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Objective: This study investigates how astaxanthin (AST) counters tert-butyl hydroperoxide (tBHP)-induced cellular damage in C28/I2 chondrocytes, focusing on the circ-HP1BP3/miR-139-5p/SOD1 signaling pathway and its use in sustained-release microspheres for osteoarthritis treatment. Methods: We employed a variety of techniques including real-time quantitative PCR, Western blot, ELISA, and dual-luciferase reporter gene assays to explore AST's molecular effects. Additionally, the efficacy of AST-loaded sustained-release microspheres was evaluated in vitro and in a mouse model of osteoarthritis. Results: AST significantly enhanced SOD1 expression, reducing apoptosis and inflammation in damaged cells. The AST-loaded microspheres showed promising in vitro drug release, improved cell viability, and reduced oxidative stress. In the osteoarthritis mouse model, they effectively decreased joint inflammation and increased the expression of chondrocyte markers. Conclusion: Astaxanthin effectively mitigates oxidative stress and inflammation in chondrocytes via the circ-HP1BP3/miR-139-5p/SOD1 pathway. The development of AST-loaded microspheres offers a novel and promising approach for osteoarthritis therapy, potentially extending to osteoarthritis treatment. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are implicated in the progression of breast cancer (BC). However, the explorations on circRNA IQ motif containing H (circIQCH) in BC progression remain limited. Functional experiments were conducted using in vitro and murine xenograft model assays, respectively. Dual‐luciferase reporter assay and RIP assay detected the associations among circIQCH, miR‐139‐5p, and nuclear factor IB (NFIB). CircIQCH was upregulated in BC, and the silencing of circIQCH repressed BC cell growth, metastasis, and autophagy, arrested cell cycle, promoted cell apoptosis in vitro, and blocked tumor growth in vivo. CircIQCH positively modulated NFIB expression by sponging miR‐139‐5p. Moreover, the deletion of miR‐139‐5p abated the action of circIQCH deficiency on BC cell malignant behaviors. Overexpression of miR‐139‐5p repressed the malignant characteristics of BC cells, while these impacts were abolished by elevating NFIB. Collectively, CircIQCH functioned as an oncogene in BC through upregulating NFIB expression by sponging miR‐139‐5p. [ABSTRACT FROM AUTHOR]

Objective: PM2.5 is closed linked to asthma exacerbation. The Notch1 pathway acts as an important pathway, ultimately inducing T-helper cells that express GATA3 and its corresponding Th2 cytokines. The regulatory effects of miR-139-5p on the Notch1 pathway have been indicated in cancer. However, studies on miR-139-5p have not applied asthma-related models. The role of miR-139-5p and its regulatory effects on the Notch1-GATA3 pathway in asthma exacerbation induced by acute PM2.5 exposure has not been elucidated. We hypothesize that acute PM2.5 exposure induces asthma exacerbation by regulating the expression of miR-139-5p and activating the Notch1-GATA3 pathway. Methods: We first employed Diseased Human Bronchial Epithelial Cells-Asthma cells to establish an in vitro model of acute exposure to PM2.5, and explored the relationship between the different concentrations and durations of acute PM2.5 exposure and the activation of Notch1-GATA3 pathway. We investigated the protein and mRNA expression changes of Notch1, upstream Jagged1, downstream GATA3, as well as the regulatory effect of miR-139-5p involved in it. Results: The miR-139-5p expression increased within 24 h of PM2.5 exposure. However, if PM2.5 exposure was sustained, miR-139-5p expression turned to decrease, accompanied by upregulations of the mRNA and protein expression of Notch1-GATA3 pathway. Overexpression of miR-139-5p blocked Notch1-GATA3 pathway activation induced by acute PM2.5 exposure. Conclusion: Acute PM2.5 exposure can activate Notch1-GATA3 pathway in asthma bronchial epithelial cells model, which might be involved in PM2.5-induced asthma exacerbation. miR-139-5p has a potential protective role of inhibiting PM2.5-induced asthma airway inflammation by targeting Notch1. [ABSTRACT FROM AUTHOR]

Exosomes play a crucial role in regulating crosstalk between tumor and tumor stem-like cells through their cargo molecules. Circular RNAs (circRNAs) have recently been demonstrated to be critical factors in tumorigenesis. This study focuses on the molecular mechanism by which circRNAs from glioma stem-like cell (GSLC) exosomes regulate glioblastoma (GBM) tumorigenicity. In this study, we validated that GSLC exosomes accelerated the malignant phenotype of GBM. Subsequently, we found that circZNF800 was highly expressed in GSLC exosomes and was negatively associated with GBM patients. CircZNF800 promoted GBM cell proliferation and migration and inhibited GBM cell apoptosis in vitro. Silencing circZNF800 could improve the GBM xenograft model survival rate. Mechanistic studies revealed that circZNF800 activated the PIEZO1/Akt signaling pathway by sponging miR-139-5p. CircZNF800 derived from GSLC exosomes promoted GBM cell tumorigenicity and predicted poor prognosis in GBM patients. CircZNF800 has the potential to serve as a promising target for further therapeutic exploration. [ABSTRACT FROM AUTHOR]

Objective To evaluate the impact of microRNAs (miRNAs) on lung cancer and elucidate the specific mechanism, providing theoretical basis for the development of anti-cancer biological agents. Methods Differential expression of miRNAs in lung cancer tissues and normal lung tissues was identified by sequencing. The relationship between miRNAs and lung cancer was validated using data from The Cancer Genome Atlas (TCGA) database. Cell viability, invasion, migration, and anti-apoptotic capacity were assessed using Cell Counting Kit-8 (CCK-8), transwell, and flow cytometry assays after miRNA intervention. Bioinformatics analysis of miRNA target genes and functional validation were conducted. Results Sequencing revealed decreased expression of miR-139-5 p in lung cancer tissues compared to normal lung tissues. TCGA data confirmed the role of miR-139-5 p in lung cancer, suggesting its potential as a tumor suppressor. Functional assays demonstrated that miR-139-5 p inhibited the viability, invasion, and anti-apoptotic capacity of lung cancer cells. Mechanistic studies revealed the involvement of autophagy in the development of lung cancer, and miR-139-5 p directly targeted and inhibited the autophagy gene unc-51-like kinase 1 (ULK1), thereby suppressing autophagy in lung cancer. Downregulation of ULK1 reduced the viability, invasion, and anti-apoptotic capacity of lung cancer cells, while upregulation of ULK1 had the opposite effects. Conclusion MiR-139-5 p attenuates autophagy in non-small cell lung cancer by targeting ULK1, thereby weakening the carcinogenic effects of autophagy. [ABSTRACT FROM AUTHOR]

Background: Circular RNAs (circRNAs) are an intriguing family of RNA molecules due to their crucial roles in the pathogenesis of oral squamous cell carcinoma (OSCC). Here, we sought to define the action of human circ_0004674 in OSCC progression. Methods: The functional role of circ_0004674 was validated by determining its effect on cell growth, apoptosis, and tube formation ability of OSCC cells. For protein quantification, a western blot or immunohistochemistry method was applied. The interaction between miR‐139‐5p and circ_0004674 or zinc finger and BTB domain containing 2 (ZBTB2) was predicted by online algorithms, and their relationships were confirmed by dual‐luciferase reporter and RIP assays. Xenograft models were established to uncover circ_0004674's role in tumor growth. Results: Circ_0004674 expression was upregulated in OSCC. Functionally, knocking down circ_0004674 led to suppressed OSCC cell progression in vitro and delayed tumor growth in vivo. Mechanistically, circ_0004674 post‐transcriptionally controlled ZBTB2 expression by competitively pairing to miR‐139‐5p. Furthermore, the deficiency of miR‐139‐5p abated circ_0004674 silencing‐mediated OSCC cell progression repression, and augmentation of ZBTB2 reversed the anticancer effect of miR‐139‐5p on OSCC. Conclusion: Our findings uncover a novel regulatory cascade, the circ_0004674/miR‐139‐5p/ZBTB2 axis, with the ability to affect OSCC development in vitro and in vivo, providing a potential opportunity for development of OSCC therapy. [ABSTRACT FROM AUTHOR]

Objective This study investigates how astaxanthin (AST) counters tert-butyl hydroperoxide (tBHP)-induced cellular damage in C28/I2 chondrocytes, focusing on the circ-HP1BP3/miR-139-5p/SOD1 signaling pathway and its use in sustained-release microspheres for osteoarthritis treatment.Methods We employed a variety of techniques including real-time quantitative PCR, Western blot, ELISA, and dual-luciferase reporter gene assays to explore AST's molecular effects. Additionally, the efficacy of AST-loaded sustained-release microspheres was evaluated in vitro and in a mouse model of osteoarthritis.Results AST significantly enhanced SOD1 expression, reducing apoptosis and inflammation in damaged cells. The AST-loaded microspheres showed promising in vitro drug release, improved cell viability, and reduced oxidative stress. In the osteoarthritis mouse model, they effectively decreased joint inflammation and increased the expression of chondrocyte markers.Conclusion Astaxanthin effectively mitigates oxidative stress and inflammation in chondrocytes via the circ-HP1BP3/miR-139-5p/SOD1 pathway. The development of AST-loaded microspheres offers a novel and promising approach for osteoarthritis therapy, potentially extending to osteoarthritis treatment.

In this study, we aimed to investigate the molecular mechanism of Krüppel-like factor 7 (KLF7) in colorectal cancer (CRC) cell invasion and migration. The expression pattern of KLF7 in CRC tissues and the correlation between KLF7 expression and clinical symptoms of CRC were analyzed. CRC cell lines were transfected with si-KLF7, followed by qRT-PCR or western blot detection of KLF7, miR-139-5p, and tumor protein D52 (TPD52) expression, cell counting kit-8 (CCK-8) assay to detect cell viability, and transwell detection of invasion and migration. Chromatin immunoprecipitation (ChIP) analyzed the enrichment KLF7 in the miR-139-5p promoter. The dual-luciferase reporter assay verified the binding relationship between KLF7 and miR-139-5p, and between miR-139-5p and TPD52. In the subcutaneous tumorigenesis experiment, tumor growth was observed and ki67-positive expression was detected. KLF7 is abundantly expressed in CRC cells KLF7 silencing inhibits CRC cell viability, invasion, and migration. KLF7 represses miR-139-5p expression by binding to the miR-139-5p promoter. miR-139-5p targets TPD52 expression. miR-13-5p inhibition or TPD52 overexpression partially counteracted the effect of KLF7 silencing in CRC cells. KLF7 silencing suppresses tumor growth in vivo. In conclusion, KLF7 suppresses miR-139-5p expression by binding to the miR-139-5p promoter, thereby upregulating TPD52 expression and enhancing CRC cell invasion and migration.

Deciphering the lncRNA‐associated competitive endogenous RNA (ceRNA) network is essential in decoding glioblastoma multiforme (GBM) pathogenesis by regulating miRNA availability and controlling mRNA stability. This study aimed to explore novel biomarkers for GBM by constructing a lncRNA‐miRNA‐mRNA network. A ceRNA network in GBM was constructed using lncRNA, mRNA and miRNA expression profiles from the TCGA and GEO datasets. Seed nodes were identified by protein–protein interaction (PPI) network analysis of deregulated‐mRNAs (DEmRNAs) in the ceRNA network. A lncRNA‐miRNA‐seed network was constructed by mapping the seed nodes into the preliminary ceRNA network. The impact of the seed nodes on the overall survival (OS) of patients was assessed by the GSCA database. Functional enrichment analysis of the deregulated‐lncRNAs (DElncRNA) in the ceRNA network and genes interacting with OS‐related genes in the PPI network were performed. Finally, the positive correlation between seed nodes and their associated lncRNAs and the expression level of these molecules in GBM tissue compared with normal samples was validated using the GEPIA database. Our analyzes revealed that three novel regulatory axes AL161785.1/miR‐139‐5p/MS4A6A, LINC02611/miR‐139‐5p/MS4A6A and PCED1B‐AS1/miR‐433‐3p/MS4A6A may play essential roles in GBM pathogenesis. MS4A6A is upregulated in GBM and closely associated with shorter survival time of patients. We also identified that MS4A6A expression positively correlates with genes related to tumour‐associated macrophages, which induce macrophage infiltration and immune suppression. The functional enrichment analysis demonstrated that DElncRNAs are mainly involved in neuroactive ligand–receptor interaction, calcium/MAPK signalling pathway, ribosome, GABAergic/Serotonergic/Glutamatergic synapse and immune system process. In addition, genes related to MS4A6A contribute to immune and inflammatory‐related biological processes. Our findings provide novel insights to understand the ceRNA regulation in GBM and identify novel prognostic biomarkers or therapeutic targets. [ABSTRACT FROM AUTHOR]

Objective To investigate the effects of metformin(Met) on the proliferation of pancreatic cancer cells under different glucose concentration culture conditions, and to find the potential role of miR-139-5p in the process. Methods PANC-1 cells were treated with different concentrations of metformin(0/5/10/20 mmol/L) in 25 mmol/L(high-glucose group,HG) or 5 mmol/L(normal-glucose group,NG) glucose culture, cell proliferation, apoptosis, migration and cell cycle were detected after 48 h. The expression of miR-139-5p was quantitatively detected by RT-qPCR, and the miR-139-5p mimics were transfected into PANC-1 cells to clarify the role of miR-139-5p. Results Metformin inhibited the proliferation, promoted apoptosis, and induced S phase and G2/M phase arrest of PANC-1 cells under in high glucose and normal glucose culture conditions, and its anti-proliferation and pro-apoptosis effects were more significant in the normal glucose groups. The expression of miR-139-5p was up-regulated by metformin treatment in normal but not in high glucose culture. Further studies showed that miR-139-5p mimics inhibited of PANC-1 cells proliferation without metformin pre-incubation and enhanced the anti-proliferation effect of 5 mmol/L metformin. The pro-apoptotic effect of 10 mmol/L metformin in normal glucose culture conditions. Conclusions In normal-glucose culture conditions, metformin can inhibit proliferation, induce apoptosis and cell cycle arrest of PANC-1 cells more significantly than in higher-glucose culture, which may be partly related to the up-regulation of miR-139-5p.

Summary: Background: Esophageal squamous cell carcinoma (ESCC) is the most prevalent histological subtype of esophageal cancer. miR-139-5p has been shown to have abnormal expression in ESCC. We intend to probe into the roles of miR-139-5p in ESCC, thus providing references for investigating underlying therapeutic targets. Methods: miR-139-5p expression in esophageal carcinoma was predicted by the Starbase online website. miR-139-5p expression in human ESCC cell lines (KYSE-150, KYSE-410, KSE-30) and human esophageal epithelial cell line Het1A was determined by reverse transcription quantitative polymerase chain reaction (RT-qPCR). KYSE-150 cells were manipulated with miR-139-5p mimic to upregulate miR-139-5p. Cell colony formation, viability, apoptosis, migration, and invasion were assessed by colony formation assay, CCK‑8, flow cytometry, wound healing test, and Transwell. The targeted binding between miR-139-5p and TGIF1 was predicted on Starbase, Targetscan, and miRDB online websites and verified by Dual-Luciferase assay. Cells were transfected with miR-139-5p mimic and pcDNA3.1 TGIF1. The phosphorylation levels of TGFβ pathway-related proteins Smad2 and Smad3 were assessed by RT-qPCR and western blot. Results: miR-139-5p was underexpressed in ESCC cells. miR-139-5p overexpression reduced ESCC cell viability, migration, and invasion, and promoted apoptosis. TGIF1 overexpression averted miR-139-5p mimic-inhibited ESCC cell growth. miR-139-5p overexpression decreased the phosphorylation levels of TGFβ pathway-related proteins Smad2 and Smad3, while the phosphorylation levels were increased by additional TGIF1 vector transfection. Conclusion: miR-139-5p mediates TGIF1 to regulate TGFβ pathway and inhibit ESCC cell growth. [ABSTRACT FROM AUTHOR]

In this study, we aimed to investigate the molecular mechanism of Krüppel-like factor 7 (KLF7) in colorectal cancer (CRC) cell invasion and migration. The expression pattern of KLF7 in CRC tissues and the correlation between KLF7 expression and clinical symptoms of CRC were analyzed. CRC cell lines were transfected with si-KLF7, followed by qRT-PCR or western blot detection of KLF7, miR-139-5p, and tumor protein D52 (TPD52) expression, cell counting kit-8 (CCK-8) assay to detect cell viability, and transwell detection of invasion and migration. Chromatin immunoprecipitation (ChIP) analyzed the enrichment KLF7 in the miR-139-5p promoter. The dual-luciferase reporter assay verified the binding relationship between KLF7 and miR-139-5p, and between miR-139-5p and TPD52. In the subcutaneous tumorigenesis experiment, tumor growth was observed and ki67-positive expression was detected. KLF7 is abundantly expressed in CRC cells KLF7 silencing inhibits CRC cell viability, invasion, and migration. KLF7 represses miR-139-5p expression by binding to the miR-139-5p promoter. miR-139-5p targets TPD52 expression. miR-13-5p inhibition or TPD52 overexpression partially counteracted the effect of KLF7 silencing in CRC cells. KLF7 silencing suppresses tumor growth in vivo. In conclusion, KLF7 suppresses miR-139-5p expression by binding to the miR-139-5p promoter, thereby upregulating TPD52 expression and enhancing CRC cell invasion and migration. [ABSTRACT FROM AUTHOR]

Objective To investigate the effects of metformin(Met) on the proliferation of pancreatic cancer cells under different glucose concentration culture conditions, and to find the potential role of miR-139-5p in the process. Methods PANC-1 cells were treated with different concentrations of metformin(0/5/10/20 mmol/L) in 25 mmol/L(high-glucose group,HG) or 5 mmol/L(normal-glucose group,NG) glucose culture, cell proliferation, apoptosis, migration and cell cycle were detected after 48 h. The expression of miR-139-5p was quantitatively detected by RT-qPCR, and the miR-139-5p mimics were transfected into PANC-1 cells to clarify the role of miR-139-5p. Results Metformin inhibited the proliferation, promoted apoptosis, and induced S phase and G2/M phase arrest of PANC-1 cells under in high glucose and normal glucose culture conditions, and its anti-proliferation and pro-apoptosis effects were more significant in the normal glucose groups. The expression of miR-139-5p was up-regulated by metformin treatment in normal but not in high glucose culture. Further studies showed that miR-139-5p mimics inhibited of PANC-1 cells proliferation without metformin pre-incubation and enhanced the anti-proliferation effect of 5 mmol/L metformin. The pro-apoptotic effect of 10 mmol/L metformin in normal glucose culture conditions. Conclusions In normal-glucose culture conditions, metformin can inhibit proliferation, induce apoptosis and cell cycle arrest of PANC-1 cells more significantly than in higher-glucose culture, which may be partly related to the up-regulation of miR-139-5p. [ABSTRACT FROM AUTHOR]

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Background: Hepatocellular carcinoma (HCC) continues to endanger human health worldwide. Regulatory networks of competing endogenous RNAs (ceRNAs) play important roles in HCC. TP53 is the second most often altered gene in HCC and has a significant role in regulating target genes such as miRNAs and lncRNAs. Methods: Data from patients with TP53 mutation were collected through the cBioPortal database and differential analysis was performed to screen RNAs related to TP53 mutation. The lncRNA-miRNA–mRNA relationship was predicted by the miRcode, miRDB, and TargetScan databases. The ceRNA networks were screened and visualized by Cytoscape. Core ceRNA networks were generated by differential analysis, coexpression analysis, prognostic analysis and subcellular localization. Finally, methylation, mutation, PPI, GSEA, immunity and drug sensitivity analyses of MEX3A were performed to determine the role of MEX3A in HCC. Results: We identified 1508 DEmRNAs, 85 DEmiRNAs and 931 DElncRNAs and obtained a ceRNA network including 28 lncRNAs, 4 miRNAs and 31 mRNAs. Twenty hub DERNAs in the TP53-altered-related ceRNA network were screened out by Cytoscape and the core ceRNA network (LINC00491/TCL6-hsa-miR-139-5p-MEX3A) was obtained by multiple analyses. In addition, we discovered that the methylation level of MEX3A was decreased and the mutation frequency was raised in HCC. Furthermore, elevated MEX3A expression was associated with alterations in the HCC immunological microenvironment. Conclusion: We successfully constructed a reciprocal ceRNA network, which could provide new ideas for exploring HCC mechanisms and therapeutic approaches.

Bo Gao,1,* Rui Li,2,* Xiaojia Song,3 Shan Hu,4 Fengmei Yang4 1Departments of Laboratory Medicine, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, People’s Republic of China; 2Departments of Medical office, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, People’s Republic of China; 3Shiyan Prefecture Center for Disease Control and Prevention, Shiyan, Hubei, 442000, People’s Republic of China; 4Departments of Obstetrics and Gynecology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fengmei Yang, Email 29256175@qq.comBackground: Lung squamous cell carcinoma (LUSC) is a type of lung cancer that originates from segmental or subsegmental bronchial mucosa. There is evidence that miRNA plays an important role in the occurrence and progression of tumors.Methods: In this study, plasma samples of patients with early LUSC and healthy volunteers were subjected to miRNA sequencing, and the levels of differentially expressed miRNAs (DEMs) in LUSC tissues were analyzed using R language. Cox regression and Kaplan–Meier (K-M) survival curve analyses were performed to determine the relationship between DEMs and prognosis in LUSC, and PCR method was verified for the plasma expression level of DEMs in patients with LUSC. The levels of CYFRA21-1 and SCC-Ag in plasma were measured, and area under curve (AUC) was used to evaluate the diagnostic value of the DEMs.Results: A total of 21 DEMs were screened out by sequencing. The expression levels of DEMs in tissue samples in the TCGA database were analyzed, and four DEMs with consistent expression levels were further screened from plasma and tissue samples. Regression analysis and K-M curve were performed to select two DEMs (miR-139-5p, miR-451a) that were correlated with the prognosis. PCR verification results showed that the levels of miR-451a and miR-139-5p were low in patients, and the level of miR-139-5p in late stages III & IV with the patients of LUSC was higher than that in stages I & II. The AUC values of the four indicators (SCC-Ag, CYFRA21-1, miR-451a and miR-139-5p) in the diagnosis of LUSC, early and late cases were 0.884, 0.935 and 0.778, respectively.Conclusion: The detection of miR-139-5p and miR-451a levels in plasma has a certain potential in the non-invasive diagnosis, especially in patients with early stages of LUSC.Keywords: miR-139-5p, LUSC, miR-451a, diagnosis, prognosis

Long noncoding RNAs (lncRNAs) participate in tumorigenesis and tumor progression. However, whether lncRNA AC012360.1 contributes to hepatocellular carcinoma (HCC) is unknown. In HCC tissues, differentially expressed lncRNAs were identified by bioinformatics. AC012360.1 level was validated and its role in HCC progression was investigated. Among the top 10 upregulated lncRNAs, AC012360.1 exhibited the greatest increase in HCC tissues. Additionally, AC012360.1 was upregulated in HCC tissues/cells. Moreover, AC012360.1 knockdown refrained cell proliferation/metastasis and tumor growth. Conversely, AC012360.1 overexpression showed an oncogenic role. AC012360.1 and lysophosphatidylcholine acyltransferase 1 (LPCAT1) contained miR‐139‐5p binding sites. Furthermore, miR‐139‐5p silencing partially mitigated the role of AC012360.1 knockdown, while LPCAT1 knockdown partially abolished the tumor‐promoting effect of AC012360.1 overexpression. In conclusion, AC012360.1 exhibited its oncogenic function in HCC through sponging miR‐139‐5p and upregulating LPCAT1 expression. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is a common malignancy and has extremely poor prognosis and outcome. Homo sapiens deoxyribonuclease II (DNASE2) has been reported to participate in HCC progression. Here, the role of DNASE2 in HCC cells and the putative upstream circRNA that mediates DNASE2 expression was investigated. Methods: The expression of RNAs in liver hepatocellular carcinoma (LIHC) samples was analyzed by bioinformatic analysis. The proliferation, apoptosis, migration, invasion, and gene expression in HCC cells were investigated using a Cell Counting Kit ‐8, colony formation, flow cytometry analysis, wound healing, transwell, western blotting, and a quantitative reverse transcriptase‐PCR. The binding relationship among circ_0073228, miR‐139‐5p and DNASE2 was measured by RNA pulldown and luciferase reporter assays. Results: DNASE2 knockdown inhibited proliferation and promoted apoptosis of HCC cells, whereas DNASE2 overexpression showed the opposite results. miR‐139‐5p targeted DNASE2 and suppressed its expression. Overexpression of miR‐139‐5p inhibited malignant phenotypes of HCC cells. RPS23‐derived circ_0073228, which bound to miR‐139‐5p, was found to be upregulated in HCC cells. Inhibition of miR‐139‐5p or overexpression of DNASE2 counteracted the inhibitory effects of circ_0073228 knockdown on HCC cell progression. Conclusions: circ_0073228 serves as an oncogene to facilitate growth and inhibit apoptosis of HCC cells by regulating the miR‐139‐5p/DNASE2 axis. [ABSTRACT FROM AUTHOR]

Abstract Background Circular RNAs (circRNAs) have been shown to be essential for the emergence and growth of different cancers. However, further research is required to validate the function of circRNA in glioblastoma (GBM). Methods CircNDC80 expression in both normal brain tissues (NBTs) and glioma tissues was determined using real-time PCR. The impact of circNDC80 on GBM cell proliferation, migration, and invasion was then confirmed by CCK-8, colony formation, EdU incorporation, Transwell, and wound healing assays. To determine how circNDC80 affects the capacity of glioma stem cells (GSCs) to maintain their stemness and self-renewal, a CellTiter-Glo assay, clonogenic assay and extreme limiting dilution assay were utilized. To ascertain the impact of circNDC80 in vivo, intracranial xenograft models were established. Results When compared to NBT, glioblastoma tissue had a higher level of circNDC80 expression. In functional assays, circNDC80 promoted glioblastoma cell proliferation, migration, and invasion, while sustaining the stemness and fostering the self-renewal of glioma stem cells. In addition, a dual luciferase reporter assay and circRIP were used to verify that circNDC80 simultaneously affects the expression of ECE1 mRNA by sponging miR-139-5p, and a rescue experiment was used to verify the above results further. Conclusions According to our research, circNDC80 is an oncogenic factor that promotes glioblastoma through the miR-139-5p/ECE1 pathway. This implies that circNDC80 may be employed as a novel therapeutic target and a possible predictive biomarker.

The abnormal immune response mediated by malignant melanoma is related to PD1. Paeonol has pharmacological antitumor activity. Previous studies have indicated that paeonol induces tumor cell apoptosis, but its underlying mechanism in tumor immunity remains unknown. In this study, malignant melanoma was established in normal and thymectomized mice to determine the important role of the thymus in the antitumor effects of paeonol. Paeonol-treated thymocytes were cocultured with melanoma cell spheres to further evaluate the regulatory role of thymocytes in tumor immune dysfunction. Studies have shown that PD1 may be targeted by miR-139–5p. Our results revealed that tumor-induced thymic atrophy was significantly accompanied by high PD1 expression and low miR-139–5p expression. Interestingly, paeonol significantly reversed thymic atrophy and largely protected thymocytes against low PD1 expression and high miR-139–5p expression. Dual-luciferase assays indicated that miR-139–5p interacted with the 3′ untranslated region (3′-UTR) of PD1. These results showed that paeonol alleviates PD1-mediated antitumor immunity by reducing miR-139–5p expression and demonstrated a novel mechanism for melanoma immunotherapy. • We have demonstrated through both in vivo and in vitro experiments that paeonol can suppress the progression of melanoma by decreasing the expression of PD1, which is mediated by miR-139–5p in thymocytes. This is a novel pharmacological effect of paeonol in tumor immune regulation, and it provides a new avenue for further exploration of tumor immune regulation therapies and drug development. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to experimentally validate dysregulated expression of miRNA candidates selected through updated meta‐analysis of most commonly deregulated miRNAs in oral cancer and to explore their diagnostic and prognostic potential. Materials and methods: Five miRNAs (miR‐31‐3p, miR‐135b‐5p, miR‐18a‐5p, miR‐30a‐5p and miR‐139‐5p) from updated meta‐signature were selected for validation by qRT‐PCR method in 35 oral cancer clinical specimens and adjacent non‐cancerous tissue. Results: Updated meta‐analysis has identified 13 most commonly deregulated miRNAs in oral cancer. Seven miRNAs were consistently up‐regulated (miR‐21‐5p, miR‐31‐3p, miR‐135b‐5p, miR‐31‐5p, miR‐424‐5p, miR‐18a‐5p and miR‐21‐3p), while five were down‐regulated (miR‐139‐5p, miR‐30a‐3p, miR‐375‐3p, miR‐376c‐3p and miR‐30a‐5p). Increased expression of miR‐31‐3p and miR‐135b‐5p, and decreased expression of miR‐139‐5p and miR‐30a‐5p were confirmed in oral cancer compared to adjacent non‐cancerous tissue. A three miRNAs combination (miR‐31‐3p, miR‐139‐5p and miR‐30a‐5p) gave the most promising diagnostic potential for discriminating oral cancer from non‐cancerous tissue (AUC: 0.780 [95% CI: 0.673–0.886], p < 0.0005, sensitivity 94.3%, specificity 51.4%). High expression of miR‐135b‐5p, miR‐18a‐5p and miR‐30a‐5p was associated with poor survival (p = 0.003, p = 0.048, p = 0.016 respectively). Conclusion: miR‐31‐3p, miR‐139‐5p and miR‐30a‐5p panel was confirmed as a potential diagnostic biomarker when distinguishing oral cancer from non‐cancerous tissue. miR‐135b‐5p, miR‐18a‐5p and miR‐30a‐5p might serve as potential biomarkers of poor survival of oral cancer patients. [ABSTRACT FROM AUTHOR]

Background Asthma is a chronic respiratory disease characterised by the contraction of smooth muscle and remodelling of the airway wall, which is correlated with increased airway smooth muscle mass. Circular RNA (circRNA) circ_0002594 has been reported as a pro-inflammatory factor in allergic asthma. Therefore, this study is designed to explore the role and mechanism of circ_0002594 in human airway smooth muscle cells (HASMC) proliferation and metastasis. Methods Cell proliferative ability, invasion, and migration were detected by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT), 5-ethynyl-2’-deoxyuridine (EdU), Transwell, and Wound healing assays. The protein levels of E-cadherin, N-cadherin, and tripartite motif 8 (TRIM8) were detected by western blot assay. The levels of interleukin-6 (IL-6) and IL-13 were detected using Enzyme-linked immunosorbent assays (ELISA). Levels of circ_0002594, microRNA-139-5p (miR-139-5p), TRIM8 were determined by real-time quantitative polymerase chain reaction (RT-qPCR). The binding between miR-139-5p and circ_0002594 or TRIM8 was predicted by Circinteractome or Starbase v2.0, and then verified by a dual-luciferase reporter and RNA Immunoprecipitation (RIP) assays. Results Platelet-derived growth factor-BB (PDGF-BB) could trigger HASMC proliferation, metastasis, and inflammation. Circ_0002594 and TRIM8 were elevated in asthma patients and PDGF-BB-treated HASMC, and the miR-139-5p level was decreased. Furthermore, circ_0002594 knockdown could suppress PDGF-BB- stimulated HASMC damage. Mechanism analysis exhibited that circ_0002594 could regulate TRIM8 expression through sponging miR-139-5p. Conclusion Our findings revealed that circ_0002594 could act as a regulator in the airway remodelling during asthma development partly by the miR-139-5p/TRIM8 axis, hinting at an underlying therapeutic strategy for asthma.

Background: Circular RNAs (circRNAs) are often dysregulated in cancers and closely related to cancer progression, including cutaneous squamous cell carcinoma (CSCC). However, the role and mechanism of circ_0068631 in CSCC progression have not been reported. Methods: The expression of circ_0068631, microRNA‐139‐5p (miR‐139‐5p), and homeobox B7 (HOXB7) was measured by real‐time quantitative polymerase chain reaction (RT‐qPCR). Cell counting kit‐8 (CCK‐8) assay, 5‐ethynyl‐2′‐deoxyuridine (EdU) assay, and colony formation assay were used to measure cell proliferation. Cell apoptosis was assessed by flow cytometry. Cell migration was detected by transwell assay. The interaction between miR‐139‐5p and circ_0068631 or HOXB7 was confirmed by dual‐luciferase reporter assay. A xenograft tumor model was established to confirm the function of circ_0068631 in vivo. Results: Circ_0068631 was upregulated in CSCC tissues and cells, and its silencing could inhibit CSCC cell proliferation and metastasis while promoting apoptosis in vitro, as well as restrain CSCC tumor growth in vivo. Circ_0068631 acted as a sponge of miR‐139‐5p, and miR‐139‐5p inhibition reversed the repressive effect of circ_0068631 knockdown on CSCC cell progression. Furthermore, HOXB7 was a target of miR‐139‐5p, and miR‐139‐5p inhibited the malignant behaviors by downregulating HOXB7 expression in CSCC cells. Further, circ_0068631 sponged miR‐139‐5p to regulate HOXB7 expression. Conclusion: Circ_0068631 functioned as a novel oncogene in CSCC progression by regulating miR‐139‐5p/HOXB7 axis, suggesting that circ_0068631 may be a potential target for CSCC treatment. Highlights: Circ_0068631 was overexpressed in CSCC tissues and cells.Circ_0068631 downregulation suppressed CSCC progression via miR‐139‐5p.Circ_0068631 regulated HOXB7 via sponging miR‐139‐5p. [ABSTRACT FROM AUTHOR]

Background: Circular RNAs (circRNAs) have been shown to be essential for the emergence and growth of different cancers. However, further research is required to validate the function of circRNA in glioblastoma (GBM). Methods: CircNDC80 expression in both normal brain tissues (NBTs) and glioma tissues was determined using real-time PCR. The impact of circNDC80 on GBM cell proliferation, migration, and invasion was then confirmed by CCK-8, colony formation, EdU incorporation, Transwell, and wound healing assays. To determine how circNDC80 affects the capacity of glioma stem cells (GSCs) to maintain their stemness and self-renewal, a CellTiter-Glo assay, clonogenic assay and extreme limiting dilution assay were utilized. To ascertain the impact of circNDC80 in vivo, intracranial xenograft models were established. Results: When compared to NBT, glioblastoma tissue had a higher level of circNDC80 expression. In functional assays, circNDC80 promoted glioblastoma cell proliferation, migration, and invasion, while sustaining the stemness and fostering the self-renewal of glioma stem cells. In addition, a dual luciferase reporter assay and circRIP were used to verify that circNDC80 simultaneously affects the expression of ECE1 mRNA by sponging miR-139-5p, and a rescue experiment was used to verify the above results further. Conclusions: According to our research, circNDC80 is an oncogenic factor that promotes glioblastoma through the miR-139-5p/ECE1 pathway. This implies that circNDC80 may be employed as a novel therapeutic target and a possible predictive biomarker. [ABSTRACT FROM AUTHOR]

Circular RNA (circRNA) has been identified as an important regulator for glaucoma progression. Our study aims to reveal the circ_0080940 roles in glaucoma progression. Transforming growth factor β1 (TGF-β1) was used to treat human Tenon's capsule fibroblasts (HTFs) to mimic glaucoma cell models. Cell function was determined by cell counting kit 8 assay, EdU assay and wound healing assay. Protein levels were determined by western blot analysis. Quantitative real-time PCR was used to measure RNA expression. Dual-luciferase reporter assay was performed to evaluate RNA interaction. Our data confirmed that TGF-β1 induced HTFs proliferation, migration and extracellular matrix (ECM) deposition. Circ_0080940 was highly expressed in glaucoma patients, and its knockdown inhibited TGF-β1-induced proliferation, migration and ECM deposition in HTFs. Circ_0080940 sponged miR-139-5p, and anti-miR-139-5p revoked the effect of si-circ_0080940 on the biological functions of TGF-β1-induced HTFs. CTGF was targeted by miR-139-5p, and overexpressed CTGF overturned the inhibition effect of miR-139-5p on the biological functions of TGF-β1-induced HTFs. Furthermore, CTGF expression could be positively regulated by circ_0080940. To sum up, we confirmed that circ_0080940 contributed to glaucoma progression by miR-139-5p/CTGF axis. [ABSTRACT FROM AUTHOR]

Objective：To investigate the effect of human circular RNA_0114428 (circ_0114428) on the lipopolysaccharide (LPS)-induced injury of human renal tubular epithelial HK-2 cells, and to clarify the possible molecular mechanism of circ_0114428 in improving the injury of HK-2 cells by regulating microRNA-139-5p ( miR-139-5p)/transforming growth factor β receptor 2 ( TGFBR2) axis. Methods：The HK-2 cells were cultured in vitro, the dual luciferase reporter gene experiment was used to verify the targeted regulation relationship between miR-139-5p and circ_0114428 or TGFBR2, and the CCK-8 method was used to screen the appropriate LPS intervention time and concentration. The HK-2 cell injury model was established by administering 10 mg·L－1 LPS for 12 h, and the HK-2 cells were divided into control group, LPS group, LPS+circ_0114428 silence control (LPS+si-NC) group, LPS+circ_ 0114428 silence (LPS+si-circ_0114428) group, LPS+circ_0114428 silence+miR-139-5p inhibitor control (LPS+si-circ_0114428+in-NC) group, and LPS+circ_0114428 silence+miR-139-5p inhibitor (LPS+si-circ_0114428+in-miR-139-5p) group. Real-time fluorescence quantitative PCR (RT-qPCR) method was used to detect the expression levels of circ_0114428, miR-139-5p and TGFBR2 mRNA in the cells in various groups, flow cytometry was used to detect the apoptotic rates of the cells in various groups, and Western blotting method was used to detect the expression levels of TGFBR2, B-cell lymphoma-2 (Bcl-2) and Bcl-2 associated X protein (Bax) proteins in the cells in various groups；enzyme linked immunosorbent assay(ELISA) was used to detect the levels of interleukin-6(IL-6), tumor necrosis factor-α (TNF-α) and interleukin-1β( IL-1β) in the cell supernatant in various groups. Results：The results of dual luciferase reporter gene experiment showed that miR-139-5p had a targeted regulatory relationship with circ_0114428 and TGFBR2 (t=10. 171, P<0. 05；t=7. 682, P<0. 05). The CCK-8 method results showed that the concentration of LPS induction was 10 mg·L－1 and the optimal time was 12 h. Compared with control group, the expression levels of circ_0114428, expression levels of TGFBR2 mRNA and protein, and expression level of Bax protein, the apoptotic rate, and levels of IL-6, TNF- α and IL-1β in cell supernatant of the HK-2 cells in LPS group were significantly increased (P<0. 05)，and the expression levels of miR-139-5p and Bcl-2 protein were significantly decreased ( P<0. 05). Compared with LPS+ si-NC group, the expression levels of circ_0114428, expression levels of TGFBR2 mRNA and protein, and expression level of Bax protein, the apoptotic rate, and the levels of IL-6, TNF- α and IL-1β in cell supernatant of the HK-2 cells in LPS+si-circ_0114428 group were significantly decreased (P<0. 05)，and the expression levels of miR-139-5p and Bcl-2 protein were significantly increased (P<0. 05). Compared with LPS+si-circ_0114428+in-NC group, the expression levels of circ_0114428, expression levels of TGFBR2 mRNA and protein, and expression level of Bax protein, the apoptotic rate, and the levels of IL-6, TNF- α and IL-1β in cell supernatant of the HK-2 cells in LPS+si-circ_0114428+in-miR-139-5p group were significantly increased (P<0. 05), and the expression levels of miR-139-5p and Bcl-2 protein were significantly decreased (P<0. 05). Conclusion：Circ_0114428 can alleviate the LPS-induced HK-2 cell injury, and its mechanism may be related to the regulation of the miR-139-5p/TGFBR2 axis. [ABSTRACT FROM AUTHOR]

Abstract Background Circular RNAs (circRNAs) are regarded as vital regulatory factors in various cancers. However, the biological functions of circDNER in the paclitaxel (PTX) resistance of lung cancer remain largely unexplored. Methods Quantitative reverse transcription polymerase chain reaction (qRT‐PCR) was used to analyze circDNER, miR‐139‐5p, and ITGB8. Cell proliferation was assessed via colony formation and MTT assays. Cell apoptosis was evaluated by flow cytometry. Western blot was performed to assess protein expression. The targeted interaction among circDNER, miR‐139‐5p, and ITGB8 were validated using dual‐luciferase reporter or RNA immunoprecipitation assays. Results Inhibition of circDNER reduced IC50 of PTX, inhibited cell proliferation, invasion and migration, as well as promoted cell apoptosis in PTX‐resistant lung cancer cells. Mechanistically, circDNER sponged miR‐139‐5p to upregulate ITGB8 expression. Overexpression of miR‐139‐5p reversed the biological functions mediated by circDNER in PTX‐resistant lung cancer cells. MiR‐139‐5p overexpression suppressed PTX resistance and malignant behaviors of PTX‐resistant lung cancer cells, with ITGB8 elevation rescued the impacts. Moreover, we demonstrated that circDNER was upregulated in plasma exosomes from lung cancer patients. The plasma exosomes derived from these patients are the key factors enhancing the migration and invasion potential of lung cancer cells. Conclusion The circDNER mediated miR‐139‐5p/ITGB8 axis suppresses lung cancer progression. Our findings suggest that circDNER might act as a potential prognostic biomarker and therapeutic target for lung cancer treatment.

This study aimed to elucidate how DHA enhances the radiosensitivity of BC and to explain its potential mechanisms of action. The circular structure of hsa_circ_0001610 was confirmed by Sanger sequencing, RNase R treatment, RT-PCR analysis using gDNA or cDNA. Cellular localization of hsa_circ_0001610 and microRNA-139–5p (miR-139–5p) was detected by fluorescence in situ hybridization. Cell counting kit-8 assay, wound healing and colony formation tests for assessing cell proliferation, while flow cytometry was utilized to estimate cell cycle progression and apoptosis. Reactive oxygen species and malondialdehyde experiments were conducted to validate ferroptosis of BC cells. The expression of ncRNAs and mRNAs was quantified via qRT-PCR, and protein expression was analyzed using Western blot. The effects of hsa_circ_0001610 and DHA on radiosensitivity of BC in vivo were studied by establishing BC mice model. In vivo and in vitro experimental results indicate that DHA promotes ferroptosis of BC cells at least partly by inhibiting hsa_circ_0001610/miR-139–5p/SLC7A11 pathway, thereby enhancing the radiosensitivity of BC cells. Our findings showed that DHA can induce ferroptosis of BC cells by down-regulation of hsa_circ_0001610, thus enhancing radiosensitivity, suggesting a promising therapeutic strategy for enhancing BC radiosensitivity that is worthy of further exploration. Schematic illustration of DHA-induced ferroptosis via hsa_circ_0001610/miR-139–5p/SLC7A11 axis in BC cells. DHA activated the ferroptosis pathway via hsa_circ_0001610 inhibition and subsequently enhanced the radiosensitivity of BC cells. [Display omitted] • Dihydroartemisinin induces ferroptosis in breast cancer cells. • Upregulation of hsa_circ_0001610 in breast cancer cells post-irradiation. • Dihydroartemisinin inhibits the hsa_circ_0001610/miR-139–5p/SLC7A11 axis. • Dihydroartemisinin enhances radiosensitivity in breast cancer. [ABSTRACT FROM AUTHOR]

This study aims to investigate the specific mechanism of miR-139-5p regulating hepatocellular carcinoma (HCC). Bioinformatic approaches was utilized to observe miR-139-5p level in HCC and unearth its target mRNA. Next, miR-139-5p and enabled homolog (ENAH) levels in HCC cell lines and normal liver cell line were evaluated with qRT-PCR. ENAH protein level was assessed by Western blot. The cell viability, migratory and invasive capacities of HepG2 cells was observed by cell functional assays. The binding of these two genes was proved through dual-luciferase method. Xenograft nude mouse model was prepared to identify the role of miR-139-5p in vivo. Poorly expressed miR-139-5p in HCC hindered the phenotypes of cancer cells. ENAH was at high level in HCC and it is a downstream target of miR-139-5p. Additionally, ENAH could reverse the suppressive impacts of miR-139-5p on HCC cell behaviors. Likewise, miR-139-5p was determined to perform tumor-suppressing function in vivo. MiR-139-5p hampered HCC cell processes by mediating ENAH, and miR-139-5p/ENAH is hopefully to be the possible target for HCC patients. [ABSTRACT FROM AUTHOR]

Background: One of the important reasons for the development of preeclampsia (PE) is the abnormal function of trophoblast cells. Many circular RNAs (circRNAs) have been confirmed to participate in the regulation of trophoblast cell function to mediate PE progression. However, whether circ_0077109 is involved in PE progression through regulating trophoblast cell function remains unclear. Methods: Quantitative real‐time PCR was utilized for measuring the expression of circ_0077109, microRNA (miR)‐139‐5p and homeobox D10 (HOXD10). Trophoblast cell proliferation, apoptosis, invasion, and angiogenesis was assessed cell counting kit 8 assay, EdU assay, flow cytometry, transwell assay and tube formation assay. In addition, western blot analysis was used to determine protein expression. The interaction between miR‐139‐5p and circ_0077109 or HOXD10 was verified by dual‐luciferase reporter assay and RIP assay. Results: Our results pointed out that circ_0077109 was a circRNA with upregulated expression in PE patients. Overexpression of circ_0077109 suppressed trophoblast cell proliferation, invasion, and angiogenesis, while increased apoptosis. MiR‐139‐5p was found to be sponged by circ_0077109, and its mimic reversed the suppressive effect of circ_0077109 on trophoblast cell function. HOXD10 was a target of miR‐139‐5p, and its overexpression inhibited trophoblast cell proliferation, invasion, and angiogenesis. MiR‐139‐5p inhibitor could repress trophoblast cell function, while this effect could be reversed by HOXD10 knockdown. Conclusion: In summary, we confirmed that circ_0077109 inhibited trophoblast cell function through the regulation of miR‐139‐5p/HOXD10 axis, which might be a potential target for PE treatment. [ABSTRACT FROM AUTHOR]

Asthma is a chronic respiratory disease characterised by the contraction of smooth muscle and remodelling of the airway wall, which is correlated with increased airway smooth muscle mass. Circular RNA (circRNA) circ_0002594 has been reported as a pro-inflammatory factor in allergic asthma. Therefore, this study is designed to explore the role and mechanism of circ_0002594 in human airway smooth muscle cells (HASMC) proliferation and metastasis. Cell proliferative ability, invasion, and migration were detected by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU), Transwell, and Wound healing assays. The protein levels of E-cadherin, N-cadherin, and tripartite motif 8 (TRIM8) were detected by western blot assay. The levels of interleukin-6 (IL-6) and IL-13 were detected using Enzyme-linked immunosorbent assays (ELISA). Levels of circ_0002594, microRNA-139-5p (miR-139-5p), TRIM8 were determined by real-time quantitative polymerase chain reaction (RT-qPCR). The binding between miR-139-5p and circ_0002594 or TRIM8 was predicted by Circinteractome or Starbase v2.0, and then verified by a dual-luciferase reporter and RNA Immunoprecipitation (RIP) assays. Platelet-derived growth factor-BB (PDGF-BB) could trigger HASMC proliferation, metastasis, and inflammation. Circ_0002594 and TRIM8 were elevated in asthma patients and PDGF-BB-treated HASMC, and the miR-139-5p level was decreased. Furthermore, circ_0002594 knockdown could suppress PDGF-BB- stimulated HASMC damage. Mechanism analysis exhibited that circ_0002594 could regulate TRIM8 expression through sponging miR-139-5p. Our findings revealed that circ_0002594 could act as a regulator in the airway remodelling during asthma development partly by the miR-139-5p/TRIM8 axis, hinting at an underlying therapeutic strategy for asthma. [ABSTRACT FROM AUTHOR]

Lung adenocarcinoma (LUAD) is the most frequent histological subtype of non-small cell lung cancer. Cyclin B1 (CCNB1) is the vital initiator and controller of mitosis. Studies have indicated that CCNB1 overexpression is closely associated with cell proliferation and tumorigenesis in many cancers. Thus, discovery of molecular mechanism of CCNB1 in LUAD is conducive to developing new diagnostic or therapeutic targets for LUAD. We acquired mature miRNA and mRNA expression information of LUAD from TCGA database, as well as related clinical data. CCNB1 expression in normal and LUAD tissue was analyzed. Relationship between CCNB1 and patient's survival and clinical stage was analyzed. Upstream regulatory gene miRNA of CCNB1 was predicted. qRT-PCR and western blot examined expression levels of CCNB1 and miR-139-5p in cells. CCK-8 tested cell proliferation. Scratch healing and Transwell determined cell migration and invasion. Flow cytometry analyzed the cell cycle. Dual-luciferase verified targeting relationship between the two genes. Compared to controls, CCNB1 expression was prominently high in LUAD patient samples, and associated with advanced tumor stages and shorter overall survival. MiR-139-5p expressed an evidently negative correlation with CCNB1 and was predicted to target CCNB1. MiR-139-5p mimics reduced CCNB1 mRNA and protein expression, and suppressed luciferase activity in a target-specific manner, as confirmed by a control construct with a mutated miR-139-5p binding site. CCNB1 overexpression fostered progression of LUAD cells. Mechanistically, miR-139-5p might negatively regulate CCNB1 in LUAD, thereby suppressing cell proliferation, migration, invasion and cell cycle. [ABSTRACT FROM AUTHOR]

Osteosarcoma is one of the commonest metastatic tumor in children and teenagers, and has a hopeless, prognosis. Long non-coding RNA (lncRNA) acts momentous roles as a regulator on the proliferation and migration of cancer. Here, we performed GEO database analysis and qPCR to identify differentially expressed lncRNAs in osteosarcoma cells. Knockdown of lncRNA LINC01140 was used to detect the effect of LINC01140 on the proliferation, invasion, and epithelial-mesenchymal transition (EMT) of osteosarcoma cells. Bioinformatics analysis and qPCR identified the LINC01140/miR-139-5p/Homeobox A9 (HOXA9) regulatory axis. RNA immunoprecipitation assay, Dual-luciferase assay, and rescue experiments confirmed the interaction of LINC01140/miR-139-5p/HOXA9 in osteosarcoma. LINC01140 was overexpressed in osteosarcoma and knocking down LINC01140 restrained the proliferation and invasion of osteosarcoma cells and EMT. In Saos2 and MG63 cells, LINC01140 sponged miR-139-5p, and a miR-139-5p inhibitor overturned the suppression of LINC01140 knockdown on the proliferation and migration of osteosarcoma cells. Moreover, miR-139-5p depressed the invasion, proliferation, and EMT of osteosarcoma cells via targeting HOXA9. Our results indicate that LINC01140 downregulation inhibits the invasion, proliferation, and EMT in osteosarcoma cells through targeting the miR-139-5p/HOXA9 axis. Therefore, LINC01140 is a potential therapeutic target for osteosarcoma.

Yubo Yan, Xiangyuan Jin, HaoBo Sun, Sainan Pang, Xianglong Kong, Jianlong Bu, Shidong Xu Department of Thoracic Surgery, Harbin Medical University Tumer Hospital, Harbin, Heilongjiang Province, 150000, People’s Republic of ChinaCorrespondence: Shidong XuDepartment of Thoracic Surgery, Harbin Medical University Tumer Hospital, No. 150, Haping Road, Nangang District, Harbin, Heilongjiang Province, 150000, People’s Republic of ChinaTel +86-13903611962Email shidongxushi@sina.comObjective: To explore relevant mechanisms of miR-139-5p in alleviating the metastasis of non-small cell lung cancer cells (NSCLC) and their resistance against cisplatin.Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot (WB) assays were carried out to determine the protein levels of miR-139-5p and YAF2, and cisplatin (DDP)-resistant NSCLC cell strains were established. Subsequently, an MTT assay was employed to evaluate the viability of the cell strains, a Transwell assay to evaluate cell invasion activity, and flow cytometry to analyze cell apoptosis rate. Finally, a Western blot assay was carried out to determine the protein levels of P-PI3K and p-p38.Results: NSCLC tissues showed lower miR-139-5p expression and higher YAF2 expression than paracancerous tissues and human normal lung epithelial cells, and miR-139-5p was related to the prognosis of NSCLC patients. Overexpression of miR-139-5p or knock-down of YAF2 inhibited the proliferation and invasion of NSCLC cells and induced their apoptosis. Additionally, the dual-luciferase reporter assay verified a targeting relationship between miR-139-5p and YAF2. Overexpression of miR-139-5p and knockdown of YAF2 reversed the resistance of A549/DDP cells against DDP, inactivated p38 and Akt proteins, and inhibited the AKT/p38 MAPK signaling pathway. Furthermore, inhibiting the AKT/p38 MAPK signaling pathway with MK2206 resisted the effects of knock-down of miR-139-5p on DDP resistance in NSCLC cells.Conclusion: MiR-139-5p targetedly regulates YAF2 and mediates the AKT/p38 MAPK signaling pathway to alleviate the metastasis of NSCLC cells and their resistance against cisplatin, which may be a novel target for improving the therapeutic effect on NSCLC.Keywords: miR-139-5p, YAF2, AKT/p38 MAPK, non-small cell lung cancer, cisplatin

Abstract Glioma is an extremely aggressive malignant neoplasm of the central nervous system. MicroRNA (miRNA) are known to bind to specific target mRNA to regulate post-transcriptional gene expression and are, therefore, currently regarded as promising biomarkers for glioma diagnosis and prognosis. The aim of the present study was to examine the pathogenesis and potential molecular markers of glioma by comparing the differential expression of miRNA and mRNA between glioma tissue and peritumor brain tissue. We explored the impact of screened core miRNA and mRNA on cell proliferation, invasion, and migration of glioma. An miRNA expression profile dataset (GSE90603) and a transcriptome profile dataset (GSE90598) were downloaded from combined miRNA-mRNA microarray chips in the Gene Expression Omnibus (GEO) database. Overall, 59 differentially expressed miRNAs (DEMs) and 419 differentially expressed genes (DEGs) were identified using the R limma software package. FunRich software was used to predict DEM target genes and miRNA-gene pairs, and Perl software was used to find overlapping genes between DEGs and DEM target genes. There were 129 overlapping genes regulated by nine miRNAs between target genes of the DEMs and DEGs. The Chinese Glioma Genome Atlas(CGGA) was analyzed in order to identify miRNAs with diagnostic and prognostic significance. MiR-139-5p, miR-137, and miR-338-3p were validated to be significantly linked to prognosis in glioma patients. Finally, we validated that miR-139-5p affected glioma malignant biological behavior via targeting gamma-aminobutyric acid A receptor alpha 1(GABRA1) through rescue experiments. Low miR-139-5p expression was correlated with survival probability and World Health Organization (WHO) grade. MiR-139-5p overexpression inhibited cell proliferation, migration, and invasion of glioma in vitro. GABRA1 was identified as a functional downstream target of miR-139-5p. Decreased GABRA1 expression was related to similar biological roles as miR-139-5p overexpression while upregulation of GABRA1 effectively reversed the inhibition effects of miR-139-5p. These results demonstrate a novel axis for miR-139-5p/GABRA1 in glioma progression and provide potential prognostic predictors and therapeutic target for glioma patients.

Background: Circular RNAs (circRNAs) are regarded as vital regulatory factors in various cancers. However, the biological functions of circDNER in the paclitaxel (PTX) resistance of lung cancer remain largely unexplored. Methods: Quantitative reverse transcription polymerase chain reaction (qRT‐PCR) was used to analyze circDNER, miR‐139‐5p, and ITGB8. Cell proliferation was assessed via colony formation and MTT assays. Cell apoptosis was evaluated by flow cytometry. Western blot was performed to assess protein expression. The targeted interaction among circDNER, miR‐139‐5p, and ITGB8 were validated using dual‐luciferase reporter or RNA immunoprecipitation assays. Results: Inhibition of circDNER reduced IC50 of PTX, inhibited cell proliferation, invasion and migration, as well as promoted cell apoptosis in PTX‐resistant lung cancer cells. Mechanistically, circDNER sponged miR‐139‐5p to upregulate ITGB8 expression. Overexpression of miR‐139‐5p reversed the biological functions mediated by circDNER in PTX‐resistant lung cancer cells. MiR‐139‐5p overexpression suppressed PTX resistance and malignant behaviors of PTX‐resistant lung cancer cells, with ITGB8 elevation rescued the impacts. Moreover, we demonstrated that circDNER was upregulated in plasma exosomes from lung cancer patients. The plasma exosomes derived from these patients are the key factors enhancing the migration and invasion potential of lung cancer cells. Conclusion: The circDNER mediated miR‐139‐5p/ITGB8 axis suppresses lung cancer progression. Our findings suggest that circDNER might act as a potential prognostic biomarker and therapeutic target for lung cancer treatment. [ABSTRACT FROM AUTHOR]

Introduction: Circular RNAs (circRNAs) are important regulators in various cancers, especially hepatocellular carcinoma. However, the role of circ RNA PTPRM (circPTPRM) in the development of non-small-cell lung cancer (NSCLC) remains unclear. Methods: We collected 26 clinical specimens (corresponding to 26 normal lung tissues) of lung adenocarcinoma and the expression of mir-139-5p and circPTPRM were first detected. Cell proliferation was detected by EdU method, invasion/migration ability of cells was evaluated by transwell method. And the correlation between circPTPRM and mir-139-5p was detected by luciferase reporter gene and RNA pull-down assay. Finally, we verified our hypothesis with BALB/c nude mice. Results: Through bioinformatics software, we found that circPTPRM was negatively correlated with mir-139-5p, and then we used human adenocarcinoma tissue samples to further verify their relationship and get the same result. EdU method, transwell method, and luciferase assay, RNA pull-down assay were applied, and the results show that the knockdown of circPTPRM inhibit proliferation, migration, and invasion of cells can be reversed by mir-139-5p inhibitor. Next, we used Starbase v2.0 to identify the target site of miR-139-5p and focused on SET domain containing 5 (SETD5). We derive the hypothesis by verifying the relationship between miR-139-5p and SETD5 that circPTPRM may interact with miR-139-5p/SETD5 axis. At last, we evaluated the effects of circPTPRM, SETD5, and miR-139-5p on tumor growth in vivo using BALB/c nude mice to prove the hypothesis. Conclusion: We thus conclude that circPTPRM promotes the progression of NSCLC by regulating the miR-139-5p/SETD5 axis. [ABSTRACT FROM AUTHOR]

Simple Summary: For hepatocellular carcinoma (HCC), the second most common cause of cancer-related death, effective therapeutic approaches are lacking. As aberrant gene methylation is a major contributor to the development of HCC, demethylating drugs such as 5-azacytidine (5-Aza) have been proposed. However, despite the potential efficacy of 5-Aza in HCC, most of its mechanisms of action are still unknown. Here, we investigate the phenotypic/molecular effects of 5-Aza with a focus on miR-139-5p. Using multiple in vitro and in vivo models of HCC, we show for the first time that 5-Aza can impair HCC development via upregulation of miR-139-5p, which in turn downregulates the ROCK2/cyclin D1/E2F1/cyclin B1 pro-proliferative pathway and the ROCK2/MMP-2 pro-migratory pathway. These observations elucidate the mechanisms of action of 5-Aza in HCC, strengthen its therapeutic potential, and provide novel information about the crosstalk among ROCK2/cyclin D1/E2F1/cyclin B1/MMP-2 in HCC. Background: For hepatocellular carcinoma (HCC), effective therapeutic approaches are lacking. As aberrant gene methylation is a major contributor to HCC development, demethylating drugs such as 5-azacytidine (5-Aza) have been proposed. As most 5-Aza mechanisms of action are unknown, we investigated its phenotypic/molecular effects. Methods: 5-Aza effects were examined in the human HCC cell lines JHH-6/HuH-7 and in the rat cell-line N1-S1. We also employed a xenograft mouse model (HuH-7), a zebrafish model (JHH-6), and an orthotopic syngeneic rat model (N1-S1) of HCC. Results: 5-Aza downregulated cell viability/growth/migration/adhesion by upregulating miR-139-5p, which in turn downregulated ROCK2/cyclin D1/E2F1 and increased p27kip1, resulting in G1/G0 cell accumulation. Moreover, a decrease in cyclin B1 and an increase in p27kip1 led to G2/M accumulation. Finally, we observed a decrease in MMP-2 levels, a stimulator of HCC cell migration. Aza effects were confirmed in the mouse model; in the zebrafish model, we also demonstrated the downregulation of tumor neo-angiogenesis, and in the orthotopic rat model, we observed impaired N1-S1 grafting in a healthy liver. Conclusion: We demonstrate for the first time that 5-Aza can impair HCC development via upregulation of miR-139-5p, which in turn impairs the ROCK2/cyclin D1/E2F1/cyclin B1 pro-proliferative pathway and the ROCK2/MMP-2 pro-migratory pathway. Thus, we provide novel information about 5-Aza mechanisms of action and deepen the knowledge about the crosstalk among ROCK2/cyclin D1/E2F1/cyclin B1/p27kip1/MMP-2 in HCC. [ABSTRACT FROM AUTHOR]

Circular RNA (circRNA) have been found to play an important role in the progression of many diseases, including interstitial cystitis (IC). However, the role of circTHBS1 in IC progression is still unclear. Exploring the role and potential molecular mechanism of circTHBS1 in the development of IC. The enzyme‐linked immunosorbent assay was used to assess the levels of inflammatory cytokines. The expression levels of circTHBS1, microRNA (miR)‐139‐5p, and mitofusin 2 (MFN2) were evaluated using quantitative real‐time PCR. Cell proliferation and migration were determined using MTT assay, Edu staining, and transwell assay. The protein levels of epithelial‐mesenchymal transition (EMT) markers and MFN2 were examined using western blot analysis. The relationship between miR‐139‐5p and circTHBS1 or MFN2 was confirmed using the dual‐luciferase reporter assay and RIP assay. CircTHBS1 was highly repressed in IC tissues and cells, and its expression was positively correlated with the inflammatory response of IC patients. CircTHBS1 could promote the proliferation, migration, EMT process, and inflammation of IC cells, while its knockdown had an opposite effect. CircTHBS1 could serve as a sponge of miR‐139‐5p, and miR‐139‐5p could participate in the regulation of circTHBS1 on IC cell progression. In addition, miR‐139‐5p could target MFN2, and it could inhibit the progression of IC cells by targeting MFN2. Furthermore, circTHBS1 sponged miR‐139‐5p to positively regulate MFN2. CircTHBS1 promoted IC cell proliferation, migration, EMT process, and inflammation by regulating the miR‐139‐5p/MFN2 axis indicating that circTHBS1 might be a potential target for IC treatment. [ABSTRACT FROM AUTHOR]

Objective: This study aims to explore the mechanism of puerarin regulating the proliferation, apoptosis and senescence of T24 and EJ cells via miR-139-5p/CCNB1 and PI3K/AKT pathways. Methods: Initially, Cell Counting Kit (CCK)-8, flow cytometry, β-galactosidase detection kit, and RT-qPCR are used to assess the effect of puerarin on the proliferation apoptosis and senescence of bladder cancer cells by regulating miR-139-5p, respectively. Then, potential complementary binding sites between miR-139-5p and the 3′ untranslated region (3′ UTR) of the CCNB1 gene are obtained by the bioinformatics software, starBase database. Further, a dual-luciferase reporter system is used to assess the targeted relationship of miR-139-5p to CCNB1. CCK-8, flow cytometry, and β-galactosidase detection kit were used to detect the influence of CCNB1 on the proliferation, apoptosis, and senescence of bladder cancer cells. RT-qPCR and Western blotting are used to determine the regulation of CCNB1 and PI3K/AKT pathways by miR-139-5p. Finally, the subcutaneous tumor formation in nude mice and immunohistochemical experiments are performed to assess the effect of puerarin on the proliferation of bladder cancer cells in vivo. Results: Puerarin induced proliferation inhibition, apoptosis, and senescence of bladder cancer cells in vitro. Puerarin down-regulated the expression of CCNB1, p-PI3K, and p-AKT proteins by overexpressing miR-139-5p, thereby exerting a tumor suppressor effect in bladder cancer. Compared with the control group, the volume and weight of subcutaneous tumors of nude mice in the puerarin administration group are reduced. Moreover, the ki-67 positive staining rate and the expression level of CCNB1, p-PI3K, and p-AKT protein are reduced. Conclusion: The experimental results showed that the anti-tumor effect of puerarin against bladder cancer might be achieved by inhibiting CCNB1 and PI3K/AKT pathway via up-regulating miR-139-5p.

Located on chromosome 11q13.4, miR-139-5p has been confirmed by several studies as a possible attractive biomarker for cancer, including breast cancer, but its mechanism of correlation in different molecular subtypes of breast cancer has not been reported. In this study, comprehensive bioinformatics analysis was used to evaluate the expression of miR-139-5p in different molecular subtypes of breast cancer (luminal A, luminal B, HER2-enriched, and basal-like). The target genes of miR-139-5p were predicted by using an online database TargetScan and miRDB, and three key genes, FBN2, MEX3A, and TPD52, were screened in combination with differentially expressed genes in different molecular subtypes of breast cancer. The expression of the three genes was verified separately, and the genes were analyzed for pathway and functional enrichment. Bone marrow mesenchymal stem cells (BMSC) are another kind of highly plastic cell population existing in bone marrow besides hematopoietic stem cells. BMSC can affect the proliferation and migration of cancer cells, promote the metastasis and development of cancer, and regulate the tumor microenvironment by secreting exosome mirnas, thus affecting the malignant biological behavior of tumor cells. Finally, human bone marrow mesenchymal stem cells exosomes were obtained by ultracentrifugation, and the morphology of exosomes was observed by transmission electron microscopy. The expression of miR-139-5p in normal breast cells MCF-10A, human breast cancer cell line MDA-MB-231 cells, and BMSCs-derived exosomes were compared; the exosomes and MDA-MB-231 cells were co-cultured to observe their effects on the proliferation of the MDA-MB-231 cells. Human bone marrow mesenchymal stem cell-derived exosomes inhibited the growth of breast cancer cells and promoted the expression of FBN2, MEX3A, and TPD52 by transporting miR-139-5p. [ABSTRACT FROM AUTHOR]

Introduction and Objectives: Nonalcoholic fatty liver disease (NAFLD) starts with the abnormal accumulation of lipids in the liver. Long noncoding RNA (lncRNA) nuclear enriched abundant transcript 1 (NEAT1) was reported to modulate hepatic metabolic homeostasis in NAFLD. However, little is known about the molecular mechanisms of NAFLD. Materials and Methods: To establish a NAFLD cellular model, HepG2 cells and LO2 cells were treated with 1 mMfree fatty acids (FFAs) for 24 h. NEAT1, miRNA (miR)-139-5p, c-Jun and sterol-regulatory element binding protein-1c (SREBP-1c) were evaluated using qPCR. The protein levels of c-Jun, SREBP1c, acetyl-CoA carboxylase (ACC) and fatty acid synthetase (FAS) were determined using western blotting. Moreover, Oil Red O staining was employed to assess lipid accumulation. In addition, a kit assay was performed to evaluate TG levels. Finally, the interactions among NEAT1, miR-139-5p, c-Jun and SREBP1c were identified by dual luciferase reporter gene assay. Results: NEAT1, c-Jun and SREBP1c expression was markedly elevated, while miR-139-5p expression was reduced in the NAFLD cellular model. NEAT1 knockdown restrained lipid accumulation in the NAFLD cellular model by directly targeting miR-139-5p. Moreover, miR-139-5p overexpression suppressed lipid accumulation by directly suppressing c-Jun expression. In addition, c-Jun silencing suppressed lipid accumulation by directly targeting SREBP1c. Finally, miR-139-5p inhibition mitigated the inhibitory effect of sh-NEAT1 on lipid accumulation. Conclusion: NEAT1 aggravated FFA-induced lipid accumulation in hepatocytes by regulating the c-Jun/SREBP1c axis by sponging miR-139-5p, indicating the potential of NEAT1 as a promising therapeutic target for NAFLD. [ABSTRACT FROM AUTHOR]

Jinrui Sun,1 Shanshan Wang,2 Ping Liu,1 Yulan Liu3 1Department of Gynecology, Shanxi Provincial People’s Hospital, Taiyuan, Shanxi Province 030012, People’s Republic of China; 2Department of Cardiology, Yidu Central Hospital of Weifang City, Weifang, Shandong, People’s Republic of China; 3Department of Gynecology, Maternal and Child Health Hospital of Hubei Province, Wuhan, Hubei 430070, People’s Republic of ChinaCorrespondence: Yulan LiuDepartment of Gynecology, Maternal and Child Health Hospital of Hubei Province, NO. 745 Wuluo Road, Hongshan, Wuhan, Hubei 430070, People’s Republic of ChinaTel +86-15698784852Email yulantang885@163.comObjective: To verify that miR-139-5p-zinc finger E-box-binding homeobox 1 (ZEB1) is a molecular regulator of the biological function and epithelial–mesenchymal transition (EMT) of cervical cancer (CC) cells.Methods: Cancerous tissues, corresponding paracancerous tissues, and serum were sampled from patients with CC. MiR-139-5p and ZEB1 in tissue specimens, serum specimens, and purchased CC cell lines were quantified, and Pearson correlation coefficient was adopted for correlation analysis of miR-139-5p in clinical specimens. Receiver operating characteristic (ROC) curves were adopted to analyze the diagnostic value of miR-139-5p and ZEB1 for CC. The expression of genes in CC cells was changed by transfection. The proliferation, colony formation, invasion, and apoptosis of cells were determined, and the protein level of EMT markers (N-cadherin, vimentin, and E-cadherin) was also quantified. Moreover, the targeting relationship between miR-139-5p and ZEB1 was determined.Results: Our data showed that the expression of miR-139-5p decreased greatly in CC tissues, and it also significantly decreased in the serum, while the expression of serum ZEB1 was opposite. In addition, the miR-139-5p expression in CC tissues was positively correlated with that in serum, while serum miR-139-5p was negatively correlated with serum ZEB1. The areas under the curves (AUCs) of the two for identifying CC were 0.923 and 0.890, respectively. Both up-regulation of miR-139-5p and down-regulation of ZEB1 suppressed the colony formation, proliferation, invasion, and EMT of CC cells, and intensified their apoptosis. Moreover, miR-139-5p negatively regulated the transcription of ZEB1, and down-regulation of the former could reverse the molecular regulatory effects of down-regulating ZEB1 on the above biological behaviors of CC cells.Conclusion: The above data imply that miR-139-5p-ZEB1 axis may be the key to curbing the progression of CC.Keywords: cervical cancer, miR-139-5p, ZEB1, growth, invasion, epithelial–mesenchymal transition

Jia-Quan Liang,1,* Hai-Rong Liao,1,* Cai-Xia Xu,1 Xiao-Ling Li,1 Ze-Xu Wei,2 Guo-Jun Xie,1 Yong Cheng1,2 1Department of Psychiatry, The Third People’s Hospital of Foshan, Foshan, Guangdong, People’s Republic of China; 2Center on Translational Neuroscience, Minzu University of China, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guo-Jun Xie; Yong Cheng Email xiegjfs@163.com; yongcheng@muc.edu.cnBackground: MicroRNAs (miRs) have been suggested to be biomarkers to inform the diagnosis of major depressive disorder (MDD). We have previously shown that exosome-derived miR-139-5p had potential in differentiating between patients with MDD and healthy control (HC) subjects.Materials and Methods: To validate the potential of exosome-derived miR-139-5p as a biomarker for MDD, here we recruited 30 patients with MDD and 30 HC subjects, and used TaqMan probes to detect serum exosomal miR-139-5p levels.Results: The data showed that patients with MDD had significantly increased exosomal miR-139-5p levels when compared with controls. Correlation analysis suggested that sex, age, and body mass index did not significantly affect blood exosomal miR-139-5p levels in the tested subjects. The ROC curve showed that serum-derived miR-139-5p had reasonable performance in discriminating patients with MDD and HC subjects, with a sensitivity of 0.867 and specificity of 0.767, and the AUC was 0.807.Discussion: Taken together, these results demonstrated that patients with MDD were accompanied by significantly increased blood exosomal miR-139-5p levels, and exosomal miR-139-5p is a promising biomarker for the diagnosis of MDD.Keywords: major depressive disorder, exosome, miR-139-5p, biomarker

Abstract Background Accumulating evidence indicates that long non-coding RNAs (lncRNAs) acting as crucial regulators in tumorigenesis. However, its biological functions of lncRNAs in colorectal cancer (CRC) have not been systematically clarified. Methods An unbiased screening was performed to identify disregulated lncRNAs revealed to be implicated in CRC carcinogenesis according to an online-available data dataset. In situ hybridization (ISH), RT-qPCR and RNA fluorescence in situ hybridization (RNA-FISH) were applied to detect RP11-757G1.5 expression in CRC tissues and cell lines. The associations of RP11-757G1.5 with clinicopathological characteristics were analyzed. Their effects on prognosis were analyzed by the Kaplan-Meier analysis, Log-rank test, Univariate and Multivariate Cox regression analysis. The potential biological function of RP11-757G1.5 in CRC was investigated by Colony formation, Edu cell proliferation, Flow cytometry, Wound healing and Transwell assays. Bioinformatics binding site analysis, Luciferase reporter assay, Ago2 immunoprecipitation assays, RNA pull-down assay, RT-qPCR and Western blotting were utilized to demonstrate the mechanism of RP11-757G1.5 acts as a molecular sponge of miR-139-5p to regulate the expression of YAP1. Finally, we further explore the potential role of RP11-757G1.5 in CRC orthotopic xenografts in vivo. Results We discovered a novel oncogenic lncRNA RP11-757G1.5, that was overexpressed in CRC tissues, especially in aggressive cases. Moreover, up-regulation of RP11-757G1.5 strongly correlated with poor clinical outcomes of patients with CRC. Functional analyses revealed that RP11-757G1.5 promoted cell proliferation in vitro and in vivo. Furthermore, RP11-757G1.5 stimulated cell migration and invasion in vitro and in vivo. Mechanistic studies illustrated that RP11-757G1.5 regulated the expression of YAP1 through sponging miR-139-5p and inhibiting its activity thereby promoting CRC progression and development. Conclusions Altogether, these results reveal a novel RP11-757G1.5/miR-139-5p/YAP1 regulatory axis that participates in CRC carcinogenesis and progression.

miR-139-5p has a tumor suppressor effect in some cancers and negatively regulates CXCR4. To this end, we examined the expression and mechanism of of action of miR-139-5p and CXCR4 in oral squamous cell carcinoma (OSCC). miRNA-139-5p was down-regulated whereas CXCR4 was increased in tissues and cells of OSCC. Moreover, low expression of miR-139-5p was associated with a low survival. Overexpression of miR-139-5p in OSCC inhibited in vitro and in vivo cell proliferation and in vitro mobility of OSCC and inhibited the expression of WNT responsive c-myc, cyclinD1, and Bcl-2, and such effects were all reversible by an inhibitor of miR-139-5p or over-expression of CXCR4. The inverse relation between expression of miR-139-5p and CXCR4 might be related to the fact that miR-139-5p negatively regulates CXCR4 expression by virtue of direct binding. These findings underscore the importance of miR-139-5p and CXCR4 in regulation of OSCC.

ObjectiveThis study aimed to explore the regulatory mechanism of miR-139-5p on the biological characteristics of breast cancer cells by targeting Collagen type XI alpha 1 chain (COL11A1). MethodGEO2R was used to identify the differentially expressed genes (DEGs) of breast cancer in GEO database. miRDB, miRanda and TargetScan databases were used to predict the miRNAs that regulate COL11A1. qRT-PCR was used to detect the expressions of COL11A1 and miR-139-5p in breast cancer cells, and western blot was used to detect the protein level of COL11A1. RNA binding protein immunoprecipitation assay was employed to test the targeted relationship between miR-139-5p and COL11A1, which was further verified by dual-luciferase reporter gene assay. CCK-8 assay was performed to detect the cell proliferation, and flow cytometry was carried out to examine the cell apoptosis. Moreover, western blot was used for the detection of caspase-3, Bax and Bcl-2 protein levels. ResultsA total of five DEGs were screened from the GEO database, of which COL11A1 was the only highly expressed in breast cancer. According to the database analysis, we predicted that miR-139-5p was much likely to target the expression of COL11A1. MiR-139-5p was poorly expressed in breast cancer cells and targeted inhibited COL11A1. Silencing COL11A1 or overexpressing miR-139-5p both could inhibit the proliferation and promote the apoptosis, while overexpressing the two factors simultaneously could reverse such effect. ConclusionOverexpression of miR-139-5p inhibits the proliferation and promotes the apoptosis of breast cancer cells by inhibiting the expression of COL11A1.

Stem cells and progenitor cells have been identified as potential new therapeutic options for severe limb ischemia to induce angiogenesis, and hyaluronic acid (HA) is commonly applied as a biomaterial in tissue engineering. However, the efficiency of HA combined with human umbilical cord blood-derived endothelial colony forming cells (ECFCs) and human umbilical-derived mesenchymal stem cells (MSCs) on angiogenesis is unclear. In the present study, we showed that HA promoted angiogenesis induced by MSCs-ECFCs in Matrigel plugs and promoted blood perfusion of murine ischemic muscles. Laser confocal microscopy revealed that human-derived cells grew into the host vasculature and formed connections, as shown by mouse-specific CD31+/human-specific CD31+ double staining. In vitro assays revealed that HA supported cell proliferation and migration, enhanced CD44 expression and reduced microRNA (miR)-139-5p expression. Further analysis revealed that miR-139-5p expression was negatively regulated by CD44 in ECFCs. Flow cytometry assays showed that HA increased CD31 positive cells proportion in MSC-ECFC and could be reversed by miR-139-5p mimics transfection. Moreover, the improvement of MSC-ECFC proliferation and migration induced by HA could be blocked by upregulation of miR-139-5p expression. In conclusion, HA facilitates angiogenesis of MSCs-ECFCs, and this positive effect be associated with activation of the CD44/miR-139-5p pathway, providing a promising strategy for improving severe limb ischemia.

Located on chromosome 11q13.4, miR-139-5p has been confirmed by several studies as a possible attractive biomarker for cancer, including breast cancer, but its mechanism of correlation in different molecular subtypes of breast cancer has not been reported. In this study, comprehensive bioinformatics analysis was used to evaluate the expression of miR-139-5p in different molecular subtypes of breast cancer (luminal A, luminal B, HER2-enriched, and basal-like). The target genes of miR-139-5p were predicted by using an online database TargetScan and miRDB, and three key genes, FBN2, MEX3A, and TPD52, were screened in combination with differentially expressed genes in different molecular subtypes of breast cancer. The expression of the three genes was verified separately, and the genes were analyzed for pathway and functional enrichment. Bone marrow mesenchymal stem cells (BMSC) are another kind of highly plastic cell population existing in bone marrow besides hematopoietic stem cells. BMSC can affect the proliferation and migration of cancer cells, promote the metastasis and development of cancer, and regulate the tumor microenvironment by secreting exosome mirnas, thus affecting the malignant biological behavior of tumor cells. Finally, human bone marrow mesenchymal stem cells exosomes were obtained by ultracentrifugation, and the morphology of exosomes was observed by transmission electron microscopy. The expression of miR-139-5p in normal breast cells MCF-10A, human breast cancer cell line MDA-MB-231 cells, and BMSCs-derived exosomes were compared; the exosomes and MDA-MB-231 cells were co-cultured to observe their effects on the proliferation of the MDA-MB-231 cells. Human bone marrow mesenchymal stem cell-derived exosomes inhibited the growth of breast cancer cells and promoted the expression of FBN2, MEX3A, and TPD52 by transporting miR-139-5p.