Background: Molecular-targeted therapy plays an important role in the combined treatment of breast cancer. Long noncoding RNA (LncRNA) plays a significant role in regulating breast cancer progression. The present study is to reveal the potential roles and molecular mechanism that the secretory carrier-associated membrane protein 1-transcript variant 2 (SCAMP1-TV2) has in breast. Methods: Cell Counting Kit-8 (CCK-8), RNA Immunoprecipitation (RIP), and RNA pull-down assays were employed to determine the interactions between SCAMP1-TV2 and Pumilio RNA binding family member 2 (PUM2). The luciferase reporter assays and chromatin immunoprecipitation (ChIP) assays were used to get to know the effect of human insulinoma-associated 1 (INSM1) directly on the SAM and SH3 domain containing 1 (SASH1) promoter. Results: Silenced SCAMP1-TV2 inhibited the proliferation, migration, and invasion of breast cancer cells, and promoted cell apoptosis. Meanwhile, SCAMP1-TV2 downregulation decreased its binding to PUM2 and increased the binding of PUM2 to INSM1 messenger RNA (mRNA), thus promoting the degradation of INSM1 mRNA. Silencing INSM1 decreased its inhibitory effect on SASH1 transcription and inhibited the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. The xenograft tumor growth in a nude mice was significantly inhibited by the silencing of SCAMP1-TV2 in combination with the overexpression of PUM2. Conclusions: SCAMP1-TV2/PUM2/INSM1 pathway plays an important role in regulating the biological behavior of breast cancer cells.

The obstacle in delivering therapeutics to glioblastoma (GBM) is tumor-induced angiogenesis which leads to the formation of abnormal vessels and a dysfunctional blood-tumor barrier. Here, we elucidated the effect of endothelial-monocyte activating polypeptide II (EMAP II) on the GBM-induced angiogenesis as well as its potential mechanisms. Our results proved that EMAP II inhibited the viability, mitochondrial membrane potential, migration and tube formation of GBM-induced endothelial cells (GECs) by inducing cell autophagy, demonstrated by cell viability assay, JC-1 staining assay, transwell assay and tube formation assay, respectively. Cell autophagy was induced by EMAP II through the observation of autophagic vacuoles formation and the up-regulation of microtubule-associated protein-1 light chain-3 (LC3)-II and p62/SQSTM1 expression, demonstrated by transmission electron microscopy analysis, immunofluorescence assay and Western blot assay. The activity of PI3K/AKT/mTOR signal pathway could be inhibited by the EMAP II treatment. Furthermore, unfolded protein response (UPR)-related proteins (GRP78, eIF2α, and CHOP) were up-regulated by EMAP II, which suggest that GECs exposed to EMAP II experienced endoplasmic reticulum stress. Further, mechanistic investigations found that EMAP II reduced the miR-96 expression which could directly target the 3'-UTR of these UPR-related proteins, and over-expression of miR-96 inhibited LC3 and p62/SQSTM1 expression by down-regulating these UPR-related proteins in GECs. Moreover, the combination of EMAP II with miR-96 inhibitor showed the inhibitory effect on the viability, migration, and in vitro tube formation of GECs, which are critical for angiogenesis. Taken together, we have demonstrated the fact that EMAP II resulted in the decreased GBM-induced angiogenesis by inducing autophagy, which might contribute to establishing potential strategies for human GBM treatment.

Recent studies indicate circular RNAs are related to dysregulation of vascular endothelial cell function, yet the underlying mechanisms have remained elusive. Here, we characterized the functional role of circular RNA USP1 (circ-USP1) in the regulation of the blood-tumour barrier (BTB) permeability and the potential mechanisms. In the current study, the circ-USP1 expressing level was up-regulated in glioma cerebral microvascular endothelial cells (GECs) of the BTB model in vitro. Knockdown of circ-USP1 disrupted the barrier integrity, increased its permeability as well as reduced tight junction-related protein claudin-5, occludin and ZO-1 expressions in GECs. Bioinformatic prediction and luciferase assay indicated that circ-USP1 bound to miR-194-5p and suppressed its activity. MiR-194-5p contributed to circ-USP1 knockdown-induced increase of BTB permeability via targeting and down-regulating transcription factor FLI1. Furthermore, FLI1 regulated the expressions of claudin-5, occludin and ZO-1 in GECs through binding to their promoter regions. Single or combined treatment of circ-USP1 and miR-194-5p effectively promoted anti-tumour drug doxorubicin across BTB to induce apoptosis of glioma cells. Overall, this present study identified the crucial regulation of circ-USP1 on BTB permeability via miR-194-5p/FLI1 axis-mediated regulation of tight junction proteins, which might facilitate the development of therapeutics against human gliomas.

This study was performed to determine whether EMAP II increases the permeability of the blood-tumor barrier (BTB) by affecting the expression of miR-330-3p as well as its possible mechanisms. We determined the over-expression of miR-330-3p in glioma microvascular endothelial cells (GECs) by Real-time PCR. Endothelial monocyte-activating polypeptide-II (EMAP-II) significantly decreased the expression of miR-330-3p in GECs. Pre-miR-330-3p markedly decreased the permeability of BTB and increased the expression of tight junction (TJ) related proteins ZO-1, occludin and claudin-5, however, anti-miR-330-3p had the opposite effects. Anti-miR-330-3p could enhance the effect of EMAP-II on increasing the permeability of BTB, however, pre-miR-330-3p partly reversed the effect of EMAP-II on that. Similarly, anti-miR-330-3p improved the effects of EMAP-II on increasing the expression levels of PKC-α and p-PKC-α in GECs and pre-miR-330-3p partly reversed the effects. MiR-330-3p could target bind to the 3'UTR of PKC-α. The results of in vivo experiments were similar to those of in vitro experiments. These suggested that EMAP-II could increase the permeability of BTB through inhibiting miR-330-3p which target negative regulation of PKC-α. Pre-miR-330-3p and PKC-α inhibitor decreased the BTB permeability and up-regulated the expression levels of ZO-1, occludin and claudin-5 while anti-miR-330-3p and PKC-α activator brought the reverse effects. Compared with EMAP-II, anti-miR-330-3p and PKC-α activator alone, the combination of the three combinations significantly increased the BTB permeability. EMAP-II combined with anti-miR-330-3p and PKCα activator could enhance the DOX's effects on inhibiting the cell viabilities and increasing the apoptosis of U87 glioma cells. Our studies suggest that low-dose EMAP-II up-regulates the expression of PKC-α and increases the activity of PKC-α by inhibiting the expression of miR-330-3p, reduces the expression of ZO-1, occludin and claudin-5, and thereby increasing the permeability of BTB. The results can provide a new strategy for the comprehensive treatment of glioma.

The blood-brain barrier (BBB) strongly restricts the entry of anti-glioma drugs into tumor tissues and thus decreases chemotherapy efficacy. Malignant gliomas are highly invasive tumours that use the perivascular space for invasion and co-opt existing vessels as satellite tumor form. Because regulation of the effect of noncoding RNA on BBB function is attracting growing attention, we investigated the effects of noncoding RNA on the permeability of glioma conditioned normal BBB and the mechanism involved using PIWI-associated RNA piR-DQ590027 as a starting point.

Glioma, a common malignant tumour of the human central nervous system, has poor prognosis and limited treatment options. Dissecting the biological mechanisms underlying glioma pathogenesis can facilitate the development of better therapies. Here, we investigated the endogenous expression of BTB and CNC homolog 2 (BACH2), fused in sarcoma (FUS), TSLNC8 and microRNA (miR)-10b-5p in glioma cells and tissues. We studied the interaction between BACH2 and FUS and its contribution to glioma progression. We demonstrated that the interaction between BACH2 and FUS promoted glioma progression via transcriptional inhibition of TSLNC8. Overexpression of TSLNC8 restrained glioma progression by suppressing miR-10b-5p. Binding of TSLNC8 to miR-10b-5p attenuated the suppression of WWC family member 3 (WWC3) by miR-10b-5p and activated the Hippo signalling pathway. Growth of subcutaneous xenografts could be inhibited by knockdown of BACH2 or FUS, by overexpressing TSLNC8 or a combination of the three, also leading to a prolonged survival in nude mice. Our results indicate that the BACH2 and FUS/TSLNC8/miR-10b-5p/WWC3 axis is responsible for glioma development and could serve as a potential target for the development of new glioma therapies.

Accumulating evidence has highlighted the potential role of long non-coding RNAs (lncRNAs) in the biological behaviors of glioblastoma stem cells (GSCs). Here, we elucidated the function and possible molecular mechanisms of the effect of lncRNA-SOX2OT on the biological behaviors of GSCs.

Warburg effect is a hallmark of cancer cells, wherein glycolysis is preferred over oxidative phosphorylation even in aerobic conditions. Reprogramming of glycometabolism is especially crucial for malignancy in glioma. RNA-binding proteins and long noncoding RNAs are important for aerobic glycolysis during malignant transformation. Thus, we determined the expression and function of RNA-binding protein Lin28A, long noncoding RNA SNHG14, and transcription factor IRF6 in human glioma cells to elucidate the mechanism(s) underlying their role in glycolysis. Quantitative real-time polymerase chain reaction and western blotting showed that Lin28A and SNHG14 were overexpressed and IRF6 was downregulated in glioma. Depleting Lin28A from cells decreased the stability and expression of SNHG14. Furthermore, depleting SNHG14 reduced IRF6 mRNA degradation by targeting its 3' untranslated region and inhibiting STAU1-mediated degradation, thereby increasing the expression of IRF6. PKM2 is an important enzyme in aerobic glycolysis, and GLUT1 is the primary transporter that facilitates glucose uptake. IRF6 inhibited the transcription of PKM2 and GLUT1, thereby impairing glycolysis and cell proliferation and inducing apoptosis in glioma. Notably, depleting Lin28A and SNHG14 and overexpressing IRF6 reduced the growth of xenograft tumors in vivo and prolonged the survival of nude mice. Taken together, our data revealed that the Lin28A/SNHG14/IRF6 axis is crucial for reprogramming glucose metabolism and stimulating tumorigenesis in glioma cells. Thus, targeting this axis might help in the development of a novel therapeutic strategy for glioma metabolism.

Upstream ORF (uORF) is a translational initiation element located in the 5'UTR of eukaryotic mRNAs. Studies have found that uORFs play an important regulatory role in many diseases. Based on The Cancer Genome Atlas database, the results of our experiments and previous research evidence, we investigated transcription factor AP-4 (TFAP4) and its uORF, LIM and SH3 protein 1 (LASP1), long noncoding RNA 00520 (LINC00520), and microRNA (miR)-520f-3p as candidates involved in glioma malignancy, which is a poorly understood process. Both TFAP4-66aa-uORF and miR-520f-3p were downregulated, and TFAP4, LASP1, and LINC00520 were highly expressed in glioma tissues and cells. TFAP4-66aa-uORF or miR-520f-3p overexpression or TFAP4, LASP1, or LINC00520 knockdown inhibited glioma cell proliferation, migration, and invasion, but promoted apoptosis. TFAP4-66aa-uORF inhibited the translation of TFAP4 by binding to the TFAP4 mRNA. MicroRNA-520f-3p inhibited TFAP4 expression by binding to its 3'UTR. However, LINC00520 could promote the expression of TFAP4 by competitively binding to miR-520f-3p. In addition, TFAP4 transcriptionally activated LASP1 and LINC00520 expression by binding to their promoter regions, forming a positive feedback loop of TFAP4/LINC00520/miR-520f-3p. Our findings together indicated that TFAP4-66aa-uORF inhibited the TFAP4/LINC00520/miR-520f-3p feedback loop by directly inhibiting TFAP4 expression, subsequently leading to inhibition of glioma malignancy. This provides a basis for developing new therapeutic approaches for glioma treatment.

Angiogenesis plays a critical role in the progression of glioma. Previous studies have indicated that RNA-binding proteins (RBPs) interact with RNAs and participate in the regulation of the malignant behaviors of tumors. As a type of endogenous non-coding RNAs, circular RNAs (circRNAs) are abnormally expressed in various cancers and are involved in diverse tumorigeneses including angiogenesis.

Glioma is the most common primary malignancy in the brain, and vasculogenic mimicry (VM) is one of the blood supply methods. Here we investigated the possibility that lncRNAs regulate the stability of transcription factors through the SMD pathway, which affects proliferation, migration, invasion, and the ability to form VMs in glioma. Expression of PABPC5, HCG15, and ZNF331 was detected by real-time qPCR or western blot in glioma. Cell Counting Kit-8, Transwell assays, and in vitro VM tube formation were used to investigate PABPC5, HCG15, and ZNF331 function in cell proliferation, migration, invasion, and VM, respectively. ChIP assays were used to ascertain the interaction betweenZNF331 and LAMC2 or PABPC5. PABPC5 and HCG15 were highly expressed in glioma cells. ZNF331 was lowly expressed. PABPC5 bound HCG15 to increase its stability. Knockdown HCG15 reduced the degradation of ZNF331 mRNA by the SMD pathway. ZNF331 inhibited transcription through binding to the promoter region of LAMC2 and PABPC5 and inhibited the ability to form VMs in glioma cells. The PABPC5/HCG15/ZNF331 feedback loop plays an important role in regulating VM formation in glioma and provides new targets for glioma treatment.

Angiogenesis plays an important role in the progress of glioma. RNA-binding proteins (RBPs) and circular RNAs (circRNAs), dysregulated in various tumors, have been verified to mediate diverse biological behaviors including angiogenesis.

Aberrant expression of noncoding RNAs in glioma cells, including long noncoding RNAs (lncRNAs) and microRNAs, may participate in the progression of glioma. Encoded by Growth Arrest-Specific 5 (GAS5) gene, lncRNA Gas5 was reported to be a negative regulator for survival and proliferation of several cancers. Here, Gas5 is found to be downregulated in glioma specimens and U87 and U251 glioma cell lines. We showed that the introduction of Gas5 by plasmid transfection increased the expression of tumor suppressor Bcl-2-modifying factor (bmf) and Plexin C1 via directly targeting and reducing the expression of miR-222. Downregulated expression of miR-222 inhibited U87 and U251 cell proliferation and promoted the apoptosis by upregulating bmf. As downstream signaling molecules of bmf, Bcl-2 and Bax were involved in the process. Meanwhile, knockdown of miR-222 attenuated U87 and U251 cell migration and invasion by upregulating Plexin C1, and cofilin was a crucial regulator targeted by Plexin C1. Gas5 combined with the knockdown of miR-222 resulted in the smallest tumor volumes and the longest survivals of nude mice in vivo. In summary, we show that Gas5 suppresses tumor malignancy by downregulating miR-222, which may serve as a promising therapy for glioma.

Glioma is the most common intracranial neoplasm with vasculogenic mimicry formation as one form of blood supply. Many RNA-binding proteins and long non-coding RNAs are involved in tumorigenesis of glioma.

Accumulating evidence has highlighted the potential role of RNA binding proteins (RBPs) in the biological behaviors of glioblastoma cells. Herein, the expression and function of RNA binding proteins FXR1 were investigated in human glioma cells.

Glioma is the most common and lethal type of malignant brain tumor. Accumulating evidence has highlighted that RNA binding protein APOBEC1 complementation factor (A1CF) is involved in various cellular processes by modulating RNA expression, and acts as an oncogene in breast cancer. However, the function of A1CF in glioma remained unclear.

Glioma is the most common and aggressive primary adult brain tumor. Long non-coding RNAs (lncRNAs) have important roles in a variety of biological properties of cancers. Here, we elucidated the function and the possible molecular mechanisms of lncRNA HOTAIR in human glioma U87 and U251 cell lines. Quantitative RT-PCR demonstrated that HOTAIR expression was up-regulated in glioma tissues and cell lines. Knockdown of HOTAIR exerted tumor-suppressive function in glioma cells. Further, HOTAIR was confirmed to be the target of miR-326 and miR-326 mediated the tumor-suppressive effects of HOTAIR knockdown on glioma cell lines. Moreover, over-expressed miR-326 reduced the FGF1 expression which played an oncogenic role in glioma by activating PI3K/AKT and MEK 1/2 pathways. In addition, the in vivo studies also supported the above findings. Taken together, knockdown of HOTAIR up-regulated miR-326 expression, and further inducing the decreased expression of FGF1, these results provided a comprehensive analysis of HOTAIR-miR-326-FGF1 axis in human glioma and provided a new potential therapeutic strategy for glioma treatment.

Background: Traumatic brain injury (TBI) is a brain function change caused by external forces, which is one of the main causes of death and disability worldwide. The aim of this study was to identify early diagnostic markers and potential therapeutic targets for TBI. Methods: Differences between TBI and controls in GSE89866 and GSE104687 were analyzed. The two groups of differentially expressed genes (DEGs) were combined for coexpression analysis, and the modules of interest were performed using enrichment analysis. Hub genes were identified by calculating area under curve (AUC) values of module genes, PPI network analysis, and functional similarity. Finally, the difference in immune cell infiltration between TBI and control was calculated by ssGSEA. Results: A total of 4,817 DEGs were identified in GSE89866 and 1,329 DEGs in GSE104687. They were clustered into nine modules. The genes of modules 1, 4, and 7 had the most crosstalk and were identified as important modules. Enrichment analysis revealed that they were mainly associated with neurodevelopment and immune inflammation. In the PPI network constructed by genes with top 50 AUC values in module genes, we identified the top 10 genes with the greatest connectivity. Among them, down-regulated RPL27, RPS4X, RPL23A, RPS15A, and RPL7A had similar functions and were identified as hub genes. In addition, DC and Tem were significantly up-regulated and down-regulated between TBI and control, respectively. Conclusion: We found that hub genes may have a diagnostic role for TBI. Molecular dysregulation mechanisms of TBI are associated with neurological and immune inflammation. These results may provide new ideas for the diagnosis and treatment of TBI.

The presence of the blood-tumor barrier (BTB) severely impedes the transport of anti-neoplasm drugs to the central nervous system, affecting the therapeutic effects of glioma. Glioma endothelial cells (GECs) are the main structural basis of the BTB. Circular RNA is considered to be an important regulator of endothelial cell growth. In this study, we found that polypyrimidine tract binding protein 1 (PTBP1) and circRNA_001160 were remarkably upregulated in GECs. Knockdown of PTBP1 or circRNA_001160 significantly increased BTB permeability, respectively. As a molecular sponge of miR-195-5p, circRNA_001160 attenuated its negative regulation of the target gene ETV1 by adsorbing miR-195-5p. In addition, ETV1 was overexpression in GECs. ETV1 bounded to the promoter regions of tight junction-related proteins and increased the promoter activities, which significantly promoted the expression levels of tight junction-related proteins. The present study showed that the combined application of PTBP1, circRNA_001160, and miR-195-5p with the anti-tumor drug Dox effectively promoted Dox through BTB and extremely induced the apoptosis of glioma cells. Our results demonstrated that the PTBP1/circRNA_001160/miR-195-5p/ETV1 axis was critical in the regulation of BTB permeability and provided new targets for the treatment of glioma.

The blood-tumor barrier limits the delivery of therapeutic drugs to brain tumor tissues. Selectively opening the blood-tumor barrier is considered crucial for effective chemotherapy of glioma. RNA-binding proteins have emerged as crucial regulators in various biologic processes. This study found that RNA-binding Fox-1 homolog 1 (RBFOX1) was downregulated in glioma vascular endothelial cells derived from glioma tissues, and in glioma endothelial cells obtained by co-culturing endothelial cells with glioma cells. Overexpression of RBFOX1 impaired the integrity of the blood-tumor barrier and increased its permeability. Additionally, RBFOX1 overexpression decreased the expression of tight junction proteins ZO-1, occludin, and claudin-5. Subsequent analysis of the mechanism indicated that the overexpression of RBFOX1 increased musculoaponeurotic fibrosarcoma protein basic leucine zipper [bZIP] transcription factor F (MAFF) expression by downregulating LINC00673, which stabilized MAFF messenger RNA (mRNA) through Staufen1-mediated mRNA decay. Moreover, MAFF could bind to the promoter region and inhibit the promoter activities of ZO-1, occludin, and claudin-5, which reduced its expression. The combination of RBFOX1 upregulation and LINC00673 downregulation promoted doxorubicin delivery across the blood-tumor barrier, resulting in apoptosis of glioma cells. In conclusion, this study indicated that overexpression of RBFOX1 increased blood-tumor barrier permeability through the LINC00673/MAFF pathway, which might provide a new useful target for future enhancement of blood-tumor barrier permeability.