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Long noncoding RNAs (lncRNA) have a critical role in colorectal cancer (CRC) development and progression. However, the role of the lncRNA HOXB-AS4 in CRC remains unclear. In this study, we found that HOXB-AS4 was markedly upregulated in tumor tissues compared to precancerous tissues. Loss-of-function assays in HT29 and SW480 cells confirmed that knockdown of HOXB-AS4 inhibited proliferation, migration, and promoted apoptosis. In addition, HOXB-AS4 was shown to regulate histone deacetylase 7 (HDAC7) expression by acting as a molecular sponge to bind to and adsorb miR-140-5p. These findings were confirmed by the dual-luciferase reporter assay. Functional recovery experiments further demonstrated the crucial role of the HOXB-AS4/miR-140-5p/HDAC7 axis in modulating the malignant phenotype of CRC cells. Collectively, our data suggested that HOXB-AS4 regulated the malignant tumor aggression of HT29 and SW480 cells through the miR-140-5p/HDAC7 axis and PI3K/AKT signaling pathway. Our study provides novel insights into the mechanism of action of HOXB-AS4 in CRC and highlights its potential use as a targeted therapy.

Background: Existing studies have found that circular RNAs (circRNAs) act as sponges for micro RNAs (miRNAs) to control downstream genes. However, the specific functionalities and mechanisms of circRNAs in human clear cell renal cell carcinoma (ccRCC) have yet to be thoroughly investigated., Methods: Patient cohorts from online databases were used to screen candidate circRNAs, while another cohort from our hospital was obtained for validation. CircSOD2 was identified as a potential oncogenic target, and its relevant characteristics were investigated during ccRCC progression through various assays. A positive feedback loop containing downstream miRNA and its target gene were identified using bioinformatics and validated by luciferase reporter assays, RNA pull-down, and high-throughput sequencing., Results: CircSOD2 expression was elevated in tumor samples and significantly correlated with overall survival (OS) and the tumor stage of ccRCC patients, which appeared in the enhanced proliferation, invasion, and migration of tumor cells. Through competitive binding to circSOD2, miR-532-3p can promote the expression of PAX5 and the progression of ccRCC, and such regulation can be salvaged by miR-532-3p inhibitor., Conclusion: A novel positive feedback loop, PAX5/circSOD2/miR-532-3p/PAX5 was identified in the study, indicating that the loop may play an important role in the diagnosis and prognostic prediction in ccRCC patients., (© 2024. The Author(s).)

The poultry skeletal system serves multiple functions, not only providing structural integrity but also maintaining the balance of essential minerals such as calcium and phosphorus. However, in recent years, the consideration of skeletal traits has been overlooked in the selective breeding of broilers, resulting in an inadequate adaptation of the skeletal system to cope with the rapid increase in body weight. Consequently, this leads to lameness and bone diseases such as tibial dyschondroplasia (TD), which significantly impact the production performance of broilers. Accumulating evidence has shown that microRNAs (miRNA) play a crucial role in the differentiation, formation, and disease of cartilage. However, the miRNA-mediated molecular mechanism underlying chicken TD formation is still poorly understood. The objective of this study was to investigate the biological function and regulatory mechanism of miRNA in chicken TD formation. Based on transcriptome sequencing of tibial cartilage in the healthy group and TD group, miR-206a-3p was found to be highly expressed in TD cartilage. The function of miR-206a-3p was explored through the transfection test of miR-206a-3p mimics and miR-206a-3p inhibitor. In this study, we utilized qRT-PCR, CCK-8, EdU, western blot, and flow cytometry to detect the proliferation, differentiation, and apoptosis of chondrocytes. The results revealed that miR-206a-3p suppressed the proliferation and differentiation of TD chondrocytes while promoting their programmed cell death. Furthermore, through biosynthesis and dual luciferase assays, it was determined that BMP6 was the direct target gene of miR-206a-3p. This finding was further supported by rescue experiments which confirmed the involvement of BMP6 in the regulatory pathway governed by miR-206a-3p. Our results suggest that miR-206a-3p can inhibits the proliferation and differentiation promote apoptosis through the target gene BMP-6 and suppressing the Smad2/3 signaling pathway in chicken TD chondrocytes., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Hyperlipidemia is a common metabolic disorder that can lead to cardiovascular disease. PDK4 is a key enzyme that regulates glucose and fatty acid metabolism and homeostasis. The aim of this study is to explore the correlation between PDK4 expression and dyslipidemia in obese children, and to find new therapeutic targets for hyperlipidemia in children. The expression of PDK4 in serum was detected by qRT-PCR. Receiver operating characteristic curve was used to analyze the relationship between PDK4 and dyslipidemia. Upstream miRNAs of PDK4 were predicted by the database and verified by dual luciferase reporter gene assay and detected by qRT-PCR. The hyperlipidemia mouse model was established by high-fat diet (HFD) feeding, and the metabolic disorders of mice were detected. PDK4 is poorly expressed in the serum of obese children. The upstream of PDK4 may be inhibited by miR-107, miR-27a-3p, and miR-106b-5p, which are highly expressed in the serum of obese children. Overexpression of PDK4 improves lipid metabolism in HFD mice. miR-27a-3p silencing upregulates PDK4 to improve lipid metabolism. In conclusion, PDK4 has a diagnostic effect on dyslipidemia in children, while lipid metabolism in hyperlipidemic mice could be mitigated by upregulation of PDK4, which was inhibited by miR-107, miR-27a-3p and miR-106b-5p on upstream., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Metabolic syndrome (MetS) prevalence has increased dramatically worldwide and has become a public health issue. Polycyclic aromatic hydrocarbons (PAHs) were identified as risk factors of MetS, while essential metals are integral parts of metalloenzymes catalyzing metabolic processes. However, effects of co-exposure to PAHs and essential metals have not been investigated yet. We aimed to assess whether essential metals could modify the hazard effects of PAHs on MetS, and underlying mediation effects of microRNA (miRNAs) were further explored. A cross-sectional study of 1451 males including 278 MetS cases was conducted. Internal exposure levels of 5 classes of PAH metabolites, 7 essential metals, as well as expressions of PAHs-associated 8 plasma miRNAs were assessed. Multiple exposure models, Bayesian kernel machine regression (BKMR), and quantile g-computation (QGcomp) were used simultaneously to identify MetS-related critical chemicals. Mutual effect modification between chemicals and mediation effects of miRNAs on chemical-MetS association was testified. In this study, hydroxyphenanthrene (OHPhe) and selenium (Se) were consistently identified as MetS-related key chemicals in three statistical methods. OHPhe was positively associated with MetS [OR (95 % CI) = 1.79 (1.21, 2.65), P = 0.004], while Se had a negative relationship with MetS [OR (95 % CI) = 0.61 (0.43, 0.87), P = 0.007]. Effect modification analysis observed the association between OHPhe and MetS was weakened with increased Se exposure. Only the expression of miR-24-3p was negatively associated with MetS [OR (95 % CI) = 0.81 (0.66, 0.95), P = 0.048] and could mediate 16.1 % of OHPhe-MetS association in subjects with low Se exposure (≤0.87 μg/mmol creatinine) (P = 0.019). We found a mutual effect modification between OHPhe and Se on MetS, and the positive OHPhe-MetS association was attenuated with increased Se exposure. Mediation effects of miR-24-3p on OHPhe-MetS association were dependent on Se dose. Our findings may provide new insight into the prevention and intervention of MetS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: With the advancements in bioinformatic technology, an increasing number of circular RNAs (circRNAs) have been discovered and their crucial roles in the development and progression of various malignancies have been confirmed through multiple pathways. However, the specific mechanisms involving protein-binding circRNAs in colorectal cancer (CRC) remain largely unexplored., Methods: Differential circRNA expression was assessed using a human circRNA microarray in five CRC tissue and paired normal samples. CircGPRC5A expression was then confirmed in the CRC tissues and paired normal samples using qRT-PCR. The biological function of circGPRC5A in CRC were studied in vitro and in vivo. Western blotting, fluorescence in situ hybridization, immunofluorescence, RNA pulldown, mass spectrometry, immunoprecipitation, quantitative phosphoproteomics, and RNA-binding protein immunoprecipitation assays were used to study circGPRC5A., Results: Our analysis revealed that circGPRC5A expression was higher in CRC tissues compared to normal tissues and was associated with tumor size, tumor stage and lymph node status. CircGPRC5A promoted CRC cell proliferation, migration, and metastasis in vitro and in vivo. CircGPRC5A could stabilize PPP1CA protein by inhibiting the binding between UBA1 and PPP1CA, and increasing YAP dephosphorylation., Conclusions: Our study revealed that circGPRC5A plays an essential function in CRC progression by stabilizing PPP1CA protein and enhancing YAP dephosphorylation. CircGPRC5A could act as a novel and potential target for CRC., (© 2023. The Author(s).)

Objective: Chinese herbal formulas show considerable therapeutic benefits in dementia. This study specifically explored the protective action of Zishen Huoxue recipe on the neurovascular unit (NVU) of rats with vascular dementia (VD)., Methods: VD rat models were established by permanent bilateral common carotid artery occlusion and treated with Zishen Huoxue recipe. In vitro glucose‑oxygen deprivation (OGD)-injured NVU models were established and treated with miR-124-3p agomir or rat medicated serum. The neurological damage, histopathological changes, and neuronal injury in the rat hippocampus were assessed using Morris water maze test and histological stainings. Expression of miR-124-3p was determined using RT-qPCR. The blood-brain barrier/NVU injury, cell pyroptosis, NLRP3 inflammasome activation, and release of inflammatory factors were analyzed mainly by immunofluorescence analysis, TUNEL staining, Western blot, and ELISA. QS-21 (an NLRP3 activator) was used to verify the role of miR-124-3p/NLRP3., Results: Zishen Huoxue recipe ameliorated the learning/memory deficits, neuronal injury, NVU insults, cell pyroptosis, activation of NLRP3 inflammasome, and extensive secretion of lactate dehydrogenase/IL-1β/IL-18 in VD rats. miR-124-3p was downregulated in VD rats but upregulated after treatment of this recipe. miR-124-3p overexpression ameliorated NVU insults, reduced cell pyroptosis, lowered NLRP3 inflammasome activation, and suppressed inflammatory responses in OGD-injured NVU models. NLRP3 inflammasome activation partly counteracted the amelioration effect of miR-124-3p on pyroptosis. Zishen Huoxue recipe could upregulate miR-124-3p to suppress pyroptosis and protect NVU function., Conclusion: Zishen Huoxue recipe can upregulate miR-124-3p expression to repress the inflammatory cascade-evoked pyroptosis, thereby protecting against neuronal injury in the NVU of VD rats., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

N7-methylguanosine (m 7 G) modification has been notably linked with the development of many tumors. However, no investigations have been conducted on whether m 7 G-related miRNA (m 7 G-miRNA) is a prognostic index of hepatocellular carcinoma (HCC). Therefore, this investigation aimed to establish a predictive m 7 G-miRNA signature for efficient HCC prognosis and elucidate the associated immune cell infiltration (ICI) and functions in the tumor microenvironment. RNA sequencing and clinical data on 375 HCC and 50 healthy tissue samples were acquired from The Cancer Genome Atlas database. The m 7 G-miRNA regulators methyltransferase-like 1 and WD repeat domain 4 were acquired from the TargetScan database. Univariate Cox regression analysis was conducted on the 63 differentially expressed m 7 G-miRNAs identified. A prognostic signature that consisted of seven miRNAs was identified. According to their risk scores, individuals with HCC were divided into high-risk (HR) and low-risk (LR) cohorts. A Kaplan-Meier test revealed that survival in the HR HCC patients was poorer than in the LR cohort (p < 0.001). The area under the receiver operating characteristic curves of 1-, 3-, and 5-year overall survival were 0.706, 0.695, and 0.715, respectively. A nomogram of sex, risk score, age, and stage indicated the HCC patients' overall survival. Furthermore, it was indicated that the HR and LR patients had different degrees of ICI and immune function. A pathway enrichment analysis revealed the association of several immunity-linked pathways with the risk model. In conclusion, the signature established has great prognostic value and could be used as a new immunotherapy target for individuals with HCC.

TiO 2 nanotubes (TNTs) significantly promote osteogenic differentiation and bone regeneration of cells. Nevertheless, the biological processes by which they promote osteogenesis are currently poorly understood. Long non-coding RNAs (lncRNAs) are essential for controlling osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Epigenetic chromatin modification is one of the pathways in which lncRNAs regulate osteogenic differentiation. Here, we reported that TNTs could upregulate lncRNA RMRP , and inhibition of lncRNA RMRP in human BMSCs (hBMSCs) grown on TNTs could decrease runt-related transcription factor 2 (RUNX2), alkaline phosphatase, osteopontin, and osteocalcin (OCN) expression. Furthermore, we discovered that inhibiting lncRNA RMRP elevated the expression of lncRNA DLEU2 , and lncRNA DLEU2 knockdown promoted osteogenic differentiation in hBMSCs. RNA immunoprecipitation experiments showed that lncRNA DLEU2 could interact with EZH2 to induce H3K27 methylation in the promoter regions of RUNX2 and OCN, suppressing gene expression epigenetically. According to these results, lncRNA RMRP is upregulated by TNTs to promote osteogenic differentiation through DLEU2 /EZH2-mediated epigenetic modifications., (© 2023 IOP Publishing Ltd.)

Corneal keratoconus (KC) is a dilated (ectatic) corneal disease characterized by a central thinning of the cornea, which causes protrusion into a conical shape that seriously affects vision. However, due to the complex etiology of keratoconus, its entire mechanism remains unclear and there is no mechanism-directed treatment method. Ferroptosis is a novel programmed cell death mechanism related to lipid peroxidation, stress, and amino acid metabolism, which plays a crucial role in various diseases. This study aimed to explore the relationship between keratoconus and ferroptosis, to provide new insights into the mechanism of keratoconus development, and potential treatment options based on further elucidation of this mechanism. The corresponding mRNA microarray expression matrix data of KC patients were obtained from GEO database (GSE204791). Weighted co-expression network analysis (WGCNA) and support vector machine recursive feature elimination (SVM-RFE) were selected to screen hub genes, which were overlapped with ferroptosis genes (FRGs) from FerrDb. GO and GSEA were performed to analyze differential pathways, ssGSEA was used to determine immune status, and then, feasible drugs were predicted by gene-drug network. Additionally, we predicted the miRNA and IncRNA of hub genes to identify the underlying mechanism of disease so as to predict treatment for the disease. The epithelial transcriptome from keratoconus tissue mRNA microarray data (GSE204791) was extracted for the main analysis, including eight epithelial cells and eight epithelial control cells. The differential genes that were overlapped by WGCAN, SVM-RFE and FRGs were mainly related to oxidative stress, immune regulation, cellular inflammation, and metal ion transport. Through further analysis, aldo-keto reductase family 1 member C3 (AKR1C3) was selected, and negatively correlated with mature CD56 natural killer (NK) cells and macrophages. Then, gene-drug interaction network analysis and miRNA prediction were performed through the website. It was concluded that four immune-related drugs (INDOMETHACIN, DAUNORUBICIN, DOXORUBICIN, DOCETAXEL) and a miRNA (has-miR-184) were screened to predict potential drugs and targets for disease treatment. To our knowledge, this was the first report of KC being associated with ferroptosis and prompted search for differential genes to predict drug targets of gene immunotherapy. Our findings provided insight and a solid basis for the analysis and treatment of KC., (© 2023. Springer Nature Limited.)

Background: The incidence of renal cell carcinoma (RCC) has increased in recent years. Metastatic RCC is common and remains a major cause of mortality. A regulatory role for circular RNAs (circRNAs) in the occurrence and progression of RCC has been identified, but their function, molecular mechanisms, and potential clinical applications remain poorly understood., Methods: High-throughput RNA sequencing was used to explore the differential expression of circRNAs and their related pathways in RCC patients. Transwell and CCK-8 assays were used to assess the function of hsa&#95;circ&#95;0057105 in RCC cells. The clinical relevance of hsa&#95;circ&#95;0057105 was evaluated in a cohort of RCC patients. The hsa&#95;circ&#95;0057105 regulatory axis was defined using RNA pull-down, luciferase reporter assays, and fluorescence in situ hybridization assays, and the in vivo effect of hsa&#95;circ&#95;0057105 was validated using animal experiments., Results: Single-sample gene set enrichment analysis and correlation analysis of RNA-seq data showed that hsa&#95;circ&#95;0057105 was potentially oncogenic and may serve to regulate epithelial-mesenchymal transition (EMT) activation in RCC. Hsa&#95;circ&#95;0057105 expression was associated with advanced TNM stages and was an independent prognostic factor for poor RCC patient survival. Phenotypic studies show that hsa&#95;circ&#95;0057105 can enhance the migration and invasion abilities of RCC cells. Further, hsa&#95;circ&#95;0057105 was shown to inhibit the expression of miR-577, a miRNA that regulated the expression of both COL1A1, which induced EMT activation, and VDAC2, which modulated ferroptosis sensitivity. The dual regulatory roles of hsa&#95;circ&#95;0057105 on EMT and ferroptosis sensitivity were verified using rescue experiments. Animal studies confirmed that hsa&#95;circ&#95;0057105 increased the metastatic ability and ferroptosis sensitivity of RCC cells in vivo., Conclusions: In RCC, hsa&#95;circ&#95;0057105 regulates COL1A1 and VDAC2 expression through its sponge effect on miR-577, acting like a 'double-edged sword'. These findings provide new insight into the relationship between EMT and ferroptosis in RCC and provide potential biomarkers for RCC surveillance and treatment., (© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

The Dandy-Walker malformation (DWM) is characterized by neuron dysregulation in embryonic development; however, the regulatory mechanisms associated with it are unclear. This study aimed to investigate the role of NADH dehydrogenase 1 alpha subcomplex 4 (NDUFA4) in regulating downstream signaling cascades and neuronal proliferation and apoptosis. Ndufa4 overexpression promoted the proliferation of neurons and inhibited their apoptosis in vitro, which underwent reverse regulation by the Ndufa4 short hairpin RNAs. Ndufa4-knockout (KO) mice showed abnormal histological alterations in the brain tissue, in addition to impaired spatial learning capacity and exploratory activity. Ndufa4 depletion altered the microRNA expressional profiles of the cerebellum: Ndufa4 inhibited miR-145a-5p expression both in the cerebellum and neurons. miR-145a-5p inhibited the proliferation of neurons and promoted their apoptosis. Ndufa4 promoted and miR-145a-5p inhibited the expression of human homer protein homolog 1 and cyclin D2 in neurons. Thus, Ndufa4 promotes the proliferation of neurons and inhibits their apoptosis by inhibiting miR-145a-5p, which directly targets and inhibits the untranslated regions of Homer1 and Ccnd2 expression., (© 2023. The Author(s).)

Endometrial cancer (EC) ranks fourth among the most common gynecologic malignancies. Despite advances in medical technology, the pathogenesis is still unclear. Numerous reports have identified the involvement of lncRNA in the malignant progression of endometrial cancer. The aim of the study was to investigate the expression level of lncRNA ENST00000585827 (lncRNA E27) in endometrial cancer and the molecular mechanism that regulates the development of endometrial cancer. Combined with the results of the previous study, PCR analysis confirmed that lncRNA E27 was significantly upregulated in endometrial cancer cell lines. The results of CCK-8, wound healing assay, and transwell experiments showed that lncRNA E27 could significantly inhibit cell proliferation, migration, and invasion. Flow cytometry results confirmed that lncRNA E27 could promote apoptosis. Furthermore, based on bioinformatics predictions, dual-luciferase assay and RT-qPCR analysis confirmed that miR-424, as its downstream molecule, competitively regulates the expression of E2F6/E2F7. Rescue experiments further supported that lncRNA E27 inhibited proliferation, migration, invasion, and promoted apoptosis of endometrial cancer through miR-424/E2F6/E2F7 signaling axis. Conclusively, our findings revealed the role of lncRNA E27 in regulating the miR-424/E2F6/E2F7 signaling axis during EC progression, opening up new strategies for the treatment of endometrial cancer., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In the last few decades, microRNAs (miRNAs) are possible to effectively control and treat cancer. However, the function of miR-613 in renal cell carcinoma (RCC) is not very clear up to now. Here, the direction of this research was to investigate the influence of miR-613 for the proliferation, invasion and migration of RCC, and the underlying molecular mechanism. First, the mRNA and protein expression levels of miR-613 were determined in RCC tissues and cancer cells (786-O and ACHN). Using bioinformatics and literature review, anexelekto (AXL), as the target of miR-613 in renal cell carcinoma, was screened. Phenotype experiment and mechanism experiment illustrated the targeting relationship between miR-613 and AXL in cancer cells. Furthermore, a rescue assay with AXL overexpression was performed to make a profound study whether miR-613 disturbs RCC proliferation, invasion, and migration through direct regulation of AXL. Finally, through experiment in vivo , we observe the influence of miR-613 overexpression for tumor. These results were as follows. The present findings proved, in RCC, that the production of miR-613 was at a low level. Except for this point, this current research confirmed, in RCC cells, that the upregulation of miR-613 can control proliferation, metastasis, and invasion by reducing AXL levels and controlling the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway.

Background: To evaluate whether exosomal circRNAs could serve as diagnostic biomarkers for the accurate preoperative prediction of lymph node metastasis (LNM) risk in oral squamous cell carcinoma (OSCC) patients., Methods: A combinative strategy of exosomal circRNAs microarray and qRT-PCR verification was employed to dig LNM-related circRNA signatures. Then, a dynamic nomogram was developed based on candidate circRNAs and preoperative clinical features and the calibration, discrimination, and clinical use of the nomogram were evaluated., Results: According to the microarray, three circRNAs derived from the tumor were associated with preoperative LNM risk, including hsa&#95;circRNA&#95;047733, hsa&#95;circRNA&#95;024144 and hsa&#95;circRNA&#95;403472. The hsa&#95;circRNA&#95;047733 was further verified to be significantly downregulated in patients with LNM (+) as compared with those with LNM (-) (p = 0.007). Patients with the higher expression of hsa&#95;circRNA&#95;047733 showed a lower risk of LNM (multivariate-adjusted OR = 0.22, 95%CI: 0.06-0.83). The bioinformatics prediction showed that hsa&#95;circRNA&#95;047733 might sponge miR-4464/miR-4748 to regulate RPS21 expression. A dynamic nomogram integrating exosomal hsa&#95;circRNA&#95;047733 with five clinicopathological characteristics (tumor site, leukocyte level, maximum tumor diameter, and LNM reported by MRI and preoperative biopsy differentiation) was developed. The model displayed an excellent discrimination ability (AUC = 0.868, 95%CI: 0.781-0.955) and great calibration. The decision curve revealed a higher net benefit superior to the baseline model at an 80% threshold probability., Conclusion: The data provide preliminary evidence that exosomal hsa&#95;circRNA&#95;047733 might be a novel biomarker for the LNM of OSCC. The hsa&#95;circRNA&#95;047733-based dynamic nomogram could serve as a convenient preoperative assessment tool to predict the risk of LNM for OSCC patients., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Circular RNAs (circRNAs) have been reported to exert critical roles in human cancers. In this study, we investigated the role and molecular mechanism of hsa&#95;circ&#95;0012673 in breast cancer. Herein, we found that the expression of hsa&#95;circ&#95;0012673 was upregulated in breast cancer tissues and cell lines. Knockdown of hsa&#95;circ&#95;0012673 using RNA interference technique suppressed the proliferation, migration, and invasion of breast cancer cells. Mechanistically, hsa&#95;circ&#95;0012673 sponged miR-576-3p to stabilize SRY-box transcription factor 4 (SOX4), and thereby facilitating breast cancer cell proliferation, migration and invasion. Collectively, our study identified the oncogenic properties of hsa&#95;circ&#95;0012673/miR-576-3p/SOX4 axis in breast cancer, providing potential and exploitable diagnostic and therapeutic molecules for breast cancer., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ischemic stroke (IS) is the most common type of stroke, and its pathophysiological process is more complex. In recent years, the key regulatory roles of non-coding RNA (miRNA, circRNA) and mRNA in the development of IS have attracted more attention. In the process of cerebral ischemia/reperfusion injury, circRNA can regulate nerves, blood vessels and immune system through miRNA/mRNA axis, so as to affect the neurovascular unit of IS. The combination of these noncoding RNAs and mRNAs can be used as non-invasive biomarkers and therapeutic tools for IS diagnosis, prognosis and brain injury. Therefore, it is very important to study the potential molecular mechanism, activation pathway and treatment methods of circRNA/miRNA/mRNA network in IS. This review will focus on the latest progress of circRNA/miRNA/mRNA regulatory network, we have also included some circRNAs, which does not mediate through a miRNA, so we also include circRNA -mRNA network. And explore the application prospect of these RNAs as potential therapeutic targets in the prevention and treatment of IS., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Electroacupuncture (EA) could enhance neuroregeneration and posttraumatic conditions; however, the underlying regulatory mechanisms remain ambiguous. PDCD6 (programmed cell death 6) is an established proapoptotic regulator which is responsible for motoneuronal death. However, its potential regulatory role in post-spinal cord injury (SCI) regeneration has remained largely unknown. Further investigations are warranted to clarify the involvement of PDCD6 post-SCI recovery and the underlying mechanisms. In our study, based on bioinformatics prediction, we found that miR-34a-3p might be an upstream regulator miRNA for PDCD6, which was subsequently validated through combined utilization of the qRT-PCR, western blot, and dual-luciferase reporter system. Our in vitro results showed that miR-34a-3p might promote the in vitro differentiation of neural stem cell (NSC) through suppressing PDCD6 and regulating other important neural markers such as fibroblast growth factor receptor 1 (FGFR1), MAP1/2 (MAP kinase kinases 1/2), myelin basic protein (MBP), β III-tubulin Class III β -tubulin ( β III tubulin), and glial fibrillary acidic protein (GFAP). Notably, in the post-SCI rat model, exogenous miR-34a-3p agomir obviously inhibited the expression of PDCD6 at the protein level and promoted neuronal proliferation, motoneurons regeneration, and axonal myelination. The restorations at cellular level might contribute to the improved hindlimbs functions of post-SCI rats, which was manifested by the Basso-Beattie-Bresnahan (BBB) locomotor test. The impact of miR-34a-3p was further promoted by EA treatment in vivo . Conclusively, this paper argues that a miR-34a-3p/PDCD6 axis might be a candidate therapeutic target for treating SCI and that the therapeutic effect of EA is driven through this pathway., Competing Interests: The authors declare no competing interests., (Copyright © 2022 Lili Ma et al.)

Purpose: Lung cancer is a relatively common type of cancer, and the incidence rate has been on the rise in recent years. MicroRNAs are a class of endogenous small RNA molecules, which are essential for the posttranscriptional regulation of genes. miR-29b is closely related to the occurrence and development of tumors, including prostate cancer, colon cancer, and breast cancer. However, few studies have been performed to explore the expression and pathway of miR-29b in non-small-cell lung cancer (NSCLC)., Methods: Using bioinformatics analysis, we found that patients with low relative expression of the miR-29b gene have a low long-term survival rate. The results of in vitro research showed that when miR-29b expression was upregulated, the invasion, migration, and proliferation of A549 and NCI-H-1792 cells was inhibited, and the apoptosis was accelerated., Results: The results showed that FEM1B is a miR-29b target gene, and the expressions of FEM1B and miR-29b were negatively correlated. Like the upregulation of miR-29b expression, silencing the FEM1B expression could also impair the invasion, migration, and proliferation abilities of A549 and NCI-H-1792 cells. When FEM1B expression was restored, the inhibitory effect of miR-29b could be reversed. Reverse transcription-polymerase chain reaction (RT-PCR) and western blot (WB) analysis showed that overexpression of miR-29b could inhibit the expression of FEM1B, AKT, vascular endothelial growth factor (VEGF), and Sirt3 in A549 and NCI-H-1792 cells and upregulate the expression of FOXO1 protein., Conclusion: The results of this study indicate that miR-29b inhibits the proliferation and deterioration of NSCLC cells by targeting FEM1B and inhibiting the activation of the FOXO1/AKT pathway. miR-29b may become a new target for the clinical diagnosis and treatment of lung cancer, and it is expected to become a new inhibitor of NSCLC., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Huanrong Zhang et al.)

Circular RNAs (circRNAs) play vital regulatory roles in the development of ovarian cancer (OC). However, the functions of circRNA Atlastin GTPase 2 (circATL2) in paclitaxel (PTX) resistance of OC are still unclear. As a result, circATL2 was upregulated in PTX-resistant OC tissues and cells. CircATL2 knockdown reduced IC 50 of PTX, inhibited colony formation ability and promoted cell cycle arrest and apoptosis in PTX-resistant OC cells. Silencing of circATL2 restrained PTX resistance in vivo. Furthermore, miR-506-3p could be targeted by circATL2 and miR-506-3p inhibition reversed the impacts of circATL2 knockdown on PTX resistance and cell progression in PTX-resistant OC cells. NFIB was identified as the target of miR-506-3p. MiR-506-3p overexpression suppressed PTX resistance and malignant behaviors of PTX-resistant OC cells, with NFIB elevation rescued the impacts. To summarize, circATL2 promoted the resistance of OC to PTX by sponging miR-506-3p to upregulate NFIB expression, providing a new sight in chemoresistance of OC., (© 2021 Wiley Periodicals LLC.)

Background: Ferroptosis is principally caused by iron catalytic activity and intracellular lipid peroxidation. Long noncoding RNAs (lncRNAs) play crucial roles in tumorigenesis. However, the potential interplay between lncRNA LINC01606 and ferroptosis in colon cancer remains elusive., Methods: The expression level of LNC01606 in colon cancer tissue was detected by quantitative real-time polymerase chain reaction. The functional role of LNC01606 was investigated by gain- and loss-of-function assays both in vitro and in vivo. The LINC01606-SCD1-Wnt/β-catenin-TFE3 axis were screened and validated by DNA/RNA pull down, gas chromatography-mass spectrometry, RNA immunoprecipitation and dual-luciferase reporter., Results: The expression of lncRNA LINC01606 was frequently upregulated in human colon cancer and strongly associated with a poor prognosis. LINC01606 functioned as an oncogene and promotes colon cancer cell growth, invasion and stemness both in vitro and in vivo. Moreover, LINC01606 protected colon cancer cells from ferroptosis by decreasing the concentration of iron, lipid reactive oxygen species, mitochondrial superoxide and increasing mitochondrial membrane potential. Mechanistically, LINC01606 enhanced the expression of stearoyl-CoA desaturase 1 (SCD1), serving as a competing endogenous RNA to modulate miR-423-5p expression, subsequently activating the canonical Wnt/β-catenin signaling, and transcription factor binding to IGHM enhancer 3 (TFE3) increased LINC01606 transcription after recruitment to the promoter regions of LINC01606. Furthermore, we confirmed that upregulated LINC01606 and Wnt/β-catenin formed a positive feedback regulatory loop, further inhibiting ferroptosis and enhancing stemness., Conclusions: LINC01606 functions as an oncogene to facilitate tumor cell stemness, proliferation and inhibit ferroptosis and is a promising therapeutic target for colon cancer., (© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Congenital heart disease (CHD) is the most common birth defect. Although ASXL transcriptional regulator 3 (ASXL3) has been reported to cause hereditary CHD, ASXL3-mediated mechanisms in heart development remain unclear. In this study, we used dimethyl sulfoxide (DMSO) to induce differentiation in P19 cells, observed cell morphology using light microscopy after ASXL3 knockdown, and determined the levels of associated myocardial cell markers using reverse transcription-quantitative polymerase chain reaction and western blotting. Subsequently, we used microRNA sequencing, messenger RNA (mRNA) sequencing, and bioinformatics to initially identify the possible mechanisms through which ASXL3-related microRNAs and mRNAs affect heart development. The results indicated that DMSO induced P19 cell differentiation, which could be inhibited by ASXL3 knockdown. We screened 1214 and 1652 differentially expressed microRNAs and mRNAs, respectively, through ASXL3 knockdown and sequencing; these differentially expressed miRNAs were largely enriched in PI3K-Akt, mitogen-activated protein kinase, and Rap1 signaling pathways. Additionally, 11 miRNAs associated with heart development were selected through a literature review. Our analysis indicated the involvement of mmu-miR-323-3p in P19 cell differentiation through the PI3K-Akt pathway. In conclusion, ASXL3 may be involved in the regulation of heart development. This comprehensive study of differentially expressed microRNAs and mRNAs through ASXL3 knockdown in P19 cells provides new insights that may aid the prevention and treatment of CHD.

Neutrophil migration and activation are essential for defense against pathogens. However, this process may also lead to collateral tissue injury. We used microRNA overexpression as a platform and discovered protein-coding genes that regulate neutrophil migration. Here we show that miR-99 decreased the chemotaxis of zebrafish neutrophils and human neutrophil-like cells. In zebrafish neutrophils, miR-99 directly targets the transcriptional factor RAR-related orphan receptor alpha (roraa) . Inhibiting RORα, but not the closely related RORγ, reduced chemotaxis of zebrafish and primary human neutrophils without causing cell death, and increased susceptibility of zebrafish to bacterial infection. Expressing a dominant-negative form of Rorα or disrupting the roraa locus specifically in zebrafish neutrophils reduced cell migration. At the transcriptional level, RORα regulates transmembrane signaling receptor activity and protein phosphorylation pathways. Our results, therefore, reveal previously unknown functions of miR-99 and RORα in regulating neutrophil migration and anti-microbial defense., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hsu, Wang, Syahirah, Liu, Li, Zhang, Wang, Cao, Tian, Matosevic, Staiger, Wan and Deng.)

Objective: Glioblastoma (GBM) is the most common central nervous system tumor. Temozolomide (TMZ) is a commonly used drug for GBM management. This study explored the mechanism of extracellular vesicles (EVs) regulating TMZ-resistance in GBM., Methods: LN229 cells were inducted into TMZ-resistant LN229r strain by stepwise induction. After the intervention of miR-27a-3p expression, cell viability of GBM cells treated with different concentrations of TMZ was detected by MTT and IC50 value was calculated. Cell proliferation and apoptosis were detected by colony formation and flow cytometry. EVs extracted from LN18 cells were identified and the internalization of EVs by LN229r cells was evaluated. The 100 μmol/L TMZ-treated LN229r cells were treated with EVs or EVs with downregulated miR-27a-3p to verify the effect of EVs-carried miR-27a-3p on TMZ resistance. The binding relation between BTG2 and miR-27a-3p was verified. miR-27a-3p and BTG2 expressions in GBM cells and EVs were detected by RT-qPCR. The BTG2 effect on TMZ-resistance in GBM was verified. The xenograft tumor nude mouse model was established by injecting LN229r cells and treated with EVs and 100 μmol/L TMZ., Results: miR-27a-3p was highly expressed in LN229r cells. IC50 value and proliferation of LN229r cells with silenced miR-27a-3p were decreased and apoptosis was increased, indicating that miR-27a-3p silencing reduced the drug-resistant cell LN229r resistance to TMZ. LN18-derived EVs could be internalized by LN229r cells, and release its encapsulated miR-27a-3p into LN229r cells and increase miR-27a-3p expression. EV treatment increased LN229r cell proliferation and reduced apoptosis, while EVs with silenced miR-27a-3p showed the opposite trend. miR-27a-3p targeted BTG2. BTG2 overexpression reduced LN229r cell resistance to TMZ. In vivo, after EVs treatment, tumor volume and weight, Ki67-positive rate, and miR-27a-3p were increased, while BTG2 expression was decreased., Conclusion: GBM-derived EVs were internalized by GBM cells, released miR-27a-3p into GBM cells, upregulated miR-27a-3p expression, and targeted BTG2, thus promoting TMZ resistance., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Endemic fluorosis is a chronic systemic disease that seriously endangers human health. In high fluoride areas, people consume excessive fluoride for a long time through drinking water or food, which leads to chronic cumulative fluorosis in the body. Fluorosis can cause changes in the expression of some miRNA in cells, and the miRNA can participate in fluoride-induced osteoblast activation through various signal pathways. To observe the differential expression of apoptosis-related microRNA (miRNA) in mouse osteoblasts under the action of excessive fluoride. Primary cultured mouse osteoblasts, identified by osteocalcin (OC) and alkaline phosphatase (ALP) staining, were treated with 20 mg/L sodium fluoride and 40 mg/L sodium fluoride for 12/24 hr, respectively, to establish the fluoride staining model for comparing and analyzing the sequence of miRNA among groups by bioinformatics methods; four miRNA chains were verified by fluorescence quantitative PCR. After treatment with 20 mg/L sodium fluoride for 12 hr and 24 hr, 128 miRNA expressions were up-regulated while 36 miRNA expressions were down-regulated. In Group 40 mg/L, 130 miRNA expressions were up-regulated while 29 miRNA expressions were down-regulated after 12 hr and 24 hr; 72 miRNA were up-regulated and 2 miRNA were down-regulated at the two time points. 10 up-regulated miRNA and 2 down-regulated miRNA with higher scores in Bioinformatics software were analyzed the target genes. Fluorescence quantitative PCR verified that the expressions of four miRNA were up-regulated. Target gene analysis of the 10 selected mouse osteoblastic apoptosis-related miRNA reveals their involvement of the functions of inhibiting or promoting apoptosis, which has certain theoretical significance for early identification of skeletal fluorosis. The involved signaling pathways include the Wnt signaling pathway, ubiquitin-regulated proteolysis, Toll signaling pathway, TNF signaling pathway, pluripotent stem cell signaling pathway, MAPK signaling pathway, phosphatidylinositide metabolism, FoxO signaling pathway, ErbB signaling pathway, autophagy, and so forth., (© 2021 American Association for Anatomy.)

Prostate cancer (PCa) is the most popular cancer of mankind. Our study aimed to provide the expression and the predictive significance of miR-1273 g-3p in PCa. Moreover, the effects on cell biological activities were also investigated. The relative expression of miR-1273 g-3p in PCa tissues and cell lines was validated by quantitative real-time PCR. Kaplan-Meier curve and Cox regression analyses were performed to indicate the prognostic value. The implications of miR-1273 g-3p on cell proliferation, migration, and invasion were validated using the CCK-8 and Transwell assay. Our results provided that the expression of miR-1273 g-3p was increased in PCa tissues and cell lines. The levels of miR-1273 g-3p were associated with Gleason score, TNM stage, clinical stage, and lymph node metastasis. Overexpression of miR-1273 g-3p indicated a promising overall survival rate. Cox regression results indicated miR-1273 g-3p might be an independent marker for PCa patients. Silenced miR-1273 g-3p inhibited PCa cell proliferation, migration, and invasion. In total, miR-1273 g-3p was increased in PCa and identified as a therapeutic target and a prognostic factor for PCa patients. Overexpression of miR-1273 g-3p might be an oncogene via accelerating cell proliferation, migration, and invasion., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Macrophages play an important role in the host immune response against mycobacterial infection, and this process is regulated by various factors, including circular RNAs (circRNAs). We intended to explore the role of circ&#95;0001490 in tuberculosis (TB) using Mycobacterium tuberculosis (M.tb)-infected THP-1 macrophages., Methods: Real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot assay were conducted to measure RNA and protein expression, respectively. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was conducted to analyze the viability of THP-1 macrophages. Flow cytometry was performed to analyze the apoptosis rate of THP-1 macrophages. Enzyme-linked immunosorbent assay (ELISA) was conducted to assess the release of inflammatory cytokines. Colony-forming unit (CFU) assay was conducted to analyze the survival of M.tb in THP-1 macrophages. Intermolecular target interaction was verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay., Results: Circ&#95;0001490 expression was down-regulated in the serum samples of TB patients and M.tb-infected THP-1 macrophages. Circ&#95;0001490 overexpression suppressed M.tb survival and promoted the viability and inflammatory response of THP-1 macrophages. Circ&#95;0001490 interacted with microRNA-579-3p (miR-579-3p), and circ&#95;0001490 overexpression-induced protective effects in M.tb-infected THP-1 macrophages were largely overturned by the overexpression of miR-579-3p. miR-579-3p interacted with the 3' untranslated region (3'UTR) of follistatin-like protein 1 (FSTL1). FSTL1 silencing largely overturned miR-579-3p knockdown-induced effects in M.tb-infected THP-1 macrophages. Circ&#95;0001490 acted as miR-579-3p sponge to up-regulate FSTL1 in THP-1 macrophages., Conclusion: In conclusion, our results demonstrated that circ&#95;0001490 suppressed M.tb survival and promoted the viability and inflammatory response of M.tb-infected THP-1 macrophages partly by regulating miR-579-3p/FSTL1 axis., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Trastuzumab resistance negatively influences the clinical efficacy of the therapy for human epidermal growth factor receptor 2 (HER2) positive gastric cancer (GC), and the underlying mechanisms remain elusive. Exploring the mechanisms and finding effective approaches to address trastuzumab resistance are of great necessity. Here, we confirmed that endoplasmic reticulum (ER) stress-induced trastuzumab resistance by up-regulating miR-301a-3p in HER2-positive GC cells. Moreover, we elucidated that miR-301a-3p mediated trastuzumab resistance by down-regulating the expression of leucine-rich repeats and immunoglobulin-like domains containing protein 1 (LRIG1) and subsequently activating the expression of insulin-like growth factor 1 receptor (IGF-1R) and fibroblast growth factor receptor 1 (FGFR1) under ER stress. We also found that intercellular transfer of miR-301a-3p by exosomes disseminated trastuzumab resistance. The present study demonstrated that exosomal miR-301a-3p could serve as a non-invasive biomarker for trastuzumab resistance, which was maybe a novel potential therapeutic target to overcome trastuzumab resistance and improve the curative effect of trastuzumab in HER2-positive GC patients., (© 2021. The Author(s).)

Preeclampsia (PE), a common disorder of pregnancy, is characterized by insufficient trophoblast migration and inadequate vascular remodelling, such that promotion of trophoblast proliferation might ameliorate PE. In the current study, we sought to study the underlying mechanism of extracellular vesicle (EV)-derived microRNA-18 (miR-18b) in PE. Human umbilical cord mesenchymal stem cells (HUCMSCs) isolated from placental tissues were verified through osteogenic, adipogenic and chondrogenic differentiation assays. Bioinformatics analyses and dual-luciferase reporter gene assay were adopted to confirm the targeting relationship between miR-18b and Notch2. The functional roles of EV-derived miR-18b and Notch2 in trophoblasts were determined using loss- and gain-of-function experiments, and trophoblast proliferation and migration were assayed using CCK-8 and Transwell tests. In vivo experiments were conducted to determine the effect of EV-derived miR-18b, Notch2 and TIM3/mTORC1 in a rat model of PE, with monitoring of blood pressure and urine proteinuria. TUNEL staining was conducted to observe the cell apoptosis of placental tissues of PE rats. We found down-regulated miR-18b expression, and elevated Notch2, TIM3 and mTORC1 levels in the placental tissues of PE patients compared with normal placenta. miR-18b was delivered to trophoblasts and targeted Notch2 and negatively its expression, whereas Notch2 positively mediated the expression of TIM3/mTORC1. EV-derived miR-18b or Notch2 down-regulation enhanced trophoblast proliferation and migration in vitro and decreased blood pressure and 24 hours urinary protein in PE rats by deactivating the TIM3/mTORC1 axis in vivo. In summary, EV-derived miR-18b promoted trophoblast proliferation and migration via down-regulation of Notch2-dependent TIM3/mTORC1., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background : Spinal cord injury (SCI) has high disability rate and low cure rate, which frustrates the patients and brings a heavy burden to their families. This study aimed to explore whether NF-κB1 could induce the expression of LINC00665 and form a feedback loop with miR-34a-5p to regulate inflammation and apoptosis of neurons. Results : Basso, Beattie, and Bresnahan (BBB) scoring was decreased, damage for spinal cord tissue was aggravated and neuron number was decreased in SCI rats. The levels of TNF-α, IL-1β and IL-6 in serum and the expression of LINC00665 and NF-κB1 in spinal cord tissues were all increased in SCI rats. After LPS induction, PC12 cell viability was decreased. The expression of LINC00665 and NF-κB1 in LPS-induced PC12 cells was increased, which was partially reversed by BAY11-7082 (NF-κB inhibitor). Inhibition of LINC00665 improved cell viability, suppressed apoptosis and inflammation and down-regulated the NF-κB1 expression in LPS-induced PC12 cells. Furthermore, miR-34a-5p expression was decreased in LPS-induced PC12 cells, which could be promoted by inhibition of LINC00665. miR-34a-5p inhibitor restrained the effect of inhibition of LINC00665 on NF-κB1 expression in LPS-induced PC12 cells. Conclusion : inhibition of LINC00665 improved cell viability, suppressed apoptosis and inflammation in LPS-induced PC12 cells, and the NF-κB1/LINC00665/miR-34a-5ploop might be a useful therapeutic target in SCI treatment.

In order to explore the efficacy of nanoantibiotics in rats with sepsis based on MicroRNA-195 and TGF- β 1/Smads signaling pathway, a total of 160 Wistar rats with sepsis were selected and randomly divided into 4 groups of general antibiotics (GA) treatment group and nanoantibiotics treatment (NT) group, MicroRNA-195 treatment (MT) group and TGF- β 1/Smads (TS) treatment group with 40 sepsis rates in each group. After each group was treated for 24 hours, the supernatant was centrifuged, the enzyme-labeled reagent was added to sample wall, the absorbance value of each well in sequence was measured, and the linear regression equation of the standard curve was calculated based on the concentration and absorbance value of the standard. Before and after the experiment, the changes in body weight, mental state, activity, respiration, and abdominal cavity of species rats in each group were observed and measured; the expression of Interleukin-1 (IL-1), tumor necrosis factor- α (TNF- α ), interleukin-6 (IL-6), interleukin-10 (IL-10), TGF- β 1, Smad2, Smad3, Smad7 were recorded and analyzed. The results showed that the expression levels of IL-1, TNF- α , TGF- β 1, Smad2, Smad3 and Smad7 in sepsis rats in GA group were higher than those in the NT group ( P < 0.05); the myocardial cells in MT group were significantly smaller and the cell arrangement was tighter and more orderly than those in TS group; and the expression levels of TNF- α , IL-6, TGF- β 1, Smad2, Smad3, and Smad7 were significantly reduced ( P < 0.05). In summary, the MicroRNA-195 and TGF- β 1/Smads may promote cardiac remodeling in sepsis rats by up-regulating the nanoantibiotics signaling transduction pathway, thereby having objective curative effect on sepsis rats. The study results of this paper provide a reference for further research on the efficacy of nanoantibiotics in sepsis rats based on MicroRNA-195 and TGF- β 1/Smads signaling pathway.

The long noncoding RNA cancer susceptibility candidate 9 (CASC9) has been revealed to be an oncogenic gene in several types of cancer, and high CASC9 expression is related to tumorigenesis and cancer progression. However, the role of CASC9 in bladder cancer (BC), particularly during epithelial‑mesenchymal transition (EMT), has not been characterized. RT‑qPCR, EdU, CCK‑8, wound scratch, Transwell and flow cytometric assays were performed to detect CASC9 expression, miR‑758‑3p expression and their functions in BC. RNA FISH was used to detect CASC9 subcellular localization. Luciferase reporter assay, RT‑qPCR assay and western blotting were used to explore the relationship of CASC9, miR‑758‑3p and TGF‑β2. In the present study, it was revealed that CASC9 regulated EMT in BC. CASC9 expression was significantly upregulated in BC cell lines and specimens compared to that in adjacent normal bladder tissues. Upregulated CASC9 was associated with increased invasion ability and poor prognosis of BC. CASC9 knockdown inhibited BC cell proliferation, migration and invasion. Furthermore, a bioinformatics study and luciferase reporter assays revealed that CASC9 functioned as a ceRNA for miR‑758‑3p. CASC9 inhibited microRNA (miR)‑758‑3p activity and resulted in the de‑suppression of its target transforming growth factor (TGF)‑β2. TGF‑β signaling driven by TGF‑β2 was crucial for CASC9 to promote EMT in BC. Collectively, these results indicated that CASC9 sponged miR‑758‑3p to regulate the expression of TGF‑β2, which activated the TGF‑β signaling pathway and promoted proliferation and EMT in BC.

A variety of studies have proposed that transient receptor potential vanilloid 1 (TRPV1) is involved in the progression of multiple diseases, including neuropathic pain. Although increased expression of TRPV1 in chronic constriction injury was described earlier, the underlying regulatory mechanisms of TRPV1 in neuropathic pain remain largely unknown. In our study, we constructed a chronic constriction injury (CCI) rat model to deeply analyze the mechanisms underlying TRPV1. RT-qPCR-indicated TRPV1 mRNA and protein expression were extremely upregulated in CCI rat dorsal spinal cord tissues. Then, TRPV1 was corroborated to interact with N-terminal EF-hand Ca 2+ -binding protein 2 (NECAB2). The mRNA and protein levels of NECAB2 were increased in CCI tissues. Moreover, TRPV1 and NECAB2 together regulated nociceptive procession-associated protein metabotropic glutamate receptor 5 (mGluR5), phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), and Ca 2+ in isolated microglia of CCI rats. Moreover, TRPV1 upregulation apparently increased mechanical allodynia and thermal hyperalgesia as well as the expression of inflammation-associated genes (COX-2, TNF-α, and IL-6). In addition, downregulation of NECAB2 significantly decreased mechanical allodynia and thermal hyperalgesia as well as the expression of COX-2, TNF-α, and IL-6. Furthermore, TRPV1 was confirmed to be a downstream target of miR-338-3p. TRPV1 overexpression abolished the inhibitory effect by miR-338-3p elevation on neuropathic pain development. In summary, this study proved TRPV1, targeted by miR-338-3p, induced neuropathic pain by interacting with NECAB2, which provides a potential therapeutic target for neuropathic pain treatment.

Bone marrow failure is a characteristic effect of benzene exposure. Our previous study has shown that miR-486-5p is involved in benzene induced-suppression of erythroid differentiation. However, the mechanism of miR-486-5p to initiate the above process remains unclear. In this study, we used miRTar software to predict putative miRNA targets and pathway. We found that miR-486-5p may target Ras-associated protein-1 (Rap1) signaling pathway-associated genes. Our in vitro study further showed significant dose-dependent upregulation of MAGI1 and RASSF5 expressions in hydroquinone (HQ)-induced suppression of erythroid differentiation of K562 cells. Over-expression or down-regulation of miR-486-5p altered MAGI1 and RASSF5 expression and modified erythroid differentiation. Dual-luciferase reporter assay and fluorescence-based RNA electrophoresis mobility assay (FREMSA) further confirmed that miR-486-5p directly bound to the 3'-untranslated region (3'-UTR) of MAGI1 and RASSF5. In addition, the expressions of RAPGEF2 and RAP1A, which are downstream genes of MAGI1, were also significantly increased when HQ inhibited erythroid differentiation. Knockdown of MAGI1 reversed HQ-induced inhibition of erythroid differentiation via downregulation of RAPGEF2, RAP1A and RASSF5. Together, these data indicate that miR-486-5p directly targets MAGI1 and RASSF5 and integrates with Rap1 signaling to modify HQ-induced inhibition of erythroid differentiation in K562 cells., Competing Interests: Declaration of Competing Interest The authors declare that there are not conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: To uncover the role of microRNA-20a-5p (miRNA-20a-5p) in the progression of Non-small cell lung cancer (NSCLC) and the underlying mechanism., Patients and Methods: MiRNA-20a-5p level in NSCLC tissues and cell lines was determined by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Its level in NSCLC patients with larger or smaller tumor size, and either with lymphatic metastasis or not was examined as well. Regulatory effects of miRNA-20a-5p on viability, cell cycle, and invasiveness of A549 and PC9 cells were assessed. The interaction between miRNA-20a-5p and KLF9 was explored by Dual-Luciferase Reporter Gene Assay and Spearman correlation test. At last, the role of miRNA-20a-5p/KLF9 axis in influencing the progression of NSCLC was determined., Results: MiRNA-20a-5p was upregulated in NSCLC tissues and cell lines. Its level was much pronounced in NSCLC patients with larger tumor size or accompanied with lymphatic metastasis. Overexpression of miRNA-20a-5p in A549 cells enhanced viability, cell ratio in S phase, and invasiveness, while the knockdown of miRNA-20a-5p in PC9 cells achieved the opposite trends. KLF9 was confirmed to be the direct target of miRNA-20a-5p. There was a negative correlation between the expression levels of miRNA-20a-5p and KLF9 in NSCLC tissues. In addition, KLF9 overexpression could reverse the promotive effects of upregulated miRNA-20a-5p on the proliferation and invasiveness of A549 cells. On the contrary, the knockdown of KLF9 reversed the inhibitory effects of downregulated miRNA-20a-5p on cellular behaviors of PC9 cells., Conclusions: MiRNA-20a-5p stimulates NSCLC to proliferate and invade by targeting KLF9.

Objective: Glioma is characterized by high metastasis with poor outcomes. Long non-coding RNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) was well-explored in numerous human cancers, including glioma. This study aimed to provide a novel action mechanism of MALAT1 in glioma., Materials and Methods: The expression of MALAT1, microRNA-384 (miR-384) and Golgi membrane protein 1 (GOLM1) was detected by quantitative Real-time polymerase chain reaction (qRT-PCR). The protein levels of GOLM1, light chain3 (LC3-II/LC3-I), p62, Vimentin and E-cadherin were proved by Western blot. Cell migration and invasion were monitored using the transwell assay. Bioinformatics tool starBase was used to predict target genes and associated binding sites. RNA immunoprecipitation assay (RIP) and dual-luciferase reporter assay were utilized to verify the relationship between miR-384 and MALAT1 or GOLM1. Tumor formation analysis in nude mice was conducted to ascertain the role of MALAT1 in vivo., Results: MALAT1 was highly expressed in glioma tissues and cells. MALAT1 knockdown inhibited autophagy, migration and invasion of glioma cells. MiR-384 was a target of MALAT1, and miR-384 inhibition reversed the effects of MALAT1 knockdown in glioma cells. GOLM1 was a target of miR-384, and miR-384 inhibition eliminated the function of GOLM1 downregulation in glioma cells. In addition, GOLM1 was regulated by MALAT1 through miR-384. Moreover, MALAT1 knockdown blocked tumor growth and development in vivo., Conclusions: MALAT1 knockdown depleted migration and invasion by inhibiting autophagy through MALAT1/miR-384/GOLM1 axis in glioma in vitro and in vivo. The MALAT1/miR-384/GOLM1 axis was first proposed in our report, enriching the action mechanism of MALAT1 in glioma.

Objective: Glioma is a primary intracranial tumor with an unfavorable prognosis. Evolving evidence indicates that circular RNA Tau tubulin kinase 2 (circ-TTBK2) is a cancer-associated gene. Therefore, this study was to explore the potential role of circ-TTBK2., Materials and Methods: Levels of circ-TTBK2, microRNA (miR)-761, and integrin subunit beta 8 (ITGB8) were determined by adopting quantitative real-time polymerase chain reaction (qRT-PCR) or Western blot. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed to detect cell viability, and the invaded cells were distinguished utilizing transwell assay. Iron and lipid reactive oxygen species (ROS) assays were implemented to examine the iron (total iron and ferrous iron) and lipid-based ROS in glioma cells, respectively. Besides, dual-luciferase reporter assay was administrated to illustrate the interaction between miR-761 and circ-TTBK2 or ITGB8. The role of circ-TTBK2 was identified via xenograft tumor model., Results: Levels of circ-TTBK2 and ITGB8 were upregulated, whereas miR-761 level was low-expressed in glioma tissues and cells. Circ-TTBK2 was a sponge of miR-761 to modulate ITGB8. Additionally, circ-TTBK2 knockdown or miR-761 increase could retard cell proliferation, invasion, and promote ferroptosis in glioma cells. Interestingly, miR-761 inhibitor could abolish the repressive impact of circ-TTBK2 silencing on cell growth in vitro. Also, the influence of miR-761 mimic on cell phenotypes was regained after ITGB8 upregulation. Meanwhile, circ-TTBK2 deficiency caused the decrease of tumor growth., Conclusions: Circ-TTBK2 regulated cell proliferation, invasion and ferroptosis via targeting ITGB8 by sponging miR-761 in glioma, providing a promising biomarker for the clinical therapy of human glioma.

Objective: The aim of this study was to uncover the expression pattern and biological function of circ&#95;0001982 in the progression of colorectal cancer (CRC)., Patients and Methods: Relative expression level of circ&#95;0001982 in 66 paired CRC tissues and adjacent normal tissues was detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). The association between circ&#95;0001982 level and clinical indexes of CRC patients was assessed. The effect of circ&#95;0001982 on cellular behaviors of HT29 and HCT-116 cells was evaluated in vitro. Dual-Luciferase reporter gene assay was conducted to verify the binding relation between circ&#95;0001982 and microRNA-144. Finally, rescue experiments were performed to assess the role of the circ&#95;0001982/microRNA-144 axis in mediating the progression of CRC., Results: Circ&#95;0001982 was significantly up-regulated in CRC tissues when compared with adjacent normal ones. CRC patients with a high expression level of circ&#95;0001982 showed a significantly higher rate of distant metastasis and worse survival. Knockdown of circ&#95;0001982 remarkably attenuated the proliferative, migratory, and invasive capacities of HCT-116 cells. However, opposite results were observed after the overexpression of circ&#95;0001982 in HT29 cells. MicroRNA-144 was verified as a target gene of circ&#95;0001982, which could be negatively regulated by circ&#95;0001982. Furthermore, microRNA-144 was capable of reversing the regulatory effect of circ&#95;0001982 on the proliferative, migratory, and invasive capacities of CRC cells., Conclusions: Up-regulated circ&#95;0001982 was closely related to distant metastasis and poor prognosis of CRC. In addition, circ&#95;0001982 attenuated the progression of CRC by negatively regulating microRNA-144.

Background: Brain metastasis (BM) is one of the principal causes of mortality for lung cancer patients. While the molecular events that govern BM of lung cancer remain frustrating cloudy., Methods: The miRNA expression profiles are checked in the paired human BM and primary lung cancer tissues. The effect of miR-143-3p on BM of lung cancer cells and its related mechanisms are investigated., Results: miR-143-3p is upregulated in the paired BM tissues as compared with that in primary cancer tissues. It can increase the invasion capability of in vitro blood brain barrier (BBB) model and angiogenesis of lung cancer by targeting the three binding sites of 3'UTR of vasohibin-1 (VASH1) to inhibit its expression. Mechanistically, VASH1 can increase the ubiquitylation of VEGFA to trigger the proteasome mediated degradation, further, it can endow the tubulin depolymerization through detyrosination to increase the cell motility. m 6 A methyltransferase Mettl3 can increase the splicing of precursor miR-143-3p to facilitate its biogenesis. Moreover, miR-143-3p/VASH1 axis acts as adverse prognosis factors for in vivo progression and overall survival (OS) rate of lung cancer., Conclusions: Our work implicates a causal role of the miR-143-3p/VASH1 axis in BM of lung cancers and suggests their critical roles in lung cancer pathogenesis.

Background: Human are often simultaneously exposed to polycyclic aromatic hydrocarbons (PAHs) and metals, yet relatively little is known regarding their co-exposure effects on oxidative damage. Genetic factors and the gene-environment interactions can also determine the severity of oxidative damage. Four polymorphisms in microRNA (miRNA) genes (rs11614913, rs2292832, rs2910164, and rs3746444) have been well-studied to be associated with oxidative damage-related diseases., Objective: To investigate the influences of PAH-metal co-exposure, four polymorphisms, and their interactions on oxidative damage levels., Methods: We conducted a cross-sectional study in 1385 coke oven workers. We quantified exposure levels of PAHs and metals by urinary monohydroxy-PAHs, plasma benzo[a]pyrene-7,8-diol-9,10-epoxide-albumin adducts, and urinary metals, respectively, and measured oxidative damage levels by 8-iso-prostaglandin-F2α and 8-hydroxydeoxyguanosine. We also genotyped four polymorphisms., Results: In multiple-pollutant models, 8-iso-prostaglandin-F2α and 8-hydroxydeoxyguanosine were associated with multiple PAH exposure biomarkers, as well as with multiple metals (p trend  < 0.05). Metabolites of phenanthrene and pyrene interacted synergistically with lead and zinc to influence 8-iso-prostaglandin-F2α (β interaction  > 7.75%, false discovery rate-adjusted p interaction  ≤ 2.25 × 10 - 5 ). Significantly higher 8-hydroxydeoxyguanosine was observed in carriers of rs11614913 CC variant homozygote than TC carriers (p = 0.037). Associations of the number of rs11614913 C allele with increased 8-iso-prostaglandin-F2α and 8-hydroxydeoxyguanosine were significant (β std  > 0, p trend  < 0.05) and more pronounced in workers with lower metals [p for modifying effect (p ME ) < 0.040]. Positive associations of some PAHs and metals with 8-iso-prostaglandin-F2α and 8-hydroxydeoxyguanosine were weaker in carriers of rs11614913 CC genotype or C allele (p ME  < 0.05)., Conclusion: PAH-metal co-exposure, rs11614913, and their interactions may affect oxidative damage levels in Chinese population in a complex manner that are worthy of further investigation., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Neutrophil migration is essential for inflammatory responses to kill pathogens; however, excessive neutrophilic inflammation also leads to tissue injury and adverse effects. To discover novel therapeutic targets that modulate neutrophil migration, we performed a neutrophil-specific microRNA (miRNA) overexpression screen in zebrafish and identified 8 miRNAs as potent suppressors of neutrophil migration. Among those, miR-199 decreases neutrophil chemotaxis in zebrafish and human neutrophil-like cells. Intriguingly, in terminally differentiated neutrophils, miR-199 alters the cell cycle-related pathways and directly suppresses cyclin-dependent kinase 2 (Cdk2), whose known activity is restricted to cell cycle progression and cell differentiation. Inhibiting Cdk2, but not DNA replication, disrupts cell polarity and chemotaxis of zebrafish neutrophils without inducing cell death. Human neutrophil-like cells deficient in CDK2 fail to polarize and display altered signaling downstream of the formyl peptide receptor. Chemotaxis of primary human neutrophils is also reduced upon CDK2 inhibition. Furthermore, miR-199 overexpression or CDK2 inhibition significantly improves the outcome of lethal systemic inflammation challenges in zebrafish. Our results therefore reveal previously unknown functions of miR-199 and CDK2 in regulating neutrophil migration and provide directions in alleviating systemic inflammation., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

Neutrophil migration is essential for battling against infections but also drives chronic inflammation. Since primary neutrophils are terminally differentiated and not genetically tractable, leukemia cells such as HL-60 are differentiated into neutrophil-like cells to study mechanisms underlying neutrophil migration. However, constitutive overexpression or inhibition in this cell line does not allow the characterization of the genes that affect the differentiation process. Here we apply the tet-on system to induce the expression of a zebrafish microRNA, dre-miR-722, in differentiated HL-60. Overexpression of miR-722 reduced the mRNA level of genes in the chemotaxis and inflammation pathways, including Ras-Related C3 Botulinum Toxin Substrate 2 (RAC2). Consistently, polarization of the actin cytoskeleton, cell migration and generation of the reactive oxygen species are significantly inhibited upon induced miR-722 overexpression. Together, zebrafish miR-722 is a suppressor for migration and signaling in human neutrophil like cells., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Proinflammatory macrophage (M1) is now being suggested as a potential therapeutic strategy for cancer because of its tumoricidal capacity. However, few studies have been focused directly on the effects of M1 macrophages on cancer cells. Here, we found that M1 induced a subpopulation of CD44 high /CD24 - / low or ALDH1 + cells with CSC-like phenotypes from different types of breast cancer cells (BCCs) in a paracrine manner. Stat3/NF-κB pathways in BCCs were activated by proinflammatory cytokines, igniting Lin-28B-let-7-HMGA2 axis to induce CSC through epithelial-mesenchymal transition (EMT). Previously, we reported that Stat3-coordinated Lin-28B-let-7-HMGA2 axis initiated EMT in BCCs. Here, inhibition of Stat3/NF-κB pathways or Lin-28B-let-7-HMGA2 axis suppressed EMT/CSCs program. Notably, HMGA2 knockdown directly repressed M1-induced CSC formation and expression of Klf-4 and Nanog. Meanwhile, prolonged coculture with BCCs endowed M1 with M2 properties. M1 supernatant induced CSC from non-stem cancer cells, while M2 supernatant sustained a higher proportion of ALDH1 + cells. Our data suggest that macrophages might modulate CSC formation and maintenance by transferring between M1/M2 phenotype. Given that M1 are being considered as a promising immunotherapy tool, it is important to inhibit their CSC-inducing potential by targeting key molecules and pathways., (Copyright © 2019 Elsevier B.V. All rights reserved.)

miR-223 is an evolutionarily conserved anti-inflammatory microRNA primarily expressed in myeloid cells. miR-223 post-transcriptionally regulates many genes essential in inflammation, cell proliferation, and invasion. Recent studies show that miR-223 is either endogenously expressed or transferred in exosomes or extracellular vesicles to non-phagocytic cells including cancer cells, where it exerts biological functions. In cancerous cells, miR-223 acts either as an oncomiR promoting tumors or as a tumor suppressor in a context-dependent manner. Taken together, miR-223 can regulate tumorigenesis at multiple levels, including by suppressing the inflammatory tumor microenvironment and modulating malignancy of cancer cells., (Copyright © 2019. Published by Elsevier B.V.)

Long noncoding RNAs (lncRNAs) function as competing endogenous RNAs (ceRNAs). ceRNA networks may serve important roles in various tumors, as demonstrated by an increasing number of studies; however, papillary renal cell carcinoma (PRCC)‑associated ceRNA networks mediated by lncRNAs remain unknown. Increased knowledge of ceRNA networks in PRCC may aid the identification of novel targets and biomarkers in the treatment of PRCC. In the present study, a comprehensive investigation of mRNA, lncRNA, and microRNA (miRNA) expression in PRCC was conducted using sequencing data from The Cancer Genome Atlas. Differential expression (DE) profiles of mRNAs, lncRNAs and miRNAs were evaluated, with 1,970 mRNAs, 1,201 lncRNAs and 96 miRNAs identified as genes with significantly different expression between PRCC and control paracancerous tissues. Based on the identified DEmRNAs, a protein‑protein interaction network was generated using the STRING database. Furthermore, a ceRNA network for PRCC was determined using a targeted assay combined with the DE of miRNAs, mRNAs and lncRNAs, enabling the identification of important lncRNA‑miRNA and miRNA‑mRNA pairs. Analysis of the ceRNA network led to the extraction of a subnetwork and the identification of lncRNA maternally expressed 3 (MEG3), lncRNA PWRN1, miRNA (miR)‑508, miR‑21 and miR519 as important genes. Reverse transcription‑quantitative polymerase chain reaction analysis was conducted to validate the results of the bioinformatics analyses; it was revealed that lncRNA MEG3 expression levels were downregulated in PRCC tumor tissues compared with adjacent non‑tumor tissues. In addition, survival analysis was conducted to investigate the association between identified genes and the prognosis of patients with PRCC, indicating the potential involvement of 13 mRNAs, 15 lncRNAs and six miRNAs. In conclusion, the present study may improve understanding of the regulatory mechanisms of ceRNA networks in PRCC and provide novel insight for future studies of prognostic biomarkers and potential therapeutic targets.

Mounting evidences have indicated that long noncoding RNAs (lncRNAs) play pivotal roles in human diseases, especially in cancers. Recently, TINCR was proposed to be involved in tumor progression. However, its role in colorectal cancer (CRC) remains elusive. In our study, we found that SP1-induced TINCR was significantly upregulated in CRC tissues and cell lines. Moreover, cox multivariate survival analysis revealed that high TINCR was an independent predictor of poor overall survival (OS). Functionally, knockdown of TINCR obviously suppressed CRC cells proliferation, migration and invasion in vitro, and inhibited CRC cells growth and metastasis in vivo. Mechanistically, we identified TINCR could act as a miR-7-5p sponge using RNA pull down, luciferase reporter and RIP assays. Furthermore, we showed that TINCR might promote CRC progression via miR-7-5p-mediated PI3K/Akt/mTOR signaling pathway. Lastly, we revealed that plasma TINCR expression was upregulated in CRC when compared to healthy controls and could be a promising diagnostic biomarker for CRC. Based on above results, our data indicated that TINCR might serve as a potential diagnostic and prognostic biomarker for CRC.

Insulin resistance is the major pathological characteristic of type 2 diabetes, and the elderly often develop insulin resistance. However, the deep-seated mechanisms for aging-related insulin resistance remain unclear. Here, we showed that nanosized exosomes released by bone marrow mesenchymal stem cells (BM-MSCs) of aged mice could be taken up by adipocytes, myocytes, and hepatocytes, resulting in insulin resistance both in vivo and in vitro. Using microRNA (miRNA) array assays, we found that the amount of miR-29b-3p was dramatically increased in exosomes released by BM-MSCs of aged mice. Mechanistically, SIRT1 (sirtuin 1) was identified to function as the downstream target of exosomal miR-29b-3p in regulating insulin resistance. Notably, utilizing an aptamer-mediated nanocomplex delivery system that down-regulated the level of miR-29b-3p in BM-MSCs-derived exosomes significantly ameliorated the insulin resistance of aged mice. Meanwhile, BM-MSCs-specific overexpression of miR-29b-3p induced insulin resistance in young mice. Taken together, these findings suggested that BM-MSCs-derived exosomal miR-29b-3p could modulate aging-related insulin resistance, which may serve as a potential therapeutic target for aging-associated insulin resistance.

Progesterone is often used to protect the endometrium and prevent endometrial cancer. An intensive study on its molecular mechanism in endometrial cancer would contribute to the development of more promising therapies. Relevant lncRNAs and mRNAs expression data in endometrial cancer cell line Ishikawa pretreated and post-treated with progesterone were derived from Gene Expression Omnibus (accession no. GSE29435), and then we analyzed long noncoding RNAs and mRNAs with differential expressions in two different conditions. The Cytoscape software, TargetScan, miRanda, and Human microRNA Disease Database (HMDD) websites were employed. Gene set enrichment analysis (GSEA) was used to determine related Kyoto Encyclopedia of Genes and Genomes pathways alteration in Ishikawa cells treated with progesterone. In addition to bioinformatics analysis, Reverse Transcription-Polymerase Chain Reaction (RT-PCR), Western blot, and dual-luciferase reporter assays were performed. The impact of progesterone on cell propagation and cell cycle was testified by colony formation and flow cytometry analysis. LncRNA nuclear enriched abundant transcript 1 (NEAT1) was the most significantly downregulated lncRNA in endometrial cancer cells treated with progesterone. Lymphoid enhancing factor 1 (LEF1) was positively associated with NEAT1, and eventually hsa&#95;miR-146b-5p was validated to target both LEF1 and NEAT1. Wnt/β-catenin signaling pathway was identified to involve in endometrial cancer. NEAT1 or LEF1 was overexpressed in endometrial cancer cells while downregulated following post-treatment with progesterone. Conversely, miR-146b-5p was notably decreased in Ishikawa cells while upregulated after treatment with progesterone. Downstream gene c-myc or MMP9 regulated by upstream gene LEF1 in Wnt/β-catenin signaling pathway was remarkably increased in Ishikawa cells and positively related with NEAT1. Progesterone inhibited cell cycle and viability through regulating NEAT1/miR-146b-5p axis via Wnt/β-catenin signaling pathway. Progesterone exerted suppressive influence on endometrial cancer progression via regulation of lncRNA NEAT1/miR-146b-5p-mediated Wnt/β-catenin signaling pathway, which might reveal new strategies for developing more effective therapeutics. © 2018 IUBMB Life, 71(1):223-234, 2019., (© 2018 International Union of Biochemistry and Molecular Biology.)

Objective: This study aimed to investigate the associations of multiple metals with chromosome damage, and further explore the mediation roles of microRNAs (miRNAs) and their potentials in lung cancer., Methods: We determined the urinary levels of 23 metals, lymphocytic micronucleus (MN) frequency, and ten candidate miRNAs in plasma among 365 healthy workers. Poisson and linear regression models were conducted to analyze the associations of urinary metals with MN frequency and miRNAs, respectively. The mediation effects of miRNAs on the metal-MN frequency associations were assessed by causal mediation analysis. Additionally, the levels of effective metal and miRNAs were measured in 43 pair-wised tumor and normal lung tissues., Results: The urinary level of titanium was inversely associated with MN frequency after Bonferroni correction [frequency ratio (FR) and 95% confidence interval (95%CI) = 0.88 (0.82, 0.94), p = 5.0 × 10 -4 ]. A doubling in urinary titanium was associated with 14.72%-38.17% decrease in plasma miRNAs. After multiple comparison, miR-24-3p and miR-28-5p significantly mediated 24.8% (7.7%, 70.0%) and 20.4% (5.7%, 52.0%) of the association between titanium and MN frequency (p mediation  = 0.002 and 0.004, respectively). Besides, a doubling in titanium was associated with a separate 53.4% and 47.2% decreased miR-24-3p and miR-28-5p expression in normal lung tissues. Lower titanium but higher levels of miR-24-3p and miR-28-5p were shown in tumor than normal tissues of lung squamous cell carcinoma patients (all p < 0.05)., Conclusions: Our study proposed the negative associations of titanium with chromosome damage and lung cancer, and highlighted the mediating roles of miR-24-3p and miR-28-5p. Further investigations are warranted to validate these associations and uncover the underlying mechanisms., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

MicroRNA-21 (miR-21) is one of the most abundant microRNAs in mammalian cells. It has been intensively studied for its role in regulating apoptosis and oncogenic transformation. However, the impact of miR-21 on host anti-tumor immunity remains unknown. Tumor-associated macrophages are a major leukocyte type that infiltrates tumors and predominantly develops into immunosuppressive, tumor-promoting M2-like macrophages. In contrast, the pro-inflammatory M1-like macrophages have tumoricidal activity. In this study, we show that genetic deficiency of miR-21 promotes the polarization of macrophages toward an M1-like phenotype in vivo and in vitro in the presence of tumor cells; thus it confers host mice with enhanced anti-tumor immunity. By downregulating JAK2 and STAT1, miR-21 inhibits the IFN-γ-induced STAT1 signaling pathway, which is required for macrophage M1 polarization. We also show that the expression of miR-21 in macrophages is regulated upon polarization stimuli as well as upon macrophages co-culturing with tumor cells. Thus, tumor cells may stimulate miR-21 expression in tumor-associated macrophages to prevent tumoricidal M1 polarization. However, augmented STAT1 signaling mediated by miR-21 deficiency upregulates PD-L1 expression in macrophages, which is known to inhibit phagocytic anti-tumor activity. This adverse effect can be alleviated by PD-1 blockade; indeed, miR-21 depletion in macrophages and PD-1 antibody treatment offer superior anti-tumor activity than either agent alone. These studies shed lights on potential application of the combination of miR-21 inhibition and immune checkpoint blockade to target the tumor microenvironment.