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Long non‐coding RNA (lncRNA) have been the focus of increasing attention due to the role they play in many diseases, including osteosarcoma. The function of taurine upregulated gene 1 (TUG1) and its mechanism in osteosarcoma remain unclear. In our research, we found that TUG1 was elevated and correlated with a poor prognosis in osteosarcoma patients. In addition, the following functional experiment showed that decreased TUG1 could remarkably inhibit osteosarcoma cell migration and invasion, indicating that TUG1 functioned as an oncogene in osteosarcoma. Moreover, we revealed that TUG1 and Rho‐associated coiled‐coil‐containing protein kinase 1 (ROCK1), a metastasis‐related gene targeted by microRNA‐335‐5p (miR‐335‐5p), had the same miR‐335‐5p combining site. The subsequent luciferase assay verified TUG1 was a target of miR‐335‐5p. Furthermore, the results of a real‐time quantitative PCR showed that TUG1 and miR‐335‐5p could affect each other's expression. respectively. Finally, we affirmed that TUG1 affected ROCK1 expression and ROCK1‐mediated migration/invasion by working as a competitive endogenous RNA (ceRNA) via miR‐335‐5p. In summary, the findings of this study, based on ceRNA theory, combining the research foundation of miR‐335‐5p and ROCK1, and taking TUG1 as a new study point, provide new insight into molecular‐level reversing migration and invasion of osteosarcoma. TUG1 was a target of miR‐335‐5p in osteosarcoma tissues and cell lines. TUG1 could increase ROCK1 expresion and promote ROCK1 mediated migration/invasion by working as a ceRNA of miR‐335‐5p.

Klotho deficiency is a common feature of premature aging and chronic kidney disease (CKD). As such, restoring Klotho expression could be a logic strategy for protecting against various nephropathies. In this study, we demonstrate that KP1, a Klotho-derived peptide, inhibits cellular senescence by restoring endogenous Klotho expression. The effects of KP1 on cellular senescence and Klotho expression were assessed in mouse models of CKD. RNA-sequencing was employed to identify the microRNA involved in regulating Klotho by KP1. Gain- or loss-of-function approaches were used to assess the role of miR-223-3p and IncRNA-TUG1 in regulating Klotho and cellular senescence. KP1 inhibited senescence markers p21, p16 and γ-H2AX in tubular epithelial cells of diseased kidneys, which was associated with its restoration of Klotho expression at the posttranscriptional level. Profiling of kidney microRNAs by RNA sequencing identified miR-223-3p that bound to Klotho mRNA and inhibited its protein expression. Overexpression of miR-223-3p inhibited Klotho and induced p21, p16 and γ-H2AX, which were negated by KP1. Conversely, inhibition of miR-223-3p restored Klotho expression, inhibited cellular senescence. Furthermore, miR-223-3p interacted with lncRNA-TUG1 and inhibited its expression. Knockdown of lncRNA-TUG1 increased miR-223-3p, aggravated Klotho loss and worsened cellular senescence, whereas KP1 mitigated all these changes. These studies demonstrate that KP1 inhibits cellular senescence and induces Klotho expression via posttranscriptional regulation mediated by miR-223-3p and lncRNA-TUG1. By restoring endogenous Klotho, KP1 elicits a broad spectrum of protective actions and could serve as a promising therapeutic agent for fibrotic kidney disorders.

Background Human urine-derived stem cells (USCs)-derived exosomes (USC-Exo) could improve kidney ischemia/reperfusion injury (IRI), while the underlying mechanisms of this protective effect remain unclear. Methods Human USCs and USC-Exo were isolated and verified by morphology and specific biomarkers. The effects of USC-Exo on ferroptosis and kidney injury were detected in the IRI-induced acute kidney injury (AKI) model in C57BL/6 mice. The effects of USC-Exo on ferroptosis and lncRNA taurine-upregulated gene 1 (TUG1) were detected in hypoxia/reoxygenation (H/R)-treated human proximal tubular epithelial cells (HK-2). The interaction of SRSF1 and TUG1, ACSL4 was checked via RNA pull-down/RIP and RNA stability assays. The effects of LncRNA TUG1 on SRSF1/ACSL4-mediated ferroptosis were verified in H/R-treated HK-2 cells and the IRI-induced AKI mouse models. Results USC-Exo treatment improved kidney injury and ameliorated ferroptosis in IRI-induced AKI mouse models. USC-Exo were rich in lncRNA TUG1, which suppressed ferroptosis in HK-2 cells exposed to H/R. Mechanistically, lncRNA TUG1 regulates the stability of ACSL4 mRNA by interacting with RNA-binding protein SRSF1. In addition, SRSF1 upregulation or ACSL4 downregulation partially reversed the protective effect of lncRNA TUG1 on ferroptosis in H/R-treated HK-2 cells. Further, ACSL4 upregulation partially reversed TUG1’s repression on kidney injury and ferroptosis in IRI-induced AKI mice. Conclusion Collectively, lncRNA TUG1 carried by USC-Exo regulated ASCL4-mediated ferroptosis by interacting with SRSF1 and then protected IRI-induced AKI. Potentially, USC-Exo rich in lncRNA TUG1 can serve as a promising therapeutic method for IRI-AKI.

Bladder cancer is a common serious disease around the world. Long noncoding RNAs (lncRNAs) have been demonstrated to participate in the development and progression of various cancers, including bladder cancer. The aim of this study was to investigate the effects of lncRNA taurine upregulated gene 1 (TUG1) on proliferation and apoptosis in bladder cancer cell lines and the underlying mechanism. The levels of TUG1 were detected by quantitative real time polymerase chain reaction (qRT-PCR) in bladder cancer tissues and cells. The mRNA and protein levels of zinc finger E-box binding homeobox 2 (ZEB2) were measured by qRT-PCR and Western blot analysis, respectively. The functional targets of TUG1 were predicted by online softwares and confirmed by luciferase reporter assay. The effects of TUG1 on cell proliferation and apoptosis were examined by MTT and apoptosis assay, respectively. The expression levels of β-catenin, cyclinD1, and c-Myc in T24 cells were determined by Western blot analysis. The levels of TUG1 and ZEB2 were significantly increased in bladder cancer tissues and cells. Knockdown of either TUG1 or ZEB2 inhibited proliferation and induced apoptosis in bladder cancer cells. Interestingly, ZEB2 overexpression reversed the effects of TUG1 knockdown on cell proliferation and apoptosis. Moreover, ZEB2 was verified as a direct target of miR-142 and miR-142 could specially bind to TUG1. In addition, downregulation of TUG1 inhibited the Wnt/β-catenin pathway by regulating ZEB2 expression in bladder cancer cells. Downregulation of TUG1 expression inhibited proliferation and induced apoptosis in bladder cancer cells by targeting ZEB2 mediated by miR-142 through the inactivation of Wnt/β-catenin pathway.

Tumor immune evasion relies on the crosstalk between tumor cells and adaptive/innate immune cells. Immune checkpoints play critical roles in the crosstalk, and immune checkpoint inhibitors have achieved promising clinical effects. The long non‐coding RNA taurine‐upregulated gene 1 (TUG1) is upregulated in hepatocellular carcinoma (HCC). However, how TUG1 is upregulated and the effects on tumor immune evasion are incompletely understood. Here, METTL3‐mediated m6A modification led to TUG1 upregulation is demonstrated. Knockdown of TUG1 inhibited tumor growth and metastasis, increased the infiltration of CD8+ T cells and M1‐like macrophages in tumors, promoted the activation of CD8+ T cells through PD‐L1, and improved the phagocytosis of macrophages through CD47. Mechanistically, TUG1 regulated PD‐L1 and CD47 expressions by acting as a sponge of miR‐141 and miR‐340, respectively. Meanwhile, TUG1 interacted with YBX1 to facilitate the upregulation of PD‐L1 and CD47 transcriptionally, which ultimately regulated tumor immune evasion. Clinically, TUG1 positively correlated with PD‐L1 and CD47 in HCC tissues. Moreover, the combination of Tug1‐siRNA therapy with a Pdl1 antibody effectively suppressed tumor growth. Therefore, the mechanism of TUG1 in regulating tumor immune evasion is revealed and can inform existing strategies targeting TUG1 for enhancing HCC immune therapy and drug development. METTL3 mediates m6A modification leading to upregulation of lncRNA TUG1 in HCC. Knockdown of TUG1 promotes anti‐tumor immunity by restoring the activation of CD8+ T cells and improves phagocytosis of tumor cells by macrophages. TUG1 sponges miR‐141 and miR‐340, and interacts with YBX1 to regulate PD‐L1 and CD47, which provides a promising immunotherapeutic strategy for the treatment of HCC.

LncRNA TUG1 has been reported to be highly expressed in CRC samples and cells and promoted metastasis by affecting EMT, indicating a poor prognosis for colorectal cancer (CRC). In this study, we determined the underlying mechanism for tumor oncogenesis of lncRNA TUG1 in CRC metastasis. The expressions of miR-600 and KIAA1199 in 76 CRC patients and CRC cells and CRC metastatic tissues were determined using qRT-PCR. Epithelial-mesenchymal transition (EMT)-related proteins were determined using western blot. CRC cell metastasis was assessed by colony formation, wound healing and transwell assay. Luciferase reporter gene assay was used to confirm miR-600 binding to KIAA1199 3'UTR. Our data showed that lncRNA TUG1 was upregulated in CRC cells, miR-600 was downregulated in CRC tissues, cell lines and CRC metastatic tissues, and low miR-600 expression predicted a poor clinical prognosis. Overexpression of miR-600 suppressed CRC cell migration/invasion and EMT-related proteins in vitro, inhibited tumor volume and weight, and decreased the number of CRC liver metastasis in vivo. KIAA1199 was upregulated in CRC tissues, and was negatively regulated by miR-600. KIAA1199 overexpression promoted CRC cell migration and invasion, which reversed the inhibition effect of miR-600 mimic on migration and invasion of CRC cells. Moreover, TUG1 negatively regulated miR-600, and inhibition of TUG1 suppressed CRC cell migration and invasion and EMT-related proteins via regulating miR-600. Our study proved that TUG1 promoted KIAA1199 expression to accelerate EMT and metastasis of CRC cell through inhibition of miR-600 expression.

The purpose of this study was to probe the specific role of long noncoding RNA taurine upregulation 1 (LncRNA TUG1) in viral myocarditis (VMC). The mouse model of VMC was induced by Coxsackievirus type B3 (CVB3). LncRNA TUG1 was subsequently silenced, and micro-140-3p (miR-140-3p) was overexpressed in VMC mice. GenePharma synthesized wild-type and mutant LncRNA TUG1 or CXCL8 (C-X-C Motif Chemokine Ligand 8, Interleukin-8) fragments containing the miR-140-3p binding site and cloned them into the pmirGLO luciferase reporter vector. Dual luciferase reporter assays were performed to test the activity of LncRNA TUG1 or CXCL8 fragments containing miR-140-3p mimic and mimic NC. The effects of silencing LncRNA TUG1 on cell proliferation, apoptosis, and inflammation in the VMC mouse model and in vitro were investigated by flow cytometry, enzyme linked immunosorbent assay, and western blot. In the VMC mouse model, LncRNA TUG1 and CXCL8 were upregulated, while miR-140-3p was downregulated. Suppressing LncRNA TUG1 led to inhibition of CXCL8 by promoting miR-140-3p. Suppressing LncRNA TUG1 or CXCL8 or restoring miR-140-3p were observed to increase cell viability and decrease apoptosis rate of cardiomyocytes. LncRNA TUG1 knockdown suppresses inflammation and damage of VMC cardiomyocytes via the miR-140-3p/CXCL8 axis.

Background/Aims: Pancreatic carcinoma (PC) is the one of the most common and malignant cancers worldwide. LncRNA taurine upregulated gene 1 (TUG1) was initially identified as a transcript upregulated by taurine, and the abnormal expression of TUG1 has been reported in many cancers. However, the biological role and molecular mechanism of TUG1 in PC still needs further investigation. Methods: Quantitative real-time PCR (qRT-PCR) was performed to measure the expression of TUG1 in PC cell lines and tissues. MTT and colony formation assays were used to measure the effect of TUG1 on cell proliferation. A wound healing assay, transwell assay and western blot assay were employed to determine the effect of TUG1 on cell migration and the epithelial mesenchymal transition (EMT) phenotype. RNA-binding protein immunoprecipitation (RIP) and a biotin-avidin pulldown system were performed to confirm the interaction between miR-328 and TUG1. A gene expression array analysis using clinical samples and RT-qPCR suggested that enhancer of zeste homolog 2 (EZH2) was a target of miR-382 in PC. Results: In this study, we reported that TUG1 was overexpressed in PC tissues and cell lines, and high expression of TUG1 predicted poor prognosis. Further experiments revealed that overexpressed TUG1 promoted cell proliferation, migration and contributed to EMT formation, whereas silenced TUG1 led to opposing results. Additionally, luciferase reporter assays, an RIP assay and an RNA-pulldown assay demonstrated that TUG1 could competitively sponge miR-382 and thereby regulate EZH2. Conclusion: Collectively, these findings revealed that TUG1 functions as an oncogenic lncRNA that promotes tumor progression, at least partially, by functioning as an endogenous ‘sponge’ and competing for miR-382 binding to the miRNA target EZH2.

LncRNAs and microRNAs play critical roles in osteoblast differentiation and bone formation. However, their exact roles in osteoblasts under fluid shear stress (FSS) and the possible mechanisms remain unclear. The aim of this study was to explore whether and how miR‐34a regulates osteoblast proliferation and apoptosis under FSS. In this study, FSS down‐regulated miR‐34a levels of MC3T3‐E1 cells. MiR‐34a up‐regulation attenuated FSS‐induced promotion of proliferation and suppression of apoptosis. Luciferase reporter assay revealed that miR‐34a directly targeted FGFR1. Moreover, miR‐34a regulated osteoblast proliferation and apoptosis via FGFR1. Further, we validated that lncRNA TUG1 acted as a competing endogenous RNA (ceRNA) to interact with miR‐34a and up‐regulate FGFR1 protein expression. Furthermore, lncRNA TUG1 could promote proliferation and inhibit apoptosis. Taken together, our study revealed the key role of the lncRNA TUG1/miR‐34a/FGFR1 axis in FSS‐regulated osteoblast proliferation and apoptosis and may provide potential therapeutic targets for osteoporosis.

Coronary microembolization (CME) is a complicated problem that commonly arises in the context of coronary angioplasty. The lncRNA taurine-up regulated gene 1 (TUG1), significantly contributes to cardiovascular diseases; however, its contribution to CME-induced myocardial damage remains elusive. Herein, we establish the rat CME model and investigate the role of TUG1 in CME. The cell viability was evaluated via CCK-8 assay. Serum and cell culture supernatant samples were evaluated via ELISA. The dual luciferase reporter (DLR) assay, RIP, and RNA-pull down were conducted to validate the associations between TUG1 and miR-186-5p as well as miR-186-5p and XIAP. The expression of TUG1, miR-186-5p, and XIAP mRNA were determined by RT-qPCR, and proteins were evaluated via immuneblotting. As a result, TUG1 and XIAP were significantly down-regulated, and the miR-186-5p level was found to be remarkably up-regulated in CME myocardial tissues. Overexpression of TUG1 alleviated CME-induced myocardial injury and pyroptosis, whereas TUG1 knockdown showed the opposite effects. The DLR assay, RIP, and RNA-pull down results reveal that TUG1 directly targets miR-186-5p and miR-186-5p directly targets XIAP. In vitro rescue experiments show that TUG1 overexpression alleviates LPS-caused cardiomyocyte injury and pyroptosis via sponging miR-186-5p and regulating XIAP, and depression of miR-186-5p reduces LPS-induced cardiomyocyte injury and pyroptosis by targeting XIAP. Concludingly, the overexpression of TUG1 alleviates NLRP3 inflammasome-mediated cardiomyocyte pyroptosis through targeting the miR-186-5p/XIAP axis in CME-induced myocardial injury.