways, including mitochondrial function together with glucose and lipid metabolism. Profiling gene expression of a metabolic panel in response to overexpression of microRNA hsa-miR-193b-3p revealed significant changes in the cellular metabolic gene expression profile, including lower expression of MTTP, MLXIPL/ChREBP, CD36, YWHAZ and GPT, and higher expression of LDLR, ACOX1, TRIB1 and PC. Overexpression of hsa-miR-193b-3p under hyperglycemia also resulted in excess accumulation of intracellular lipid droplets in HepG2 cells. This study supports further research into potential use of microRNA hsa-miR-193b-3p as a possible clinically relevant plasma biomarker for metabolic-associated fatty liver disease (MAFLD) in dysglycemic context.

Downregulation of miR-193a/b-3p during HPV-induced cervical carcinogenesis contributes to anchorage-independent growth through PI3K-AKT pathway regulators.

Cervical cancer is caused by a persistent infection with high-risk types of human papillomavirus (HPV) and an accumulation of (epi)genetic alterations in the host cell. Acquisition of anchorage-independent growth represents a critical hallmark during HPV-induced carcinogenesis, thereby yielding the most valuable biomarkers for early diagnosis and therapeutic targets. In a previous study, we found that miR-193a-3p and miR-193b-3p were involved in anchorage-independent growth. This study aimed to delineate the role of miR-193a/b-3p in HPV-induced carcinogenesis and to identify their target genes related to anchorage-independent growth. Cell viability and colony formation were assessed in SiHa cancer cells and HPV-16 and -18 immortalized keratinocytes upon miR-193a/b-3p overexpression. Both microRNAs reduced cell growth of all three cell lines in low-attachment conditions and showed a minor effect in adherent conditions. Online target-predicting programs and publicly available expression data were used to find candidate messenger RNA (mRNA) targets of miR-193a/b-3p. Seven targets showed reduced mRNA expression upon miR-193a/b-3p overexpression. For three targets, Western blot analysis was also performed, all showing a reduced protein expression. A direct interaction was confirmed using luciferase assays for six genes: LAMC1, PTK2, STMN1, KRAS, SOS2, and PPP2R5C, which are phosphatidylinositol 3-kinase/protein kinase B (PI3K-AKT) regulators. All six targets were overexpressed in cervical cancers and/or precursor lesions. Together with an observed downregulation of phosphorylated-AKT upon miR-193a/b-3p overexpression, this underlines the biological relevance of miR-193a/b-3p downregulation during HPV-induced cervical carcinogenesis. In conclusion, the downregulation of miR-193a-3p and miR-193b-3p is functionally involved in the acquisition of HPV-induced anchorage independence by targeting regulators of the PI3K-AKT pathway.

MiR-19 3b regulated the formation of coat colors by targeting WNT10A and GNAI2 in Cashmere goats.

MiRNAs as a series of small noncoding RNAs that play a crucial part in regulating coat color and hair follicle development. In the previous Solexa sequencing experiments, there were many miRNAs expressed differentially in alpacas with different coat color, including miR-193b.But the mechanism of miR-193b in mammalian pigmentation is still unknown. In this study, bioinformatics analysis showed that WNT10A and GNAI2 might be the target genes of miR-193b. qRT-PCR showed the expression of miR-193b in white Cashmere goats' skins was obviously lower than that in browns, and the expression of WNT10A and GNAI2 were similar with miR-193b. The protein levels of WNT10A and GNAI2 indicated the same findings. Furthermore, the expression of WNT10A and GNAI2 in keratinocytes were analyzed from mRNA and protein levels, the results manifested that the group of overexpression of miR-193b in HaCaT cells increased the expressions of target genes, and miR-193b inhibition group reduced expressions. Luciferase report assays confirmed that the targeting relationship between miR-193b and target genes (WNT10A and GNAI2), the results showed that miR-193b was positively correlated with target genes. These experimental data showed that miR-193b might participate in adjustment of coat color in skin tissue of Cashmere goat by targeting WNT10A and GNAI2.

Qishen Yiqi dropping pills improve cardiomyocyte hypertrophy via the lncRNA TINCR/miR-193b-3p/RORA axis.

Background: This study was designed to explore the therapeutic effect and mechanism of action of Qishen Yiqi dropping pills (QYDP) in chronic heart failure (CHF) via a long non-coding RNA (lncRNA)-microRNA (miRNA)-messenger RNA (mRNA) axis. Here, the mechanism of action of the lncRNA terminal differentiation-induced non-coding RNA (TINCR), miR-193b-3p, and RAR-related orphan receptor A (RORA) mRNA was analyzed in an angiotensin (Ang) II-induced H9C2 cardiomyocyte hypertrophy model treated with QYDP. Methods: Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to analyze the gene expression changes of lncRNA, miRNA, and mRNA in H9C2 induced by QYDP on Ang II. The Gene Expression Omnibus (GEO) was used to analyze differentially expressed genes (DEGs) potentially affecting CHF progression. Cell Counting Kit-8 (CCK-8) was used to analyze the effect of QYDP on the proliferation of H9C2, RNA pull-down was used to analyze the binding of lncRNA and miRNA, and dual luciferase was used to analyze the targeting of miRNA and lncRNA or mRNA. Results: Ang II induced TINCR and RORA downregulation, miR-193b-3p upregulation, and hypertrophy in the H9C2 cardiomyocytes, which were alleviated by QYDP. In contrast, TINCR inhibition reversed the effects of QYDP by increasing miR-193b-3p expression and downregulating RORA expression. According to subsequent double luciferase and RNA pull-down experiments, TINCR adsorbed miR-193b-3p by acting as a competitive endogenous RNA sponge and miR-193b-3p directly targeted RORA. Lastly, we showed that the Ang-II-induced inhibition of TINCR and RORA expression and promotion of cardiac hypertrophy were both reversed by a TINCR overexpression plasmid (ov-TINCR), whereas the effects of ov-TINCR were suppressed by a miR-193b-3p mimic. Conclusions: Administration of QYDP improves Ang II-induced H9C2 cardiomyocyte hypertrophy and increase cell proliferation rate through the TINCR/miR-193b-3p/RORA axis.

miR-193b-3p Promotes Proliferation of Goat Skeletal Muscle Satellite Cells through Activating IGF2BP1.

As a well-known cancer-related miRNA, miR-193b-3p is enriched in skeletal muscle and dysregulated in muscle disease. However, the mechanism underpinning this has not been addressed so far. Here, we probed the impact of miR-193b-3p on myogenesis by mainly using goat tissues and skeletal muscle satellite cells (MuSCs), compared with mouse C2C12 myoblasts. miR-193b-3p is highly expressed in goat skeletal muscles, and ectopic miR-193b-3p promotes MuSCs proliferation and differentiation. Moreover, insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1) is the most activated insulin signaling gene when there is overexpression of miR-193b-3p; the miRNA recognition element (MRE) within the IGF1BP1 3' untranslated region (UTR) is indispensable for its activation. Consistently, expression patterns and functions of IGF2BP1 were similar to those of miR-193b-3p in tissues and MuSCs. In comparison, ectopic miR-193b-3p failed to induce PAX7 expression and myoblast proliferation when there was IGF2BP1 knockdown. Furthermore, miR-193b-3p destabilized IGF2BP1 mRNA, but unexpectedly promoted levels of IGF2BP1 heteronuclear RNA (hnRNA), dramatically. Moreover, miR-193b-3p could induce its neighboring genes. However, miR-193b-3p inversely regulated IGF2BP1 and myoblast proliferation in the mouse C2C12 myoblast. These data unveil that goat miR-193b-3p promotes myoblast proliferation via activating IGF2BP1 by binding to its 3' UTR. Our novel findings highlight the positive regulation between miRNA and its target genes in muscle development, which further extends the repertoire of miRNA functions.

Exosomal miR-193b-3p Contributes to Cisplatin Sensitivity in Seminoma by Targeting ZBTB7A.

A previous study confirmed that miRNAs play an important role in the chemosensitivity of seminoma. Increasing evidence reveals that exosomes participate in the regulation of cisplatin resistance by carrying miRNAs. In this study, we further explored whether exosomes regulated the chemosensitivity of seminoma TCam-2 cells to cisplatin. Initially, cisplatin-resistant TCam-2 cells were induced. Our results revealed that exosomes from cisplatin-resistant TCam-2 cells (rExos) could affect the viability of TCam-2 cells in the context of cisplatin treatment through regulation of both cell apoptosis and the cell cycle. Meanwhile, the levels of γ-H2AX were negatively modulated by rExos, which indicated that rExos could decrease the DNA damage from cisplatin. Furthermore, miR-193b-3p was enriched in rExos, and exosomal miR-193b-3p enhanced the proliferative ability of TCam-2 cells under cisplatin treatment. Mechanistically, exosomal miR-193b-3p targets ZBTB7A, which further decreases apoptosis and promotes cell cycle progression. Taken together, these findings indicate that exosomal miR-193b-3p regulates the chemosensitivity of TCam-2 cells to cisplatin through ZBTB7A signaling and could be a promising drug target for patients with chemoresistant seminoma.

PPARGC1A Is a Moderator of Skeletal Muscle Development Regulated by miR-193b-3p.

Meat production performance is one of the most important factors in determining the economic value of poultry. Myofiber is the basic unit of skeletal muscle, and its physical and chemical properties determine the meat quality of livestock and poultry to a certain extent. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) as a transcriptional coactivator has been found to be widely involved in a series of biological processes. However, PPARGC1A is still poorly understood in chickens. In this manuscript, we reported that PPARGC1A was highly expressed in slow-twitch myofibers. PPARGC1A facilitated mitochondrial biogenesis and regulated skeletal muscle metabolism by mediating the flux of glycolysis and the TCA cycle. Gain- and loss-of-function analyses revealed that PPARGC1A promoted intramuscular fatty acid oxidation, drove the transformation of fast-twitch to slow-twitch myofibers, and increased chicken skeletal muscle mass. Mechanistically, the expression level of PPARGC1A is regulated by miR-193b-3p. Our findings help to understand the genetic regulation of skeletal muscle development and provide a molecular basis for further research on the antagonism of skeletal muscle development and fat deposition in chickens.

MiR-193b as an effective biomarker in human cancer prognosis for Asian patients: a meta-analysis.

Background: MiR-193b has been widely investigated in the last few years and an aberrant association has been observed between its expression levels and the prognosis of several human malignancies. We performed a meta-analysis to evaluate the prognostic effect of miR-193b on human cancers. Methods: PMC, PubMed, Web of Science (WOS), Embase in English and VIP, Wanfang, SinoMed and the China National Knowledge Infrastructure (CNKI) in Chinese were searched up to May 16, 2020. The pooled hazard ratio (HR) with a 95% confidence interval (CI) was calculated to evaluate its prognosis in human cancers. Also, the pooled odd ratios and the relevant 95% CIs were computed to assess the association of miR-193b levels and clinicopathological characteristics of cancer patients. Results: In overall analysis, a significant association was identified between miR-193b levels and overall survival (HR =0.77, 95% CI: 0.64-0.92), but this association was not significant in the random pooling model. Then, two outliers were identified through sensitivity analysis. After removing outliers, the significant association was identified with random pooling model (HR =0.45, 95% CI: 0.30-0.69). In addition, the significance exited among Asian (HR =0.45, 95% CI: 0.28-0.74), studies with the sample size (≥100) (HR =0.39, 95% CI: 0.27-0.56) and sample size (<100) (HR =0.51, 95% CI: 0.28-0.92), Newcastle-Ottawa scale (NOS) scores (≥8) (HR =0.44, 95% CI: 0.30-0.67) and NOS scores (<8) (HR =0.45, 95% CI: 0.25-0.80) and patients of non-digestive carcinoma (HR =0.35, 95% CI: 0.24-0.52), digestive carcinoma (HR =0.54, 95% CI: 0.31-0.92), non-urogenital carcinoma (HR =0.52, 95% CI: 0.33-0.82) or urogenital carcinoma (HR =0.28, 95% CI: 0.16-0.50). Lower expression of miR-193b was found to be related to larger tumor size and the potential of lymph node metastasis and distance metastasis. Discussion: We have demonstrated that miR-193b serves as an ideal biomarker in the cancer prognosis for Asian patients, and the low expression levels of miR-193b is significantly associated with poor overall survival rates in various human malignancies. Moreover, the patients with lower miR-193b tend to develop the cancers with higher potential of metastasis.

miRNA-193b-5p Suppresses Pancreatic Cancer Cell Proliferation, Invasion, Epithelial Mesenchymal Transition, and Tumor Growth by Inhibiting eEF2K.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer deaths in the US due to the lack of effective targeted therapeutics and extremely poor prognosis. OBJECTIVE: The study aims to investigate the role of miR-193b and related signaling mechanisms in PDAC cell proliferation, invasion, and tumor growth. METHODS: Using PDAC cell lines, we performed cell viability, colony formation, in vitro wound healing, and matrigel invasion assays following transfection with miR-193b mimic or control-miR. To identify potential downstream targets of miR-193b, we utilized miRNA-target prediction algorithms and investigated the regulation of eukaryotic elongation factor-2 kinase (eEF2K) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathways and mediators of epithelial mesenchymal transition (EMT). The role of miR-193b in PDAC tumorigenesis was evaluated in in vivo tumor growth of Panc-1 xenograft model in nude mice. RESULTS: We found that miR-193b is under expressed in PDAC cells compared to corresponding normal pancreatic epithelial cells and demonstrated that ectopic expression of miR-193b reduced cell proliferation, migration, invasion, and EMT through downregulation of eEF2K signaling in PDAC cells. miR-193b expression led to increased expression of E-Cadherin and Claudin-1 while decreasing Snail and TCF8/ZEB1 expressions via eEF2K and MAPK/ERK axis. In vivo systemic injection of miR-193b using lipid-nanoparticles twice a week reduced tumor growth of Panc-1 xenografts and eEF2K expression in nude mice. CONCLUSIONS: Our findings suggest that miR-193b expression suppresses PDAC cell proliferation, migration, invasion, and EMT through inhibition of eEF2K/MAPK-ERK oncogenic axis and that miR-193b-based RNA therapy might be an effective therapeutic strategy to control the growth of PDAC.

MicroRNA-193b-3p reduces oxidative stress and mitochondrial damage in rats with cerebral ischemia-reperfusion injury via the seven in absentia homolog 1/Jun N-terminal kinase pathway.

Ischemic stroke is one of the major causes of death and disability among adults. This study sought to explore the mechanism of microRNA (miR)-193b-3p in rats with cerebral ischemia-reperfusion (I/R) injury. The cerebral I/R injury models of rats were established using the suture-occluded method. The pathological changes were observed, and oxidative stress (OS) and mitochondrial function indexes in rat brain tissue were examined. The levels of miR-193b-3p and seven in absentia homolog 1 (SIAH1) were detected. miR-193b-3p agomir or antagomir was injected into the lateral ventricle of I/R rats to overexpress or inhibit miR-193b-3p expression. The targeting relationship between miR-193b-3p and SIAH1 was verified. The effect of SIAH1 overexpression on brain injury in I/R rats was investigated by injecting the lentivirus vector into the lateral ventricle. The phosphorylation level of Jun N-terminal kinase (JNK) was identified. miR-193b-3p was lowly expressed in I/R rats. Overexpression of miR-193b-3p alleviated the pathological damage of I/R rats and limited the OS and mitochondrial damage. miR-193b-3p targeted SIAH1. Overexpression of SIAH1 partially reversed the protection of miR-193b-3p overexpression against cerebral I/R injury. p-JNK was up-regulated in I/R rats and overexpression of miR-193b-3p inhibited p-JNK. Overall, overexpression of miR-193b-3p targeted SIAH1 to inhibit the activation of the JNK pathway and protect rats against cerebral I/R injury.