Background Increasing studies have revealed that circular RNAs (CircRNAs) make great contributions to regulating tumor progression. Therefore, we intended to explore the expression characteristics, function, and related mechanisms of a novel type of circRNA, PIP5K1A, in glioma. Methods Firstly, reverse transcription-polymerase chain reaction (RT-PCR) was carried out to examine CircPIP5K1A expression in glioma tissues and adjacent normal tissues, and the correlation between CircPIP5K1A level and the clinical-pathological indicators of glioma was analyzed. Then, the CircPIP5K1A expression in various glioma cell lines was detected, and CircPIP5K1A overexpression and knockdown cell models were constructed. Subsequently, cell proliferation and viability were detected by the CCK8 method and BrdU staining. Cell apoptosis was detected by flow cytometry, and cell invasion was examined by Transwell assay. The expression of TCF12, PI3K/AKT pathway apoptotic related proteins (Caspase3, Bax, and Bcl2) and epithelial-mesenchymal transition (EMT) markers (E-cadherin, Vimentin, and N-cadherin) was determined by western blot or RT-PCR. Results The results manifested that CircPIP5K1A was upregulated in glioma tissues (compared with that in normal adjacent tissues), and overexpressed CircPIP5K1A was related to glioma volume and histopathological grade. Functionally, overexpressing CircPIP5K1A notably elevated glioma cell proliferation, invasion, and EMT and inhibited apoptosis both in vivo and in vitro. Besides, CircPIP5K1A upregulated TCF12 and PI3K/AKT activation. Bioinformatics analysis testified that miR-515-5p was a common target of CircPIP5K1A and TCF12, while the dual-luciferase reporter assay and RNA immunoprecipitation (RIP) experiment further confirmed that CircPIP5K1A targeted miR-515-5p, which bound the 3′-untranslated region (UTR) of TCF12. Conclusions Overall, the study illustrated that CircPIP5K1A is a potential prognostic marker in glioma and regulates glioma evolvement by modulating the miR-515-5p-mediated TCF12/PI3K/AKT axis.
This research systematically profiled the global N6‐methyladenosine modification pattern of circular RNAs (circRNAs) in glioblastoma (GBM). Based on RNA methylation sequencing (MeRIP sequencing or N6‐methyladenosine sequencing) and RNA sequencing, we described the N6‐methyladenosine modification status and gene expression of circRNAs in GBM and normal brain tissues. N6‐methyladenosine–related circRNAs were immunoprecipitated and validated by real‐time quantitative PCR. Bioinformatics analysis and related screening were carried out. Compared with those of the NC group, the circRNAs from GBM exhibited 1370 new N6‐methyladenosine peaks and 1322 missing N6‐methyladenosine peaks. Among the loci associated with altered N6‐methyladenosine peaks, 1298 were up‐regulated and 1905 were down‐regulated. The N6‐methyladenosine level tended to be positively correlated with circRNA expression. Bioinformatics analysis was used to predict the biological function of N6‐methyladenosine–modified circRNAs and the corresponding signalling pathways. In addition, through PCR validation combined with clinical data mining, we identified five molecules of interest (BUB1, C1S, DTHD1, F13A1 and NDC80) that could be initial candidates for further study of the function and mechanism of N6‐methyladenosine–mediated GBM development. In conclusion, our findings demonstrated the N6‐methyladenosine modification pattern of circRNAs in human GBM, revealing the possible roles of N6‐methyladenosine–mediated novel noncoding RNAs in the origin and progression of GBM.
N6-methyladenosine (m6A) plays crucial roles in a diverse range of physiological and pathological processes, and it is believed that it tremendously promotes neoplasia and progression. However, knowledge of the molecular characteristics of m6A modification, its prognostic value, and the infiltration of immune cell populations in head and neck squamous cell carcinoma (HNSCC) is still insufficient. Therefore, a pan-cancer genomic analysis was systematically performed here by examining m6A regulators at the molecular level within 33 multiple cancer types, and the correlations between the expression of m6A molecules were researched using datasets from The Cancer Genome Atlas (TCGA). Based on the above analysis, insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) is upregulated in HNSCC and may serve as an independent prognostic factor of overall survival, thus showing potential as a prognostic biomarker in HNSCC. Genetic alteration analyses elucidated the reasons for the abnormal upregulation of IGF2BP2 in HNSCC. As a result, IGF2BP2 was selected for further univariate and multivariate analyses. The functions of the related genes were annotated through gene set enrichment analysis, and the activation states of multiple biological pathways were shown by gene set variation analysis. We found that LRRC59 and STIP1 may act as IGF2BP2-associated genes to have a regulatory function in the m6A modification. In addition, we found that the status of immune cell infiltration was correlated with the level of IGF2BP2 gene expression. Our results provide supplementation at the molecular level for epigenetic regulation in HNSCC and insight into effective immunotherapy targets and strategies.
As the most common primary tumour of the central nervous system, gliomas have a high recurrence rate after surgical resection and are resistant to chemotherapy, particularly high-grade gliomas dominated by glioblastoma multiforme (GBM). The prognosis of GBM remains poor despite improvements in treatment modalities, posing a serious threat to human health. At present, although drugs such as temozolomide, cisplatin and bevacizumab, are effective in improving the overall survival of patients with GBM, most patients eventually develop drug resistance, leading to poor clinical prognosis. The development of multidrug resistance has therefore become a major obstacle to improving the effectiveness of chemotherapy for GBM. The ability to fully understand the underlying mechanisms of chemotherapy resistance and to develop novel therapeutic targets to overcome resistance is critical to improving the prognosis of patients with GBM. Of note, growing evidence indicates that a large number of abnormally expressed noncoding RNAs (ncRNAs) have a central role in glioma chemoresistance and may target various mechanisms to modulate chemosensitivity. In the present review, the roles and molecular mechanisms of ncRNAs in glioma drug resistance were systematically summarized, the potential of ncRNAs as drug resistance markers and novel therapeutic targets of glioma were discussed and prospects for glioma treatment were outlined. ncRNAs are a research direction for tumor drug resistance mechanisms and targeted therapies, which not only provides novel perspectives for reversing glioma drug resistance but may also promote the development of precision medicine for clinical diagnosis and treatment.
Exosome-mediated delivery of circular RNAs (circRNAs) is implicated in cancer progression. However, the role of exosomal circRNAs in the chemotherapy resistance of tumours remains poorly understood. Here we identified a novel circRNA, circWDR62. It was found that circWDR62 expression was upregulated in TMZ-resistant glioma cells and TMZ-resistant glioma cell-derived exosomes compared with their controls by using high-throughput microarray analysis and quantitative real-time polymerase chain reaction, and high circWDR62 expression was associated with poor prognosis of glioma. Functionally, downregulation of circWDR62 expression could significantly inhibit the TMZ resistance and malignant progression of glioma. Further mechanistic studies showed that circWDR62 plays a role by sponging miR-370-3p as a competing endogenous RNA. Rescue experiments confirmed that MGMT is the downstream target of the circWDR62/miR-370-3p axis in glioma. In addition, circWDR62 could be transported between TMZ-resistant and TMZ-sensitive glioma cells via exosomes. Exosomal circWDR62 from TMZ-resistant cells conferred TMZ resistance in recipient sensitive cells while also enhancing the proliferation, migration and invasion of these cells. A series of clinical and in vivo trials corroborated that exosomal circWDR62 could promote TMZ chemoresistance and malignant progression of glioma. Our results demonstrate for the first time that exosome-mediated delivery of circWDR62 can promote TMZ resistance and malignant progression via targeting of the miR-370-3p/MGMT axis in vitro and in vivo in glioma, providing a new therapeutic strategy. Moreover, exosomal circWDR62 in human serum may serve as a promising therapeutic target and prognostic marker for glioma therapy.
BackgroundIncreasing studies have revealed that circular RNAs (CircRNAs) make great contribution to regulating tumor progression. Therefore, we intended to explore the expression characteristics, function, and related mechanisms of a novel type of circRNA, PIP5K1A in glioma. MethodsFirstly, RT-PCR was carried out to examine CircPIP5K1A expression in glioma tissues and adjacent normal tissues, and the correlation between CircPIP5K1A level and the clinical pathological indicators of glioma was analyzed. Then, the CircPIP5K1A expression in various glioma cell lines was detected, and a cell model of CircPIP5K1A overexpression and knockdown was constructed. Subsequently, cell proliferation and viability were detected by CCK8 method and BrdU staining, apoptosis was detected by flow cytometry, and cell invasion was examined by Transwell assay. The expression of TCF12, PI3K/AKT pathway apoptotic related proteins (including Caspase3, Bax and Bcl2) and epithelial-mesenchymal transition (EMT) markers (including E-cadherin, Vimentin and N-cadherin) by western blot or RT-PCR. ResultsThe results manifested that CircPIP5K1A was obviously upregulated in glioma tissues (compared with that in normal adjacent tissues), and overexpressed CircPIP5K1A was distinctly related to glioma volume and histopathological grade. Functionally, overexpressing CircPIP5K1A notably elevated the proliferation, invasion, EMT of glioma cells, and inhibited apoptosis both in vivo and in vitro. Besides, CircPIP5K1A also upregulated TCF12 and PI3K/AKT pathway activation. Bioinformatics analysis testified that miR-515-5p was a common target of CircPIP5K1A and TCF12, while dual luciferase reporter assay and RNA immunocoprecipitation (RIP) experiment further confirmed that CircPIP5K1A targeted miR-515-5p, which bound the 3'-untranslated region (UTR) of TCF12. ConclusionsAltogether, the study illustrated that CircPIP5K1A is a potential prognostic marker in glioma and regulates the development of glioma through the modulating miR-515-5p mediated TCF12/PI3K/AKT axis.
Since the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its resultant pneumonia in December 2019, the cumulative number of infected people worldwide has exceeded 670 million, with over 6.8 million deaths. Despite the marketing of multiple series of vaccines and the implementation of strict prevention and control measures in many countries, the spread and prevalence of SARS-CoV-2 have not been completely and effectively controlled. The latest research shows that in addition to angiotensin converting enzyme II (ACE2), dozens of protein molecules, including AXL, can act as host receptors for SARS-CoV-2 infecting human cells, and virus mutation and immune evasion never seem to stop. To sum up, this review summarizes and organizes the latest relevant literature, comprehensively reviews the genome characteristics of SARS-CoV-2 as well as receptor-based pathogenesis (including ACE2 and other new receptors), mutation and immune evasion, vaccine development and other aspects, and proposes a series of prevention and treatment opinions. It is expected to provide a theoretical basis for an in-depth understanding of the pathogenic mechanism of SARS-CoV-2 along with a research basis and new ideas for the diagnosis and classification, of COVID-19-related disease and for drug and vaccine research and development.
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