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Background Bladder cancer (BC) is one of the most common malignancies globally. Early diagnosis of it can significantly improve patients’ survival and quality of life. Urinary exosomes (UEs)-derived miRNAs might be a promising biomarker for BC detection. Method A total of 12 patients with BC and 4 non-cancerous participants (as healthy control) were recruited from a single center between March 2018 and December 2019 as the discovery set. Midstream urine samples from each participants were collected and high-throughput sequencing and differentially expression analysis were conducted. Combined with miRNA expression profile of BC tissue from The Cancer Genome Atlas (TCGA), miRNAs biomarkers for BC were determined. Candidate miRNAs as biomarkers were selected followed by verification with a quantitative reverse-transcription polymerase chain reaction assay in an independent validation cohort consisting of 53 BC patients and 51 healthy controls. The receiver-operating characteristic (ROC) curve was established to evaluate the diagnostic performance of UE-derived miRNAs. The possible mechanism of miRNAs were revealed by bioinformatic analysis and explored in vitro experiments. Results We identified that miR-93-5p, miR-516a-5p were simultaneously significantly increased both in UEs from BC compared with healthy control and BC tissue compared with normal tissue, which were verified by RT-qPCR in the validation cohort. Subsequently, the performance to discover BC of the miR-93-5p, miR-516a-5p was further verified with an area under ROC curve (AUC) of 0.838 and 0.790, respectively, which was significantly higher than that of urine cytology (AUC = 0.630). Moreover, miR-93-5p was significantly increased in muscle-invasive BC compared with non-muscle-invasive BC with an AUC of 0.769. Bioinformatic analysis revealed that B-cell translocation gene 2(BTG2) gene may be the hub target gene of miR-93-5p. In vitro experiments verified that miR-93-5p suppressed BTG2 expression and promoted BC cells proliferation, invasion and migration. Conclusion Urine derived exosomes have a distinct miRNA profile in BC patients, and urinary exosomal miRNAs could be used as a promising non-invasive tool to detect BC. In vitro experiments suggested that miR-93-5p overexpression may contribute to BC progression via suppressing BTG2 expression.

Background Long noncoding RNAs (lncRNAs) are known to regulate tumorigenesis and cancer progression, but their contributions to non-small-cell lung cancer (NSCLC) metastasis remain poorly understood. Our previous and other studies have revealed the involvement of upregulated LINC01234 in regulating gastric cancer and colon cancer cells proliferation, and we aimed to investigate whether LINC01234 overexpression also contribute to cancer cells metastasis in this study. Methods We collect the NSCLC tissues and adjacent non-tumor tissues and analyzed expression levels of LINC01234 by quantitative reverse-transcription PCR. LINC01234 were knocked down by using siRNAs or shRNAs, and overexpressed by transfection with overexpression vector; RNA levels of miRNA were downregulated or upregulated with inhibitors or mimics. Transwell assays were used to evaluate cell migration and invasive ability; in vivo metastasis experiments were performed to investigate the effect of LINC01234 on NSCLC cells metastasis. Luciferase reporter, RIP, and ChIP assays were used to determine the regulation of LINC01234 on its targets. Results LINC01234 expression is increased in NSCLC tissues, and its upregulation is associated with metastasis and shorter survival in NSCLC. Downregulation of LINC01234 impairs cell migration and invasion in vitro, and inhibits cells metastasis in vivo by acting as a competing endogenous RNA for the miR-340-5p and miR-27b-3p. LINC01234 also interacts with the RNA-binding proteins LSD1 and EZH2, leading to histone modification and transcriptional repression of the anti-proliferative genes BTG2. Conclusions Taken together, our findings identify two oncogenic regulatory axes in NSCLC centering on LINC01234: one involving miR-340-5p/miR-27b-3p in the cytoplasm and the second involving EZH2, LSD1, and BTG2 in the nucleus. Our study indicates that these genes may be targeted to reduce or prevent NSCLC metastasis.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Long non-coding RNA plays an important role in the development of HCC. This study analyzed the impact of MEG3 on malignant behavior of HCC and explored its possible molecular mechanism. Expression of MEG3 in HCC tissues and cell lines was measured by qRT-PCR. Transfection efficiency of MEG3 was verified by qRT-PCR. Cell proliferation, transwell migration, invasion and cell cloning assays were used to detect the effect of MEG3 on the proliferation, migration and invasion ability of HCC cells. The bioinformatics analysis was applied to predict the binding between miR-544b and MEG3 as well as BTG2. Luciferase reporter assay was performed to verify their interaction. Finally, the m6A modification of MEG3 by METTL3 was identified through RIP experiments. MEG3 was lowly expressed in HCC tissues and cells. Overexpression of MEG3 inhibits the proliferation, migration and invasion of HCC cells. MiR-544b can be sponged by MEG3, and overexpression of miR-544b reverses the anti-cancer effect of MEG3. We further confirmed that BTG2 gene is the target gene of miR-544b. Epigenetic studies have shown that METTL3-mediated N -methyladenosine modification led to MEG3 downregulation. In HCC, MEG3 and BTG2 are lowly expressed while miR-544b is highly expressed. MEG3 regulates the expression of BTG2 through miR-544b, thus affecting the malignant behavior of HCC. METTL3 regulates the m6A modification of MEG3 and its expression. This study clarified the role of MEG3/miR-544b/BTG2 axis in HCC and also provided new targets for HCC research.

Background Gastric cancer (GC) is the third leading cause of cancer-related mortality globally. Long noncoding RNAs (lncRNAs) are dysregulated in obvious malignancies including GC and exploring the regulatory mechanisms underlying their expression is an attractive research area. However, these molecular mechanisms require further clarification, especially upstream mechanisms. Methods LncRNA MNX1-AS1 expression in GC tissue samples was investigated via microarray analysis and further determined in a cohort of GC tissues via quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays. Cell proliferation and flow cytometry assays were performed to confirm the roles of MNX1-AS1 in GC proliferation, cell cycle regulation, and apoptosis. The influence of MNX1-AS1 on GC cell migration and invasion was explored with Transwell assays. A xenograft tumour model was established to verify the effects of MNX1-AS1 on in vivo tumourigenesis. The TEAD4-involved upstream regulatory mechanism of MNX1-AS1 was explored through ChIP and luciferase reporter assays. The mechanistic model of MNX1-AS1 in regulating gene expression was further detected by subcellular fractionation, FISH, RIP, ChIP and luciferase reporter assays. Results It was found that MNX1-AS1 displayed obvious upregulation in GC tissue samples and cell lines, and ectopic expression of MNX1-AS1 predicted poor clinical outcomes for patients with GC. Overexpressed MNX1-AS1 expression promoted proliferation, migration and invasion of GC cells markedly, whereas decreased MNX1-AS1 expression elicited the opposite effects. Consistent with the in vitro results, MNX1-AS1 depletion effectively inhibited the growth of xenograft tumour in vivo. Mechanistically, TEAD4 directly bound the promoter region of MNX1-AS1 and stimulated the transcription of MNX1-AS1. Furthermore, MNX1-AS1 can sponge miR-6785-5p to upregulate the expression of BCL2 in GC cells. Meanwhile, MNX1-AS1 suppressed the transcription of BTG2 by recruiting polycomb repressive complex 2 to BTG2 promoter regions. Conclusions Our findings demonstrate that MNX1-AS1 may be able to serve as a prognostic indicator in GC patients and that TEAD4-activatd MNX1-AS1 can promote GC progression through EZH2/BTG2 and miR-6785-5p/BCL2 axes, implicating it as a novel and potent target for the treatment of GC.

B‐cell receptor (BCR) signaling is critically activated and stable for mantle cell lymphoma (MCL), but the underlying mechanism of the activated BCR signaling pathway is not clear. The pathogenic basis of miR‐17‐92 cluster remains unclear although the oncogenic microRNA (miRNA) miR‐17‐92 cluster is highly expressed in patients with MCL. We revealed that miR‐17‐92 cluster overexpression is partly dependent on SOX11 expression and chromatin acetylation of MIR17HG enhancer regions. Moreover, miR‐17‐92 cluster regulates not only cell proliferation but BCR signaling activation in MCL cell lines. To comprehensively identify miR‐17‐92 cluster target genes, we performed pulldown‐seq, where target RNA of miRNA was captured using the biotinylated miRNA mimics and magnetic bead‐coated streptavidin, and quantified using next‐generation sequencing. The pulldown‐seq identified novel miRNA target genes, including tumor suppressors such as BTG2 (miR‐19b), CDKN2A (miR‐17), SYNE1 (miR‐20a), TET2 (miR‐18, miR‐19b, and miR‐92a), TNFRSF10A (miR‐92a), and TRAF3 (miR‐17). Notably, the gene expression profile data of patients with MCL revealed that BTG2 expression was negatively associated with that of BCR signature genes, and low BTG2 expression was associated with poor overall survival. Moreover, BTG2 silencing in MCL cell lines significantly induced BCR signaling overactivation and cell proliferation. Our results suggest an oncogenic role of miR‐17‐92 cluster‐activating BCR signaling throughout BTG2 deregulation in MCL. Furthermore, this may contribute to the prediction of the therapeutic efficacy and improved outcomes of MCL. SOX11 and enhancer‐regulated mechanism induce overexpression of miR‐17‐92 in mantle cell lymphoma (MCL). BTG2 was identified as a novel target of miR‐17‐92 cluster. miR‐17‐92 cluster activates B‐cell receptor signaling and cell proliferation by regulating BTG2 in MCL.

The androgen receptor (AR) signaling pathway is involved in the emergence of castration-resistant prostate cancer (CRPC). Here, we identified several androgen-regulated microRNAs (miRNAs) that may contribute to the development of CRPC. Seven miRNAs, miR-21, miR-32, miR-99a, miR-99b, miR-148a, miR-221 and miR-590-5p, were found to be differentially expressed in CRPC compared with benign prostate hyperplasia (BPH) according to microarray analyses. Significant growth advantage for LNCaP cells transfected with pre-miR-32 and pre-miR-148a was found. miR-32 was demonstrated to reduce apoptosis, whereas miR-148a enhanced proliferation. Androgen regulation of miR-32 and miR-148a was confirmed by androgen stimulation of the LNCaP cells followed by expression analyses. The AR-binding sites in proximity of these miRNAs were demonstrated with chromatin immunoprecipitation (ChIP). To identify target genes for the miRNAs, mRNA microarray analyses were performed with LNCaP cells transfected with pre-miR-32 and pre-miR-148a. Expression of BTG2 and PIK3IP1 was reduced in the cells transfected with pre-miR-32 and pre-miR-148a, respectively. Also, the protein expression was reduced according to western blot analysis. BTG2 and PIK3IP1 were confirmed to be targets by 3′UTR-luciferase assays. Finally, immunostainings showed a statistically significant ( P <0.0001) reduction of BTG2 protein in CRPCs compared with untreated prostate cancer (PC). The lack of BTG2 staining was also associated ( P <0.01) with a short progression-free time in patients who underwent prostatectomy. In conclusion, androgen-regulated miR-32 is overexpressed in CRPC, leading to reduced expression of BTG2. Thus, miR-32 is a potential marker for aggressive disease and is a putative drug target in PC.

Clinical and experimental evidence indicates that tumour‐associated macrophages support cancer progression. Moreover, macrophage‐derived extracellular vesicles (EVs) are involved in pathogenesis of multiple cancers, yet the functions of molecular determinants in which have not been fully understood. Herein, we aim to understand whether macrophage modulates pancreatic ductal adenocarcinoma (PDAC) progression in an EV‐dependent manner and the underlying mechanisms. microRNA (miR)‐365 was experimentally determined to be enriched in the EVs from M2 macrophages (M2‐EVs), which could be transferred into PDAC cells. Using a co‐culture system, M2‐EVs could enhance the proliferating, migrating and invading potentials of PDAC cells, while inhibition of miR‐365 in M2‐EVs could repress these malignant functions. B‐cell translocation gene 2 (BTG2) was identified to be a direct target of miR‐365, while the focal adhesion kinase (F/ATP)‐dependent tyrosine kinase (AKT) pathway was activated by miR‐365. We further demonstrated that overexpression of BTG2 could delay the progression of PDAC in vitro, whereas by impairing BTG2‐mediated anti‐tumour effect, M2‐EV‐miR‐365 promoted PDAC progression. For validation, a nude mouse model of tumorigenesis was established, in which we found that targeting M2‐EV‐miR‐365 contributed to suppression of tumour growth. Collectively, M2‐EVs carry miR‐365 to suppress BTG2 expression, which activated FAK/AKT pathway, thus promoting PDAC development.

Sulfiredoxin 1 (SRXN1) is a pivotal regulator of the antioxidant response in eukaryotic cells. However, the role of SRXN1 in hepatocellular carcinoma (HCC) is far from clear. The present study aims to elucidate whether SRXN1 participates in tumorigenesis and metastasis of HCC and to determine the molecular mechanisms. We found that SRXN1 expression was up‐regulated in HCC tissue samples and correlated with poor prognosis in HCC patients. We also observed that SRXN1 knockdown by transient siRNA transfection inhibited HCC cell proliferation, migration and invasion. Overexpression of SRXN1 increased HCC cell migration and invasion. B‐cell translocation gene 2 (BTG2) was identified as a downstream target of SRXN1. Mechanistic studies revealed that SRXN1‐depleted reactive oxygen species (ROS) modulated migration and invasion of HCC cells. In addition, the ROS/p65/BTG2 signalling hub was found to regulate the epithelial‐mesenchymal transition (EMT), which mediates the pro‐metastasis role of SRXN1 in HCC cells. In vivo experiments showed SRXN1 promotes HCC tumour growth and metastasis in mouse subcutaneous xenograft and metastasis models. Collectively, our results revealed a novel pro‐tumorigenic and pro‐metastatic function of SRXN1 in HCC. These findings demonstrate a rationale to exploit SRXN1 as a therapeutic target effectively preventing metastasis of HCC.

Pancreatic cancer (PC) remains a primary cause of cancer‐related deaths worldwide. Existing literature has highlighted the oncogenic role of microRNA‐27a (miR‐27a) in multiple cancers. Hence, the current study aimed to clarify the potential therapeutic role of PC cell–derived exosomal miR‐27a in human microvascular endothelial cell (HMVEC) angiogenesis in PC. Initially, differentially expressed genes (DEGs) and miRs related to PC were identified by microarray analysis. Microarray analysis provided data predicting the interaction between miR‐27a and BTG2 in PC, which was further verified by the elevation or depletion of miR‐27a. Next, the expression of miR‐27a and BTG2 in the PC tissues was quantified. HMVECs were exposed to exosomes derived from PC cell line PANC‐1 to investigate the effects associated with PC cell–derived exosomes carrying miR‐27a on HMVEC proliferation, invasion and angiogenesis. Finally, the effect of miR‐27a on tumorigenesis and microvessel density (MVD) was analysed after xenograft tumour inoculation in nude mice. Our results revealed that miR‐27a was highly expressed, while BTG2 was poorly expressed in both PC tissues and cell lines. miR‐27a targeted BTG2. Moreover, miR‐27a silencing inhibited PC cell proliferation and invasion, and promoted apoptosis through the elevation of BTG2. The in vitro assays revealed that PC cell–derived exosomes carrying miR‐27a stimulated HMVEC proliferation, invasion and angiogenesis, while this effect was reversed in the HMVECs cultured with medium containing GW4869‐treated PANC‐1 cells. Furthermore, in vivo experiment revealed that miR‐27a knockdown suppressed tumorigenesis and MVD. Taken together, cell‐derived exosomes carrying miR‐27a promotes HMVEC angiogenesis via BTG2 in PC.

Breast cancers (BrCas) that overexpress oncogenic tyrosine kinase receptor HER2 are treated with HER2-targeting antibodies (such as trastuzumab) or small-molecule kinase inhibitors (such as lapatinib). However, most patients with metastatic HER2⁺ BrCa have intrinsic resistance and nearly all eventually become resistant to HER2-targeting therapy. Resistance to HER2-targeting drugs frequently involves transcriptional reprogramming associated with constitutive activation of different signaling pathways. We have investigated the role of CDK8/19 Mediator kinase, a regulator of transcriptional reprogramming, in the response of HER2⁺ BrCa to HER2-targeting drugs. CDK8 was in the top 1% of all genes ranked by correlation with shorter relapse-free survival among treated HER2⁺ BrCa patients. Selective CDK8/19 inhibitors (senexin B and SNX631) showed synergistic interactions with lapatinib and trastuzumab in a panel of HER2⁺ BrCa cell lines, overcoming and preventing resistance to HER2-targeting drugs. The synergistic effects were mediated in part through the PI3K/AKT/mTOR pathway and reduced by PI3K inhibition. Combination of HER2- and CDK8/19-targeting agents inhibited STAT1 and STAT3 phosphorylation at S727 and upregulated tumor suppressor BTG2. The growth of xenograft tumors formed by lapatinib-sensitive or -resistant HER2⁺ breast cancer cells was partially inhibited by SNX631 alone and strongly suppressed by the combination of SNX631 and lapatinib, overcoming lapatinib resistance. These effects were associated with decreased tumor cell proliferation and altered recruitment of stromal components to the xenograft tumors. These results suggest potential clinical benefit of combining HER2- and CDK8/19-targeting drugs in the treatment of metastatic HER2⁺ BrCa.