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Abstract Background Circular RNAs (circRNAs) play important roles in cancer progression and metabolism regulation. Serine/glycine metabolism supports the growth of cancer cells by contributing to their anabolic demands and epigenome as well as by regulating their redox state. However, the role of circRNA in the regulation of serine/glycine metabolism has not been well elucidated. Methods Microarray analysis was used to screen differentially expressed novel circRNAs. qRT-PCR and FISH were utilized to analyzed the expression of circMYH9. CCK8, colony formation and FACS were used to analyze proliferation of colorectal cancer (CRC) cells. Xenograft experiments were used to analyze tumor growth in vivo. RNA-sequencing, immunoblot and LC–MS were used to identify the downstream metabolic pathway of circMYH9. ChIRP, Mass Spectrometry, RIP and RNA pulldown were utilized to test the interaction between circMYH9, hnRNPA2B1 and p53 pre-mRNA. ChIP-qPCR was used to analyze the binding sites of HIF-1α. Chemically-induced CRC mice were generated to evaluate the role of circMYH9 in tumorigenesis. Results We identified an intron-derived circRNA, circMYH9, which was significantly upregulated in CRC tissues. A higher circMYH9 level correlated with shorter relapse-free survival and overall survival of CRC patients. CircMYH9 promoted serine/glycine metabolism, the NAD + /NADH ratio, and glutathione recycling and inhibited reactive oxygen species (ROS) in a p53-dependent manner, impacting tumour growth. Mechanistically, circMYH9 destabilized the pre-mRNA of p53 by recruiting hnRNPA2B1 in the nucleus. hnRNPA2B1 bound to N6-methyladenosine sites on the 3' untranslated region of p53 pre-mRNA and maintained its stability. Moreover, a lack of amino acids led to an elevated level of ROS, resulting in increased HIF1α, which promoted circMYH9 expression by binding to the promoter region. Furthermore, in vivo AAV9-mediated transfection of circMYH9 could drive chemically-induced carcinogenesis by suppressing p53 in mice. Conclusions The overexpression of circMYH9 promotes CRC proliferation though modulating serine/glycine metabolism and redox homeostasis in a p53-dependent manner, and targeting circMYH9 and its pathway may be an effective strategy for the treatment of CRC.

Abstract AS (alternative splicing) is a fundamental process by which a gene can generate multiple distinct mRNA transcripts to increase protein diversity. Defects in AS influence the occurrence and development of many diseases, including cancers, and are frequently found to participate in various aspects of cancer biology, such as promoting invasion, metastasis, apoptosis resistance and drug resistance. NcRNAs (noncoding RNAs) are an abundant class of RNAs that do not encode proteins. NcRNAs include miRNAs (microRNAs), lncRNAs (long noncoding RNAs), circRNAs (circular RNAs) and snRNAs (small nuclear RNAs) and have been proven to act as regulatory molecules that mediate cancer processes through AS. NcRNAs can directly or indirectly influence a plethora of molecular targets to regulate cis-acting elements, trans-acting factors, or pre-mRNA transcription at multiple levels, affecting the AS process and generating alternatively spliced isoforms. Consequently, ncRNA-mediated AS outcomes affect multiple cellular signaling pathways that promote or suppress cancer progression. In this review, we summarize the current mechanisms by which ncRNAs regulate AS in cancers and discuss their potential clinical applications as biomarkers and therapeutic targets.

BackgroundIndividual immune-related alternative splicing (AS) events have been found to be significant in immune regulation and cancer prognosis. However, a comprehensive analysis of AS events in cancer cells based on immune-related genes (IRGs) has not been performed, and its clinical value is unknown.MethodsColon cancer cases with AS data were obtained from TCGA, and then, we identified overall survival-related AS events (OS-ASEs) based on IRGs by univariate analyses. Using Lasso regression, multivariate Cox regression, Kaplan–Meier analysis and nomograms, we constructed an AS risk model based on the calculated risk score. Furthermore, associations of the risk score with clinical and immune features were confirmed through the Wilcoxon rank sum test, association analysis, etc. Finally, by qRT–PCR, cell coculture and CCK-8 analyses, we validated the significance of OS-ASEs in colon cancer cell lines and clinical samples.ResultsA total of 3,119 immune-related AS events and 183 OS-ASEs were identified, and 9 OS-ASEs were ultimately used to construct a comprehensive risk model for colon cancer patients. Low-risk patients had better OS and DFS rates than high risk patients. Furthermore, a high risk score corresponded to high numbers of multiple tumour-infiltrating immune cells and high expression of HLA-D region genes and immune checkpoint genes. Notably, we identified for the first time that anti-PD-L1 or anti-CTLA-4 antibodies may decrease the OS of specific colon cancer patients in the low-risk group. Additionally, the in vitro experiment validated that CD46-9652-ES and PSMC5-43011-ES are positively correlated with the infiltration of immune cells and promote the growth of colon cancer cells. CD46-9652-ES can contribute to T cell-mediated tumour cell killing. PSMC5-43011-ES was observed to induce M2 polarization of macrophages.ConclusionsThis study identified and validated immune-related prognostic AS signatures that can be used as a novel AS prognostic model and provide a novel understanding of the relationship between the immune microenvironment and clinical outcomes.

Addressed to serious heat degradation problem of the braking continuously performed in the drag brake application for a long time, finite element analysis for bidirectional thermal-structure coupling is adopted to investigate temperature and stress when material properties are temperature-dependent. Based on the constitutive relations of heat transfer and strain-stress, 3-D transient finite element equilibrium equations with many kinds of boundary conditions for bidirectional thermal- structure coupling were derived. It was originally presented that start time, location, severity, and evolution laws of plastic deformation were depicted using dimensionless stress distribution contour with the yield limit related to temperature. The change laws of plastic element number and contact area vs. braking time were expressed by plasticity ratio and contact ratio curves, respectively. The laws revealed by the numerical calculation results are in accordance with the objective perception and reasoning. [ABSTRACT FROM AUTHOR]

This paper deals with thermal-plastic analysis for the metal honeycomb structure. The heat transfer equation and thermal elastoplastic constitutive equation of a multilayer panel are established and studied numerically using ANSYS software. The paper elucidates that only the outer skin produces easily plastic deformation, and the outer skin still exists some residual stress and residual deformation after cooling. The dynamic evolution of plastic deformation and material performance degradation under high energy thermal load are revealed. [ABSTRACT FROM AUTHOR]