Yibo Wu's research while affiliated with Shandong University and other places

Background The infiltrative nature of human gliomas renders complete surgical removal of tumors futile. Thus, illuminating mechanisms of their infiltrative properties may improve therapies and outcomes of glioma patients. Methods Comprehensive bioinformatic analyses of PRSS family were undertaken. Transfection of HTRA1 siRNAs was used to suppress HTRA1 expression. CCK‐8, EdU, and colony formation assay were employed to assess cell viability, and cell migration/invasion was detected by transwell, wound healing, and 3D tumor spheroid invasion assays. Immunoprecipitation was applied to study the mechanism that HTRA1 affected cell migration. In addition, in situ xenograft tumor model was employed to explore the role of HTRA1 in glioma growth in vivo. Results HTRA1 knockdown could lead to suppression of cell viability, migration and invasion, as well as increased apoptosis. Immunoprecipitation results indicates HTRA1 might facilitate combination between HDAC6 and α‐tubulin to enhance cell migration by decreasing α‐tubulin acetylation. Besides, HTRA1 knockdown inhibited the growth of xenografts derived from orthotopic implantation of GBM cells and prolonged the survival time of tumor‐bearing mice. Conclusion Our results indicate that HTRA1 promotes the proliferation and migration of GBM cells in vitro and in vivo, and thus may be a potential target for treatment in gliomas.

Background Altered branched-chain amino acid (BCAA) metabolism modulates epigenetic modification, such as H3K27ac in cancer, thus providing a link between metabolic reprogramming and epigenetic change, which are prominent hallmarks of glioblastoma multiforme (GBM). Here, we identified mitochondrial 3-hydroxymethyl-3-methylglutaryl-CoA lyase (HMGCL), an enzyme involved in leucine degradation, promoting GBM progression and glioma stem cell (GSC) maintenance. Methods In silico analysis was performed to identify specific molecules involved in multiple processes. Glioblastoma multiforme cells were infected with knockdown/overexpression lentiviral constructs of HMGCL to assess malignant performance in vitro and in an orthotopic xenograft model. RNA sequencing was used to identify potential downstream molecular targets. Results HMGCL, as a gene, increased in GBM and was associated with poor survival in patients. Knockdown of HMGCL suppressed proliferation and invasion in vitro and in vivo. Acetyl-CoA was decreased with HMGCL knockdown, which led to reduced NFAT1 nuclear accumulation and H3K27ac level. RNA sequencing-based transcriptomic profiling revealed FOXM1 as a candidate downstream target, and HMGCL-mediated H3K27ac modification in the FOXM1 promoter induced transcription of the gene. Loss of FOXM1 protein with HMGCL knockdown led to decreased nuclear translocation and thus activity of β-catenin, a known oncogene. Finally, JIB-04, a small molecule confirmed to bind to HMGCL, suppressed GBM tumorigenesis in vitro and in vivo. Conclusions Changes in acetyl-CoA levels induced by HMGCL altered H3K27ac modification, which triggers transcription of FOXM1 and β-catenin nuclear translocation. Targeting HMGCL by JIB-04 inhibited tumor growth, indicating that mediators of BCAA metabolism may serve as molecular targets for effective GBM treatment.

Background Small peptides encoded by long non-coding RNAs (lncRNAs) have attracted attention for their various functions. Recent studies indicate that these small peptides participate in immune responses and antigen presentation. However, the significance of RNA modifications remains unclear. Methods Thirteen non-m6A-related neoantigen-coding lncRNAs were selected for analysis from the TransLnc database. Next, a neoantigen activation score (NAS) model was established based on the characteristics of the lncRNAs. Machine learning was employed to expand the model to two additional RNA-seq and two single-cell sequencing datasets for further validation. The DLpTCR algorithm was used to predict T cell receptor (TCR)-peptide binding probability. Results The non-m6A-related NAS model predicted patients’ overall survival outcomes more precisely than the m6A-related NAS model. Furthermore, the non-m6A-related NAS was positively correlated with tumor cells’ evolutionary level, immune infiltration, and antigen presentation. However, high NAS gliomas also showed more PD-L1 expression and high mutation frequencies of T-cell positive regulators. Interestingly, results of intercellular communication analysis suggest that T cell-high neoplastic cell interaction is weaker in both of the NAS groups which might arise from decreased IFNGR1 expression. Moreover, we identified unique TCR-peptide pairs present in all glioma samples based on peptides encoded by the 13 selected lncRNAs. And increased levels of neoantigen-active TCR patterns were found in high NAS gliomas. Conclusions Our work suggests that non-m6A-related neoantigen-coding lncRNAs play an essential role in glioma progression and that screened TCR clonotypes might provide potential avenues for chimeric antigen receptor T cell (CAR-T) therapy for gliomas.