Circ ubiquitin-like-containing plant homeodomain and RING finger domains protein 1 increases the stability of G9a and ubiquitin-like-containing plant homeodomain and RING finger domains protein 1 messenger RNA through recruiting eukaryotic translation initiation factor 4A3, transcriptionally inhibiting PDZ and homeobox protein domain protein 1, and promotes the metastasis of hepatocellular carcinoma.

BACKGROUND AND AIM: Circular ubiquitin-like, containing PHD and ring finger domains 1 (circUHRF1) is aberrantly upregulated in human hepatocellular carcinoma (HCC) tissues. However, the underlying molecular mechanisms remain obscure. The present study aimed at elucidating the interactive function of circUHRF1-G9a-ubiquitin-like, containing PHD and ring finger domains 1 (UHRF1) mRNA-eukaryotic translation initiation factor 4A3 (EIF4A3)-PDZ and LIM domain 1 (PDLIM1) network in HCC. METHODS: Expression of circUHRF1, mRNAs of G9a, UHRF1, PDLIM1, epithelial-mesenchymal transition (EMT)-related proteins, and Hippo-Yap pathway components was determined by quantitative polymerase chain reaction (Q-PCR), immunofluorescence, or Western blot analysis. Tumorigenic and metastatic capacities of HCC cells were examined by cellular assays including Cell Counting Kit-8, colony formation, wound healing, and transwell assays. Molecular interactions between EIF4A3 and UHRF1 mRNA were detected by RNA pull-down experiment. Complex formation between UHRF1 and PDLIM1 promoter was detected by chromatin immunoprecipitation assay. Co-immunoprecipitation was performed to examine the binding between UHRF1 and G9a. RESULTS: Circular ubiquitin-like, containing PHD and ring finger domains 1, G9a, and UHRF1 were upregulated, while PDLIM1 was downregulated in HCC tissue samples and cell lines. Cellular silencing of circUHRF1 repressed HCC proliferation, invasion, migration, and EMT. G9a formed a complex with UHRF1 and inhibited PDLIM1 transcription. CONCLUSION: Eukaryotic translation initiation factor 4A3 regulated circUHRF1 expression by binding to UHRF1 mRNA promoter. circUHRF1 increased the stability of G9a and UHRF1 mRNAs through recruiting EIF4A3. Overexpression of circUHRF1 aggravated HCC progression through Hippo-Yap pathway and PDLIM1 inhibition. By elucidating the molecular function of circUHRF1-G9a-UHRF1 mRNA-EIF4A3-PDLIM1 network, our data shed light on the HCC pathogenesis and suggest a novel therapeutic strategy for future HCC treatment.

Pan-Cancer Analysis of the Cuproptosis-Related Gene DLD.

Background: Cancer affects millions of people each year and imposes a huge economic and social burden worldwide. Cuproptosis is a recently discovered novel mode of cell death. The exact function of the cuproptosis-related gene dihydrolipoamide dehydrogenase (DLD) and its role in pan-cancer is unknown. Methods: Data were retrieved from the GTEx, TCGA, and multiple online websites. These data were used to assess the expression, prognosis, and diagnostic value of DLD in various tumors. The relationship of DLD with immune microenvironment immunomodulators, immune checkpoints, tumor mutational load (TMB), microsatellite instability (MSI), and oncology drug sensitivity was explored by correlation analysis. Results: The mRNA and protein expression of DLD differs in most cancers. Survival analysis showed that DLD was associated with prognosis with KIRC, KIRP, KICH, and UCS. DLD had a strong diagnostic value in KIRC, GBM, PAAD, and LGG (AUC > 0.9). DLD promoter methylation affects the aberrant expression of LIHC, LUSC, PAAD, READ, and THCA. DLD was negatively correlated with stromal score, immune score, and ESTIMATE score in UCEC, TGCT, LUSC, and SARC. In UCS, resting memory CD4 T cells and activated NK cells were significantly correlated with DLD expression. Significant correlations were also observed between DLD expression and immunomodulators, immune checkpoints, TMB, and MSI in various cancers. Importantly, we also identified a number of potential drugs that may target DLD. Conclusion: DLD expression is associated with a variety of tumor prognoses and plays an integral role in tumorigenesis, tumor metabolism, and immunity.

Nuclear Membrane Protein SUN5 Is Highly Expressed and Promotes Proliferation and Migration in Colorectal Cancer by Regulating the ERK Pathway.

SUN5 was first identified as a nuclear envelope protein involved in spermatocyte division. We found that SUN5 was highly expressed in some cancers, but its function and mechanism in cancer development remain unclear. In the present study, we demonstrated that SUN5 was highly expressed in colorectal cancer (CRC) tissues and cells, as indicated by bioinformatics analysis, and SUN5 promoted cell proliferation and migration in vitro. Moreover, the overexpression of SUN5 upregulated phosphorylated ERK1/2 (pERK1/2), whereas the knockdown of SUN5 yielded the opposite results. PD0325901 decreased the level of pERK1/2 to inhibit cell proliferation and migration, which was partially reversed by SUN5 overexpression, indicating that drug resistance existed in patients with high SUN5 expression. The xenograft transplantation experiment showed that SUN5 accelerated tumor formation in vivo. Furthermore, we found that SUN5 regulated the ERK pathway via Nesprin2 mediation and promoted the nuclear translocation of pERK1/2 by interacting with Nup93. Thus, these findings indicated that highly expressed SUN5 promoted CRC proliferation and migration by regulating the ERK pathway, which may contribute to the clinical diagnosis and new treatment strategies for CRC.

N1-methyladenosine methylation-related metabolic genes signature and subtypes for predicting prognosis and immune microenvironment in osteosarcoma.

N1-methyladenosine methylation (m1A), as an important RNA methylation modification, regulates the development of many tumours. Metabolic reprogramming is one of the important features of tumour cells, and it plays a crucial role in tumour development and metastasis. The role of RNA methylation and metabolic reprogramming in osteosarcoma has been widely reported. However, the potential roles and mechanisms of m1A-related metabolic genes (MRmetabolism) in osteosarcoma have not been currently described. All of MRmetabolism were screened, then selected two MRmetabolism by least absolute shrinkage and selection operator and multifactorial regression analysis to construct a prognostic signature. Patients were divided into high-risk and low-risk groups based on the median riskscore of all patients. After randomizing patients into train and test cohorts, the reliability of the prognostic signature was validated in the whole, train and test cohort, respectively. Subsequently, based on the expression profiles of the two MRmetabolism, we performed consensus clustering to classify patients into two clusters. In addition, we explored the immune infiltration status of different risk groups and different clusters by CIBERSORT and single sample gene set enrichment analysis. Also, to better guide individualized treatment, we analyzed the immune checkpoint expression differences and drug sensitivity in the different risk groups and clusters. In conclusion, we constructed a MRmetabolism prognostic signature, which may help to assess patient prognosis, immunotherapy response.

Prediction of Prognosis and Immunotherapy of Osteosarcoma Based on Necroptosis-Related lncRNAs.

Background: Osteosarcoma (OS) is the most common primary tumor of bone in adolescents, and its survival rate is generally less than 20% when metastases occur. Necroptosis, a novel form of programmed necrotic cell death distinct from apoptosis, has been increasingly recognized as a promising therapeutic strategy. This study sought to identify long non-coding RNAs (lncRNAs) associated with necrotizing apoptosis to predict prognosis and target drug use to improve patient survival. Methods: Transcriptomic data and clinical data from 85 OS patients with survival time data and expression profiles from 85 random normal adipose tissue samples were extracted from the UCSC Xena website (http://xena.ucsc.edu/). Nine necroptosis-associated differential prognostic lncRNAs were then identified by analysis of variance, correlation analysis, univariate Cox (uni-Cox) regression, and Kaplan-Meier analysis. Then, patients were randomized into training or testing groups. According to uni-Cox, we obtained prognostic lncRNAs in the training group and intersected them with the abovementioned nine lncRNAs to obtain the final necrotizing apoptosis-related differential prognostic lncRNAs (NRlncRNAs). Next, we performed the least absolute shrinkage and selection operator (LASSO) to construct a risk model of NRlncRNAs. Kaplan-Meier analysis, ROC curves, nomograms, calibration curves, and PCA were used to validate and evaluate the models and grouping. We also analyzed the differences in tumor immunity and drugs between risk groups. Results: We constructed a model containing three NRlncRNAs (AL391121.1, AL354919.2, and AP000851.2) and validated its prognostic predictive power. The value of the AUC curve of 1-, 3-, and 5-year survival probability was 0.806, 0.728, and 0.731, respectively. Moreover, we found that the overall survival time of patients in the high-risk group was shorter than that in the low-risk group. GSEA and ssGSEA showed that immune-related pathways were mainly abundant in the low-risk group. We also validated the differential prediction of immune checkpoint expression, tumor immunity, and therapeutic compounds in the two risk groups. Conclusion: Overall, NRlncRNAs have important functions in OS, and these three NRlncRNAs can predict the prognosis of OS and provide guidance for immunotherapy in OS.

A Targeted Erythrocyte Membrane-Encapsulated Drug-Delivery System with Anti-osteosarcoma and Anti-osteolytic Effects.

Chemotherapy is one of the main treatment methods for osteosarcoma. However, conventional chemotherapy lacks targeting properties, and its long-term and extensive use will have serious side effects on patients. For this reason, a multifunctional nanodrug system (V-RZCD) targeting osteosarcoma was developed in this study. V-RZCD consists of two parts: (1) the core (ZCD), wherein calcium ions (Ca2+) and zoledronic acid (ZA) form a metal-organic framework for loading doxorubicin (DOX), and (2) the shell (V-R), a vascular endothelial growth factor (VEGF) ligand-modified red blood cell membrane nanovesicle. By targeting the VEGF, V-RZCD can specifically bind to the VEGF receptors that are highly expressed on the surface of osteosarcoma cells. Importantly, compared with free ZA and DOX, V-RZCD not only clearly inhibits the proliferation of osteosarcoma but also significantly inhibits osteolysis induced by osteosarcoma. In summary, V-RZCD represents a new way to treat osteosarcoma.