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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]

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]

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]

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]

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: 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]

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]

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]

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]

Evidence indicates that macrophages play an important role in the immune system. Therefore, research involving inflammatory and oxidative stress responses in macrophages is of great significance. Many factors contribute to inflammation and oxidative stress, including Salmonella. We investigated the effect of the miR-139-5p/TRAF6 axis on the inflammatory and oxidative stress responses of Salmonella -infected macrophages. Our findings revealed that miR-139-5p decreased IL-1β and TNF-α levels to inhibit Salmonella -induced inflammatory responses in the RAW264.7 macrophage cell line. Furthermore, miR-139-5p inhibited Salmonella -induced oxidative stress by strengthening SOD, CAT and GSH-PX activity, as well as lowering the malondialdehyde level in the RAW264.7 macrophages cell line. Subsequently, it was verified that TRAF6 was a downstream target of miR-139-5p in RAW264.7 cells. Rescue assays indicated that the over-expression of miR-139-5p inhibits the effects of TRAF6 on inflammatory and oxidative stress responses including Salmonella infection in RAW264.7 cells. To our knowledge, this study is the first to verify that miR-139-5p inhibits inflammatory and oxidative stress responses of Salmonella -infected macrophages through regulating TRAF6. This discovery may offer new insights on inflammatory and oxidative stress responses in macrophages. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

To investigate the expression and biological role of miR-139-5p in glioblastoma and the regulatory effect of miR-139-5p on DNA methyltransferase 1 (DNMT1). Methods qRT-PCR was used to detect the expression of miR-139-5p in glioblastoma tumor tissue, paired paracancerous tissue, human normal glioma cell line HEB, and human glioma cell line U251. The expression of miR-139-5p in U251 cells was up-regulated by transfection of miR-139-5p mimetics, and the expression of DNMT1 was down-regulated by transfection of DNMT1- targeted siRNA (DNMT1-siRNA). The expression of DNMT1 and neurofibromatosis type 2 (NF2) in tissues and cells was detected by qRT-PCR, Western blotting, immunohistochemistry and immunofluorescence. The cell counting kit-8 (CCK-8), flow cytometry and Matrigel Transwell were used to evaluate the proliferation, apoptosis and invasion ability of U251 cells. Results Compared with paracancerous tissues or HEB cells, miR-139-5p expression in glioblastoma tissues and U251 cells was suppressed (P<0.05). Compared with control cells, transfection of miR- 139-5p mimic significantly down-regulated the expression of DNMT1 and up-regulated the expression of NF2 (P<0.05). Compared with control cells, transfection of DNMT1-siRNA significantly promoted the expression of NF2 (P<0.05). Transfection of miR-139-5p mimetics or DNMT1-siRNA significantly induced U251 cell apoptosis and inhibited cell invasion (P<0.05). Conclusion miR-139-5p plays an anti-cancer role in glioblastoma, and it inhibits tumor proliferation and metastasis by targeting negative regulation of DNMT1. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is common cancer in female globally. Sevoflurane (SEV) has been reported to inhibit the metastasis of multiple cancers, including glioma, colorectal cancer, and hepatocellular carcinoma. However, the role of SEV in the metastasis of BC cells remains poorly understood. Transwell migration and invasion assays were performed to detect the migration and invasion of BC cells. Western blot assay was carried out to measure epithelial-mesenchymal transition (EMT)-related proteins in BC cells, including E-cadherin, N-cadherin, and fibronectin. Quantitative real-time polymerase chain reaction was conducted to determine the enrichment of miR-139-5p and ADP-ribosylation factor 6 (ARF6) in BC tissues and cells. The protein expression of ARF6 in BC tissues and cells was measured by western blot assay. The target of miR-139-5p was predicted by starBase software, and the target relationship between miR-139-5p and ARF6 in BC cells was confirmed by dual-luciferase reporter assay. SEV suppressed the migration, invasion, and EMT of BC cells, especially in the high-concentration SEV group. The level of miR-139-5p was lower in BC tissues and cells than that in paired normal tissues and normal mammary epithelial cells MCF-10A. MiR-139-5p was upregulated in BC cells treated with SEV. ARF6 was upregulated in BC tissues and cells compared with that in corresponding normal tissues and normal mammary epithelial cells MCF-10A. SEV reduced the mRNA and protein expression of ARF6 in BC cells. The accumulation of ARF6 or the interference of miR-139-5p reversed the suppressive effects of SEV treatment on the migration, invasion, and EMT of BC cells. MiR-139-5p bound to ARF6 and inversely modulated the level of ARF6 in BC cells. The transfection of si-ARF6 attenuated the promoting effects of miR-139-5p depletion on the migration, invasion, and EMT of BC cells treated with SEV. SEV suppressed the migration, invasion, and EMT of BC cells through downregulating the abundance of ARF6 by upregulating miR-139-5p. The miR-139-5p/ARF6 axis might be a promising target for the treatment of BC. • SEV inhibits the migration, invasion and EMT of BC cells. • MiR-139-5p is up-regulated while ARF6 is down-regulated in BC cells treated with SEV, especially in high concentration SEV group. • ARF6 is a direct target of miR-139-5p in BC cells, and it is negatively modulated by miR-139-5p. • The knockdown of ARF6 counteracts the promoting effects of miR-139-5p depletion on the migration, invasion and EMT of BC cells treated with SEV. [ABSTRACT FROM AUTHOR]

Background: 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. [ABSTRACT FROM AUTHOR]

Cutaneous wound management is a major health problem and imposes a huge economic burden worldwide. Previous studies have demonstrated that wound healing is a highly coordinated process including epithelialization, angiogenesis, remodeling and scarring. This progression requires self-renewal, preservation and repair properties of stem cells. However, our understanding of the detailed internal regulatory mechanism following injury and the means to accelerate wound healing are limited. Our previous research revealed that porcine acellular dermal matrix (ADM) effectively promotes wound healing and scar formation through epidermal stem cells (ESCs), and this process is relevant to the alteration of internal miRNA levels. In this study, we investigated the regulatory function of porcine ADM treatment on miRNAs in ESCs. We report that the treatment of porcine ADM reduced the levels of miR-124-3p.1 and miR-139-5p in wounds. MiR-124-3p.1 and miR-139-5p inhibited the expression of JAG1 and Notch1, respectively, by directly targeting miRNAs in ESCs. This work demonstrates that porcine ADM induced down-regulation of miR-124-3p.1/139-5p in wounds and up-regulation of JAG1/Notch1 in ESCs, thus enhancing cutaneous wound healing. [ABSTRACT FROM AUTHOR]

Previous studies have shown that cancer susceptibility candidate 5 (CASC5) plays important roles in several types of cancer. But its expression and clinical significance in human pan‐cancer remain largely unclear. In the present study, we comprehensively analysed the expression profile and prognostic values of CASC5 in pan‐cancer across 33 cancer types based on the online TCGA analysis databases. CASC5 was found to be abnormally expressed in 16 types of cancer. In addition, dysregulated expression of CASC5 was closely associated with patient overall survival (OS) in kidney renal papillary cell carcinoma (KIRP), lung adenocarcinoma (LUAD), pancreatic adenocarcinoma (PAAD) and thymoma (THYM). By comparative analysis, we found that CASC5 was significantly up‐regulated in LUAD and predicted poor patient OS. High CASC5 expression was closely correlated with tumour advanced stages of patients with LUAD. Through GSEA based on the KEGG database, CASC5 was found to be closely related to DNA replication and microRNA regulation in LUAD. Functionally, knockdown of CASC5 could inhibit cell proliferation of LUAD cells in vitro, rather than affecting cell migration and invasion. Mechanistically, CASC5 promoted proliferation of LUAD cells by targeting miR‐139‐5p. Collectively, our findings reveal that CASC5 is a novel oncogenic gene in LUAD and may be a potential clinical target and (or) biomarker for this human malignancy. Significance of the study: In this study, we for the first time comprehensively analysed the transcriptional level and prognostic significance of CASC5 in human pan‐cancer across 33 cancer types using online TCGA databases. Our study indicates that CASC5 is aberrantly expressed in many tumours and is closely related to the patient overall survival of several tumour types. Our findings reveal that CASC5 is a novel oncogene in LUAD based on bioinformatic analysis and functional experiments. Mechanistically, CASC5 promoted LUAD proliferation by targeting miR‐139‐5p. Results of this study suggest that CASC5 is a potential clinical target and (or) biomarker for LUAD. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer (PCa) is a common malignant tumor of the urinary system in males. LncRNA taurine-upregulated gene 1 (TUG1) has been verified to play a crucial role in progression and prognosis of PCa. However, the functional mechanism of TUG1 remains unclear with radiosensitivity of PCa. Methods: Quantitative real-time PCR (qRT-PCR) was conducted to measure the transcription levels of genes. 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and flow cytometry analysis were employed to assess cell proliferation and apoptosis, respectively. Moreover, colony formation assay was used to measure colony survival. Western blot was performed to detect the relative proteins expression. The interaction among variables was predicted by online tool starbase, and then confirmed using the dual luciferase reporter assay. A xenograft mouse model was constructed to investigate the effect of TUG1 on tumor growth in vivo. Results: The levels of lncRNA TUG1 and SMC1A were remarkably increased, while miR-139-5p was downregulated in PCa. Patients with high expression of TUG1 showed a lower survival rate and poor prognosis. Knockdown of TUG1 inhibited PCa cell proliferation and colony survival fraction, and promoted apoptosis. Downregulation of miR-139-5p reversed the effects of TUG1 deletion on proliferation, apoptosis and colony survival fraction in PCa cells treated with 4 Gy of X-ray radiation. Moreover, TUG1 sponged miR-139-5p to regulate SMC1A expression. SMC1A deletion blocked the effects of TUG1 on the progression of PCa cells treated with 4 Gy of X-ray radiation. The tumor volume and weight were illustriously reduced with radiation and TUG1 silencing in xenograft model. Conclusion: Knockdown of lncRNA TUG1 enhanced radiosensitivity in PCa via the TUG1/miR-139-5p/SMC1A axis. It may become a promising target for PCa treatment. [ABSTRACT FROM AUTHOR]

Purpose: Although X-inactive specific transcript (XIST) is known to play a critical role in the pathogenesis of melanoma, the mechanisms through which this remains unclear. Methods: RNAseq, immunohistochemistry, and qRT-PCR were used to identify the levels of XIST, miR-139-5p, and Rho-Associated Coiled-Coil Containing Protein Kinase-1 (ROCK1) in melanoma tissues and cells. A subcellular fractionation assay was used to determine the location of XIST. CCK-8 and colony formation assays were used to evaluate cellular proliferation. Cell migration and wound healing assays were used to detect the effects on cell migration. RNA pull-down was used to confirm the interaction between XIST and miR-139-5p. Besides, the xenograft tumor experiment was performed to further verify the roles of XIST in melanoma. Results: In this study, an increased level of XIST was revealed in melanoma tissues and cells, which was associated with higher TNM stage and positive lymph node metastasis. XIST was found to function as a "molecular sponge" of miR-139-5p to facilitate cellular functions. Moreover, these consequences could be partially reversed by inhibition of miR-139-5p. MiR-139-5p was found to target ROCK1 directly, leading to suppression of ROCK1 expression; this effect could be partially reversed by inhibiting XIST expression. Furthermore, the deletion of ROCK1 induced anti-oncogenic effects similar to those seen with knockout of XIST. Upregulation of miR-139-5p and knockdown of XIST could inhibit cell functions in melanoma. Conclusion: Our findings suggested that the lncRNA XIST facilitates cellular functions in melanoma via the miR-139-5p/ROCK1 pathway. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a metabolic disease characterized by an increase in blood glucose levels due to lack of insulin secretion. Previous studies have confirmed that PICK1 is critical for both β-cell function and glucose homeostasis. The aim of this study was to investigate the role of PICK1 in response to high glucose-induced β-cell dysfunction and the molecular mechanism of regulation of PICK1. We found that overexpression of PICK1 in db/db diabetic mice significantly improved glucose tolerance and increased insulin release. High glucose treatment of Min6 cells inhibited PICK1 expression, and overexpression of PICK1 protected against high glucose-induced pancreatic cell dysfunction. Activation of the PI3K/Akt pathway by PICK1 in Min6 cells resulted in increased GLUT2 expression and this increase was abolished by treatment with a PI3K-specific inhibitor. Further, we showed that expression of PICK1 is negatively regulated by miR-139-5p through directly targeting its 3′UTR. These data suggested that PICK1 may participate in the functional protection of pancreatic β-cells through PI3K/Akt signaling, promote insulin secretion, and delay the progression of diabetes, and is negatively regulated by miR-139-5p, further clarifying the regulation of pancreatic β-cell function. • PICK1 improves glucose tolerance and pancreatic β-cell function in HFD-fed mice. • PICK1 inhibits high glucose-induced dysfunction in Min6 pancreatic β-cells. • PICK1 promotes activation of PI3K/Akt pathway and GLUT2 expression. • PICK1 expression is negatively regulated by miR-139-5p. [ABSTRACT FROM AUTHOR]

Non-small-cell lung cancer (NSCLC) is a complex disease which is influenced by multiple factors. Recent studies demonstrated that long non-coding RNA (lncRNA) MIAT was involved in tumor metastasis. However, the underlying mechanism of MIAT in NSCLC remains largely unknown. In this study, MIAT, miR-139-5p and MMP2 expression were measured by quantitative reverse transcriptase PCR (QRT-PCR) or Western blotting, respectively, and we found the expression of MIAT and MMP2 were elevated, while miR-139-5p was decreased in NSCLC tissues and cell lines. Transwell assay showed MIAT and MMP2 functioned as an oncogene to induce cell migration and invasion in NSCLC, but miR-139-5p served as a tumor suppressor in NSCLC to inhibit cell migration and invasion. Besides that, in vivo experiments also indicated MIAT deletion inhibited tumor growth. The relationship between miR-139-5p and MIAT or MMP2 was then confirmed by Luciferase reporter assay, and the results showed that MIAT directly interacted with miR-139-5p and miR-139-5p targetedly suppressed MMP2 in NSCLC cells. Furthermore, expression analysis showed that MIAT indirectly regulated MMP2 by sponging miR-139-5p. Finally, rescue assay suggested that miR-139-5p restoration reversed MIAT-overexpression-induced promotion on the migration and invasion of NSCLC cells. In conclusion, our results demonstrated that lncRNA MIAT modulated the migration and invasion of NSCLC by regulating miR-139-5p and MMP2. [ABSTRACT FROM AUTHOR]

Although androgen deprivation therapy (ADT) by the anti-androgen drug enzalutamide (Enz) may improve the survival level of patients with castration-resistant prostate cancer (CRPC), most patients may eventually fail due to the acquired resistance. The reprogramming of glucose metabolism is one type of the paramount hallmarks of cancers. PKM2 (Pyruvate kinase isozyme typeM2) is a speed-limiting enzyme in the glycolytic mechanism, and has high expression in a variety of cancers. Emerging evidence has unveiled that microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) have impact on tumor development and therapeutic efficacy by regulating PKM2 expression. Herein, we found that lncRNA SNHG3, a highly expressed lncRNA in CRPC via bioinformatics analysis, promoted the invasive ability and the Enz resistance of the PCa cells. KEGG pathway enrichment analysis indicated that glucose metabolic process was tightly correlated with lncRNA SNHG3 level, suggesting lncRNA SNHG3 may affect glucose metabolism. Indeed, glucose uptake and lactate content determinations confirmed that lncRNA SNHG3 promoted the process of glycolysis. Mechanistic dissection demonstrated that lncRNA SNHG3 facilitated the advance of CRPC by adjusting the expression of PKM2. Further explorations unraveled the role of lncRNA SNHG3 as a 'sponge' of miR-139-5p and released its binding with PKM2 mRNA, leading to PKM2 up-regulation. Together, Our studies suggest that lncRNA SNHG3 / miR-139-5p / PKM2 pathway promotes the development of CRPC via regulating glycolysis process and provides valuable insight into a novel therapeutic approach for the disordered disease. • LncRNA SNHG3 has highly expression in CRPC and promotes the process of glycolysis. • PKM2 is highly expressed in enzalutamide resistant PCa. • LncRNA SNHG3 can regulate the expression of PKM2 by sponging miR-139-5p. • lncRNA SNHG3/miRNA-139-5p/PKM2 pathway promotes the development of CRPC via regulating glycolysis process. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM), a malignant and lethal tumor, remains a big threat to human health and life. Increasing explorations have confirmed that long noncoding RNAs are involved in the tumorigenesis and development of multiple cancers. Nevertheless, the regulatory mechanism of (long intergenic nonprotein coding RNA 1579 LINC01579) in GBM remains to be investigated. In this study, the expression of LINC01579 was upregulated in GBM cells and LINC01579 knockdown inhibited cell proliferation as well as promoted cell apoptosis. Additionally, LINC01579 acted as a sponge for miR‐139‐5p in GBM and eukaryotic translation initiation factor 4 gamma 2 (EIF4G2) was found to be a downstream target of miR‐139‐5p. Furthermore, the positive correlation of LINC01579 and EIF4G2 as well as the converse correlation between miR‐139‐5p and LINC01579 (or EIF4G2) were revealed by the experiments. Based on rescue assays, EIF4G2 overexpression or miR‐139‐5p inhibitor partially recovered the function of LINC01579 knockdown on cell proliferation and apoptosis. In summary, the results of this study verified that LINC01579 modulated cell proliferation and cell apoptosis in GBM by competitively binding with miR‐139‐5p to regulate EIF4G2, which provided a new clue to figure out potential therapy for patients suffered from GBM. [ABSTRACT FROM AUTHOR]

aimed to investigate the implication of miR-139-5p in CC progression. Methods: miR-139-5p expression in 40 paired CC tissues and several cell lines was determined by qRT-PCR firstly. The implications of miR-139-5p in CC cell proliferation and migration were revealed by CCK-8, EdU and transwell assays, respectively. The mechanism underlying the tumor-suppressing roles of miR-139-5p in CC was investigated sequentially by dual luciferase, qRT-PCR, and Western blot analysis. The expression of transcription factor 4 (TCF4), the validated target of miR-139-5p from our experiments, was finally detected by qRT-PCR and immunohistochemistry in CC tissues, and its expression correlates with miR-139-5p was explored. Results: We found that miR-139-5p expression was frequently decreased in CC tissues and cell lines, and its lower level was associated with positive lymph node metastasis. Cellular assays proved the significant tumor-suppressing roles of miR-139-5p by inhibiting CC cell proliferation and migration, and markedly blocking Wnt/β-catenin signaling. Since bioinformatics analysis indicated TCF4 as a novel target of miR-139-5p, our mechanistic studies validated this, and confirmed that TCF4 restoration could attenuate the tumor inhibitory activities of miR-139-5p in CC progression, and recover the normal Wnt/β-catenin signaling. Conclusion: Our data collectively demonstrated that miR-139-5p was a vital tumor suppressor in CC pathogenesis via targeting TCF4 thereby inhibiting Wnt/β-catenin signaling. The miR-139-5p/TCF4 axis may serve as a promising target for CC therapy. [ABSTRACT FROM AUTHOR]

Aims: We aimed to explore the impact of long noncoding RNA (lncRNA) nuclear enriched abundant transcript 1 (NEAT1) on cell proliferation, invasion, and migration of glioma. Methods: Differentially expressed genes were screened out from Gene Expression Omnibus data set based on the microarray analysis. The expression levels of lncRNA NEAT1, miR‐139‐5p, and CDK6 in glioma cells and tissues were examined by quantitative reverse transcription polymerase chain reaction, and the protein level of CDK6 in glioma cells was determined by western blot and immunohistochemistry. Glioma cell viability, cell cycle, and apoptosis were detected by 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazoliumbromide (MTT) and flow cytometry, respectively, whereas cell invasion and migration were analyzed by transwell assay. The target relationships among NEAT1, miR‐139‐5p, and CDK6 were confirmed by dual‐luciferase reporter gene assay. The effects of lncRNA NEAT1 on tumor growth were further testified through glioma xenografts in nude mice. Results: LncRNA NEAT1 and CDK6 were highly expressed in glioma tissues and cells, whereas miR‐139‐5p was lowly expressed. There were target relationships and correlations on expressions between miR‐139‐5p and NEAT1/ CDK6. NEAT1 and CDK6 could promote cell proliferation and metastasis of glioma cells and impeded cell apoptosis, whereas miR‐139‐5p exerted suppressive effects on the biological functions of glioma cells. NEAT1 regulated CDK6 to affect glioma growth through sponging miR‐139‐5p. Conclusions: LncRNA NEAT1 promotes cell proliferation, invasion, and migration of glioma through regulating miR‐139‐5p/CDK6 pathway. We aimed to explore the impact of long noncoding RNA (LncRNA) nuclear enriched abundant transcript 1 (NEAT1) on cell proliferation, invasion, and migration of glioma. The results of our study showed that LncRNA NEAT1 promotes cell proliferation, invasion, and migration of glioma through regulating miR‐139‐5p/CDK6 pathway. [ABSTRACT FROM AUTHOR]

Renal ischemia/reperfusion injury (IRI) is a main risk factor for the occurrence of delayed graft function or primary graft nonfunction of kidney transplantation. However, it lacks ideal molecular markers for indicating IRI in kidney transplantation. The present study is to explore novel candidate genes involved in renal IRI. Experimental renal IRI mouse models were constructed, and the differentially expressed genes were screened using a microarray assay. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed. The expression of genes was detected using real-time qPCR assay. Western blotting and immunohistochemistry staining assays were performed for protein determination. We identified that renal IRI induced the upregulation of SPRR2F, SPRR1A, MMP-10, and long noncoding RNA (lncRNA) Malat1 in kidney tissues for 479.3-, 4.98-, 238.1-, and 3.79-fold, respectively. The expression of miR-139-5p in kidney tissues of IRI-treated mice was decreased to 40.4% compared with the sham-operated mice. These genes are associated with keratinocyte differentiation, regeneration and repair of kidney tissues, extracellular matrix degradation and remodeling, inflammation, and cell proliferation in renal IRI. Identification of novel biomarkers involved in renal IRI may provide evidences for the diagnosis and treatment of renal IRI. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Expression of miR-139-5p was downregulated in prostate cancer especially metastatic prostate cancer. • MiR-139-5p repressed SOX5 expression to inhibit epithelial-mesenchymal transition in prostate cancer cells. • MiR-139-5p inhibited prostate cancer cell proliferation and migration via regulation of SOX5. Abstract Altered expression of microRNAs (miRNAs) was involved in prostate cancer progression. However, how miRNAs contributed to prostate cancer development remained unknown. Here, we reported that miR-139-5p levels were decreased in prostate cancer tumor tissues and prostate cancer cell lines. Transfection of miR-139-5p mimics reduced cell proliferation and migration ability of prostate cancer cells. Western blotting and RT-qPCR showed that elevation of miR-139-5p greatly inhibited SOX5 expression in prostate cancer cells. Through regulation of SOX5, enhanced expression of miR-139-5p downregulated TWIST, decreased N-cadherin and Vimentin expression, suggesting inhibition of epithelial-mesenchymal transition (EMT) process. The dual luciferase assay validated that SOX5 was a direct target of miR-139-5p. Additionally, a significant negative correlation between SOX5 mRNA levels and miR-139-5p levels were detected in prostate cancer tumor tissues. Our study indicated that miR-139-5p functioned as a tumor suppressor in prostate cancer cells by regulation of SOX5, and it might be a promising target for prostate cancer patients. [ABSTRACT FROM AUTHOR]

Aims: Paediatric low‐grade gliomas (pLGGs) are a heterogeneous group of brain tumours associated with a high overall survival: however, they are prone to recur and supratentorial lesions are difficult to resect, being associated with high percentage of disease recurrence. Our aim was to shed light on the biology of pLGGs. Methods: We performed microRNA profiling on 45 fresh‐frozen grade I tumour samples of various histological classes, resected from patients aged ≤16 years. We identified 93 microRNAs specifically dysregulated in tumours as compared to non‐neoplastic brain tissue. Pathway analysis of the microRNAs signature revealed PI3K/AKT signalling as one of the centrally enriched oncogenic signalling. To date, activation of the PI3K/AKT pathway in pLGGs has been reported, although activation mechanisms have not been fully investigated yet. Results: One of the most markedly down‐regulated microRNAs in our supratentorial pLGGs cohort was miR‐139‐5p, whose targets include the gene encoding the PI3K's (phosphatidylinositol 3‐kinase) catalytic unit, PIK3CA. We investigated the role of miR‐139‐5p in regulating PI3K/AKT signalling by the use of human cell cultures derived from supratentorial pLGGs. MiR‐139‐5p overexpression inhibited pLGG cell proliferation and decreased the phosphorylation of PI3K target AKT and phosphorylated‐p70 S6 kinase (p‐p70 S6K), a hallmark of PI3K/AKT/mTORC1 signalling activation. The effect of miR‐139‐5p was mediated by PI3K inhibition, as suggested by the decrease in proliferation and phosphorylation of AKT and p70 S6K after treatment with the direct PI3K inhibitor LY294002. Conclusions: These findings provide the first evidence that down‐regulation of miR‐139‐5p in supratentorial pLGG drives cell proliferation by derepressing PI3K/AKT signalling. [ABSTRACT FROM AUTHOR]

Background/Aims: In platinum-based chemotherapy for ovarian cancer, acquired drug resistance is a frequent occurrence. Because recent studies have demonstrated that dysregulation of microRNAs (miRNAs) is partly responsible for the induction of acquired drug resistance in cancers, we hypothesized that correcting the dysregulation of key miRNAs would reverse the acquired resistance to platinum-based drugs in ovarian cancer. Methods: Cisplatin-resistant SKOV3 and A2780 ovarian cancer cell lines (SKOV3-R and A2780-R, respectively) were established by long-term exposure to cisplatin. MTT assays were performed to evaluate the viability of SKOV3, SKOV3-R, A2780, and A2780-R cells. Quantitative PCR was used to examine the expression of miR-139-5p in these cell lines. The regulatory mechanism was confirmed by western blot analysis and luciferase reporter assays. After treatment with miR-139-5p and cisplatin, mitochondrial membrane potential and apoptosis were measured by using flow cytometry. Interaction with c-Jun and activating transcription factor 2 (ATF2) was evaluated by co-immunoprecipitation. Expression of B-cell lymphoma-extra large (Bcl-xl) and activation of caspase-9 and caspase-3 were detected by western blotting. Results: Expression of miR-139-5p was decreased in SKOV3-R and A2780-R cells. Recovery of miR-139-5p increased the sensitivity of SKOV3-R and A2780-R cells to cisplatin treatment, inhibited the interaction of c-Jun and ATF2, and decreased Bcl-xl expression in SKOV3-R and A2780-R cells. Expression of miR-139-5p promoted cisplatin-induced mitochondrial apoptosis through binding the 3′ untranslated region of c-Jun mRNA. Conclusion: Recovery of miR-139-5p suppressed the expression of c-Jun and thus reversed cisplatin-resistance in ovarian cancer. [ABSTRACT FROM AUTHOR]

BACKGROUND: The microRNA, miR-139-5p, plays an important role in the initiation and progression of various tumor types including osteosarcoma (OS). OBJECTIVE: This study aimed to detect the serum miR-139-5p expression in OS and analyze its association with clinical variables. METHODS: Blood samples were taken from 98 OS patients and 50 healthy individuals, and serum miR-139-5p levels were measured by quantitative reverse transcription-polymerase chain reaction. RESULTS: We found the expression of serum miR-139-5p in OS patients was significantly lower than that in healthy individuals, and miR-139-5p levels were dramatically decreased in patients with distant metastasis or in higher clinical stage. Receiver-operating characteristic (ROC) analysis revealed that serum miR-139-5p could well discriminate OS patients from healthy controls with a high sensitivity and specificity. Moreover, low serum miR-139-5p expression was strongly associated with distant metastasis, tumor stage and shorter overall survival. Both univariate and multivariate analyses showed that serum miR-139-5p level could serve as an independent prognostic marker for OS. CONCLUSIONS: Taken together, data from this study demonstrates that serum miR-139-5p could be used as a tumor biomarker for OS diagnosis and prognosis. [ABSTRACT FROM AUTHOR]

Chronic exposure to morphine can produce tolerance, dependence and addiction, but the underlying neurobiological basis is still incompletely understood. c-Jun, as an important component of the activator protein-1 transcription factor, is supposed to take part in regulating gene expression in AC/cAMP/PKA signaling. MicroRNA (miRNA) has emerged as a critical regulator of neuronal functions. Although a number of miRNAs have been reported to regulate the μ-opioid receptor expression, there has been no report about miRNAs to regulate chronic morphine-induced, naloxone-precipitated cAMP overshoot. Our results showed that chronic morphine pretreatment induced naloxone-precipitated cAMP overshoot in concentration- and time-dependent manners in HEK 293/μ cells. Chronic morphine pretreatment alone elevated both c-Jun protein and miR-139-5p expression levels, while dramatically artificial elevation of miR-139-5p inhibited c-Jun at the translational level. Furthermore, dramatically artificial upregulation of intracellular miR-139-5p limited chronic morphine-induced, naloxone-precipitated cAMP overshoot. These findings suggested that miR-139-5p was involved in regulating chronic morphine-induced, naloxone-precipitated cAMP overshoot in a negative feedback manner through its target c-Jun, which extends our understanding of neurobiological mechanisms underlying morphine dependence and addiction. [ABSTRACT FROM AUTHOR]

Abstract. Background Accumulating evidence has suggested the crucial roles of differentially expressed miRNAs in osteosarcoma progression. MiR-139-5p was decreased in various cancers. However, the role of miR-139-5p in the development of osteosarcoma and the underlying mechanism remain to be addressed. Methods MiR-139-5p and DNA methyltransferase-1 (DNMT1) mRNA expressions in osteosarcoma tissues and cells were detected by qRT-PCR and western blot analysis. The effects of miR-139-5p and DNMT1 on osteosarcoma cell migration, invasion and epithelial-mesenchymal transition (EMT) were investigated through cell migration and invasion assays, and western blot analysis. The relationship between miR-139-5p and DNMT1was explored using luciferase reporter analysis and western blot. A xenograft tumor model was employed to verify the effects of miR-139-5p on osteosarcoma. Results We found that miR-139-5p was strikingly decreased in osteosarcoma tissues and cell lines. MiR-139-5p over-expression suppressed osteosarcoma cell growth, migration and invasion, while loss of miR-139-5p promoted osteosarcoma cell proliferation, migration and invasion. Following, we characterized that DNMT1 was a direct target of miR-139-5p that interacted with the 3′-untranslated region of DNMT1. MiR-139-5p regulated a down-regulation in DNMT1 protein expression levels. We also found that DNMT1 expression was increased and negatively correlated with miR-139-5p expression in osteosarcoma tissues clinically. Xenograft tumor analysis suggested that miR-139-5p over-expression reduced tumor growth in osteosarcoma in vivo through decreasing DNMT1 expressions. Conclusion MiR-139-5p suppressed the osteosarcoma progression by reducing DNMT1, supplying new insight into the molecular mechanism uncovering osteosarcoma growth. [ABSTRACT FROM AUTHOR]

Background: LINC00152 plays a crucial role in tumorigenesis and progression of multiple types of cancer. However, the biological significance of LINC00152 and its potential role in oral squamous cell carcinoma (OSCC) remain to be determined. In the present study, we investigated the role of LINC00152 and the underlying mechanism of its oncogenic activity in OSCC. Materials and methods: The expression of LINC00152 in OSCC tissues and cell lines was detected using qRT-PCR. Cell proliferation, colony formation, migration, and invasion were measured using a cell counting kit, colony formation assay, wound healing, and transwell invasion assays, respectively. The target gene of LINC00152 was confirmed using a dual-luciferase reporter assay and qRT-PCR. A nude mouse model was established to analyze the function of LINC00152 in vivo. Results: LINC00152 expression was significantly upregulated in OSCC tissues and cell lines compared with that in normal counterparts. Upregulated LINC00152 served as an independent prognostic predictor in patients with OSCC. Moreover, knockdown of LINC00152 inhibited cell proliferation, colony formation, migration, and invasion, and suppressed the epithelial to mesenchymal transition in vitro, as well as impairing tumor growth in vivo. A mechanistic investigation indicated that LINC00152 could directly bind to miR-139-5p in OSCC. LINC00152 expression was inversely correlated with miR-139 expression in OSCC tissues. Conclusion: Taken together, these results suggested that LINC00152 may function as oncogene in OSCC and could be a potential therapeutic target in patients with OSCC. [ABSTRACT FROM AUTHOR]

Malignant tumor is characterized by recurrence and metastasis, Which is relevant to cellular proliferation and ability of invasion. Several studies have demonstrated that microRNAs (miRNAs) are associated with cancer progression and carcinogenesis at the post-transcription level. MiRNA-139-5p, which is one of the hot topics, was identified to be dysregulation in many cancers. It has been involved in various biological processes, including proliferation, cellular differentiation, invasion and metastasis, as well as chemo-resistance and prognosis of the tumor patients. Consequently, miRNA-139-5p may serve as a new potential therapeutic target for the treatment of tumor in the future. This paper reviewed the relationship between miRNA-139-5p and tumor. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are a class of small non-coding RNAs that are widely involved in a variety of biological processes. Different skeletal muscle fiber type composition exhibits characteristic differences in functional properties and energy metabolism of skeletal muscle. However, the molecular mechanism by which miRNAs control the different type of muscle fiber formation is still not fully understood. In the present study, we characterized the role of microRNA-139-5p (miR-139-5p) in the regulation of myosin heavy chain (MyHC) isoform expression and its underlying mechanisms. Here we found that the expression of miR-139-5p was significantly higher in mouse slow-twitch muscle than in fast-twitch muscle. Overexpression of miR-139-5p downregulated the expression of MyHC I and MyHC IIa, whereas inhibition of miR-139-5p upregulated them. We also found that the levels of calcineurin (CaN), NFATc1, MEF2C and MCIP1.4, which are the components of CaN/NFAT signaling pathway that has shown to positively regulate slow fiber-selective gene expression, were notably inhibited by miR-139-5p overexpression. Furthermore, treatment of phenylephrine (PE), a α1-adrenoceptor agonist, abolished the inhibitory effect of miR-139-5p on MyHC I and MyHC IIa expression. Together, our findings indicated that the role of miR-139-5p in regulating the MyHC isoforms, especially MyHC I and MyHC IIa, may be achieved through inhibiting CaN/NFAT signaling pathway. [ABSTRACT FROM AUTHOR]

Gastric cancer is one of the most common cancers in the world and glycolysis is a major feature of gastric cancer. MicroRNAs (miRNAs) involve in gastric cancer cell proliferation, glycolysis and other cellular processes. MiR-139-5p is reported as a tumor suppressor in cancers, however, the role of miR-139-5p including glycolytic metabolism is unclear in gastric cancer. So, the purpose of the present study is to elucidate the underlying mechanism in gastric cancer metabolism mediated by miR-139-5p. Our results revealed that miR-139-5p inhibited glycolysis by regulating AMP-activated, alpha 1 catalytic subunit (PRKAA1) expression in gastric cancer cells. We also found that miR-139-5p was down-regulated by long intergenic non-coding RNA 152 (LINC00152) in gastric cancer cells. Our results indicate that LINC00152/miR-139-5p facilitates gastric cancer cell glycolysis by regulating PRKAA1 expression. [ABSTRACT FROM AUTHOR]

This study clarified the possible molecular mechanisms by which the miR-139-5p/SOX4/TMEM2 axis affected angiogenesis and tumorigenesis of ovarian cancer (OC) based on GEO microarray datasets and experimental support. The expression of miR-139-5p and SOX4 was examined in clinical OC samples. Human umbilical vein endothelial cells (HUVECs) and human OC cell lines were included in vitro experiments. Tube formation assay was conducted in HUVECs. The expression of SOX4, SOX4, and VEGF in OC cells was identified using Western blot and immunohistochemistry. Luciferase assays were conducted to validate the targeting relationship between miR-139-5p and SOX4 and between SOX4 and TMEM2. A RIP assay assessed the binding of SOX4 and miR-139-5p. The impact of miR-139-5p and SOX4 on OC tumorigenesis in vivo was evaluated in nude mice. SOX4 was up-regulated, while miR-139-5p was down-regulated in OC tissues and cells. Ectopic miR-139-5p expression or SOX4 knockdown inhibited angiogenesis and tumorigenicity of OC. By targeting SOX4 in OC, miR-139-5p lowered VEGF expression, angiogenesis, and TMEM2 expression. The miR-139-5p/SOX4/TMEM2 axis also reduced VEGF expression and angiogenesis, which might curtail OC growth in vivo. Collectively, miR-139-5p represses VEGF expression and angiogenesis by targeting the transcription factor SOX4 and down-regulating TMEM2 expression, thereby impeding OC tumorigenesis. • miR-139-5p may be an important anti-oncogenic miRNA in OC. • miR-139-5p/SOX4 axis down-regulates VEGF by repressing the downstream TMEM2. • miR-139-5p/SOX4 axis inhibits proliferation, migration, invasion and angiogenesis of OC cells. • miR-139-5p/SOX4/TMEM2 axis inhibits OC angiogenesis and tumourigenesis in vivo. • Our study provides new targets for the early diagnosis and targeted treatment of OC. [ABSTRACT FROM AUTHOR]

MiR-139-5p is a suppressor in multiple types of cancer. However, whether miR-139-5p affects NSCLC is unknown. In this study, miR-139-5p expression in clinical samples was examined by real-time PCR and in situ hybridization (ISH). MiR-139-5p mimic was transfected to monitor NSCLC cell behaviors. Potential target was predicated using bioinformatics database. Next, whether miR-139-5p impacted cell behaviors via regulation of its predicted target gene were further evaluated. The result revealed that miR-139-5p was lower in NSCLC samples/cells. MiR-139-5p restrained A549 cell proliferation, accelerated apoptosis, and inhibited the β-catenin signaling. ATAD2 was a predicted target of miR-139-5p, and it was highly expressed in NSCLC tissues. ATAD2 overexpression abolished the miR-139-5p's anti-tumor effect on cell proliferation and apoptosis. TWS119 (a β-catenin signaling activator) partially reversed miR-139-5p overexpression-induced suppression of cell proliferation and promotion of cell apoptosis. In tumor xenografts, miR-139-5p restrained tumor growth. MiR-139-5p was a tumor suppressor in NSCLC by regulating the oncogene ATAD2 and β-catenin signaling. Our study provides a promising target for cancer treatment. [ABSTRACT FROM AUTHOR]

Osteogenesis of mesenchymal stem cells (MSCs) has played a necessary role in the repair of bone. According to some reports, microRNAs participate in different physiological activity of the cells, including cell differentiation. This study investigated the function that miR-139-5p plays in the osteogenic differentiation of human bone marrow MSCs (hBMSCs). In addition to miR-139-5p, the effects of alkaline phosphatase (ALP), a membrane-bound metalloenzyme that is considered an early osteogenic differentiation marker, have also been investigated. Calcium-rich deposit (mineralization) is also a typical osteogenic differentiation marker that could be visualized by alizarin red S (ARS) staining. Inhibiting miR-139-5p notably promotes the hBMSC osteoblast differentiation, which, however, will be reduced by overexpressed miR-139-5p. This result has been made based on the alternations of ALP activity, ARS staining, as well as expression of osteogenic genes, including runt-related gene-2 (Runx2), collagen I (Col-1), and osteocalcin (OCN). miR-139-5p exerts its role in BMSC osteogenesis most probably through the Wnt/β-catenin pathway, by direct targeting CTNNB1 and frizzled 4 (FZD4), essential factors of Wnt/β-catenin pathway. In conclusion, according to the present study, inhibiting miR-139-5p could be a promising strategy in hBMSC osteogenesis. [ABSTRACT FROM AUTHOR]

Objective: To study the expression and clinical significance of miR-139-5p in peripheral blood of patients with prostate cancer. Methods: Patients of prostate disease (n=65) and cases of male healthy volunteers (n=20) from April 2015 to September 2015 were included in the study. RT-qPCR method was used to detect the relative expression ofmiR-139-5p in peripheral blood of all the cases. The ROC curve was used to analyze the clinical value of peripheral blood miR-139-5p in the diagnosis of prostate cancer. Results: Compared with the hyperplasia of prostate group (n=15) and the control group (n=20), relative expression miR-139-5p in the peripheral blood of prostate cancer group (n=50) was significantly higher (P<0.05). The miR-139-5p relative expression levels in peripheral blood of prostate cancer patients with high differentiation, metastatic carcinoma and Gleason score at high risk for were significantly higher than those with low differentiation, in situ cancer and Gleason scores (P<0.05). The peripheral blood miR-139-5p had higher specificity and sensitivity in distinguishing prostate cancer from benign prostatic hyperplasia and healthy people. Conclusion: miR-139-5p in peripheral blood of patients with prostate cancer was highly expressed and could be used as a noninvasive diagnostic markers of prostate cancer. [ABSTRACT FROM AUTHOR]

25-hydroxycholesterol (25-HC) is implicated in many processes, including lipid metabolism and the immune response. However, the role of 25-HC in RANKL-induced osteoclastogenesis remains largely unknown. Our results showed that 25-HC inhibited miR-139-5p expression in mouse bone marrow macrophages (BMMs) cultured in receptor activator of NF-κB ligand (RANKL) and monocyte macrophage colony-stimulating factor (M-CSF). Further investigation suggested that 25-HC promoted the expression of nuclear factor of activated T cell cytoplasmic 1 (NFATc1) and Sp1, especially in the presence of RANKL and M-CSF. Meanwhile, 25-HC induced nuclear translocation of NFATc1, resulting in the interaction between NFATc1 and Sp1 that was confirmed by co-immunoprecipitation. Chromatin immunoprecipitation assay indicated that Sp1 could bind to miR-139-5p promoter, but NFATc1 had no binding capacity. Although forming NFATc1/Sp1 complex increased its binding to miR-139-5p promoter, the complex inhibited the transcriptional activity of Sp1. Inhibition of NFATc1 increase the expression of miR-139-5p, which might be due to the release of free Sp1 that could bind to the promoter of miR-139-5p. Enforced expression of miR-139-5p impaired osteoclastogenesis induced by co-treatment with 25-HC and RANKL. These results suggested that 25-HC induced the interaction between NFATc1 and Sp1, reducing the level of free Sp1 to inhibit miR-139-5p expression and promote osteoclastogenesis. [ABSTRACT FROM AUTHOR]

Opa interacting protein 5 (OIP5) has been reported to be over-expressed in several kinds of human cancer. However, the biological function and clinical significance of OIP5 in human breast cancer remains unknown. In this study, we found that OIP5 was notably over-expressed in breast cancer tissues compared with their corresponding nontumorous tissues. Statistical analysis showed a significant correlation of OIP5 expression with advanced clinical stage. Ablation OIP5 inhibited the proliferation of breast cancer cells. OIP5 over-expression inhibited hsa-miR-139-5p expression, antagonized its functions and led to the de-repression of its endogenous target NOTCH1, which was a core oncogene in promoting breast cancer progression. Our results suggested that OIP5 is a potential diagnosis biomarker and therapeutic target for breast cancer. [ABSTRACT FROM AUTHOR]