OMA1 competitively binds to HSPA9 to promote mitophagy and activate the cGAS-STING pathway to mediate GBM immune escape.

BACKGROUND: Immunotherapy with checkpoint inhibitors, especially those targeting programmed death receptor 1 (PD-1)/PD-1 ligand (PD-L1), is increasingly recognized as a highly promising therapeutic modality for malignancies. Nevertheless, the efficiency of immune checkpoint blockade therapy in treating glioblastoma (GBM) is constrained. Hence, it is imperative to expand our comprehension of the molecular mechanisms behind GBM immune escape (IE). METHODS: Protein chip analysis was performed to screen aberrantly expressed OMA1 protein in PD-1 inhibitor sensitive or resistant GBM. Herein, public databases and bioinformatics analysis were employed to investigate the OMA1 and PD-L1 relation. Then, this predicted relation was verified in primary GBM cell lines through distinct experimental methods. To investigate the molecular mechanism behind OMA1 in immunosuppression, a series of experimental methods were employed, including Western blotting, co-immunoprecipitation (Co-IP), mass spectrometry (MS), immunofluorescence, immunohistochemistry, and qRT-PCR. RESULTS: Our findings revealed that OMA1 competitively binds to HSPA9 to induce mitophagy and mediates the IE of GBM. Data from TCGA indicated a significant correlation between OMA1 and immunosuppression. OMA1 promoted PD-L1 levels in primary cells from patients with GBM. Next, the results of Co-IP and MS conducted on GBM primary cells revealed that OMA1 interacts with HSPA9 and induces mitophagy. OMA1 promoted not only cGAS-STING activity by increasing mitochondrial DNA release but also PD-L1 transcription by activating cGAS-STING. Eventually, OMA1 has been found to induce immune evasion in GBM through its regulation of PD-1 binding and PD-L1 mediated T cell cytotoxicity. CONCLUSIONS: The OMA1/HSPA9/cGAS/PD-L1 axis is elucidated in our study as a newly identified immune therapeutic target in GBM.

TRIB3 Interacts with STAT3 to Promote Cancer Angiogenesis.

OBJECTIVE: Vascular endothelial growth factor A (VEGFA) is a key regulator of angiogenesis, which is a hallmark of cancer that promotes cancer growth and metastasis. It is of great significance to find new intervention targets and related regulatory mechanisms of VEGFA related angiogenesis for the treatment of tumors. This study focuses on the role of tribbles pseudokinase 3 (TRIB3)/signal transducer and activator of transcription 3 (STAT3)/VEGFA signaling axis in colon cancer angiogenesis. METHODS: This study investigated the expression level of TRIB3 in colon cancer through database analysis and tissue microarray analysis. The effect of TRIB3 on proliferation, migration and tube formation ability of human umbilical vein endothelial cells (HUVECs) was further confirmed by CCK8 assay, scratch-wound assay/migration assay and tube formation assay respectively. The regulatory relationship of TRIB3/VEGFA signaling axis was identified by qPCR and Western blotting, which was further confirmed through animal experiments, and the specific regulatory mechanism was explored by immunoprecipitation (IP) and chromatin immunoprecipitation (ChIP) with colon cancer cell lines. RESULTS: TRIB3 was increased in colon cancer tissues compared to normal tissues, and elevated TRIB3 expression indicated a poor prognosis in colon cancer patients. Moreover, it was found that silencing TRIB3 could inhibit cancer angiogenesis, whereas overexpressing TRIB3 promoted cancer angiogenesis in vitro and in vivo. Mechanistically, TRIB3 physically interacted with STAT3 and enhanced STAT3-mediated transcriptional activity. Furthermore, the function of TRIB3 in cancer angiogenesis was through cooperating with STAT3 to increase the VEGFA expression. CONCLUSION: Our study provides insights into cancer angiogenesis and offers a potential therapeutic strategy for TRIB3-overexpressed cancer.