Cuijuan Duan

Elevated Golgi phosphoprotein 2 (GP73, also known as GOLPH2 or GOLM1) expression in serum and liver, which can be induced by viral infection and cytokine treatments, is intimately connected with liver disease, including acute hepatitis, cirrhosis and hepatocellular carcinoma (HCC). However, its pathogenic roles in hepatic diseases have never been clarified in detail. Here, we showed that the upregulated GP73 is indispensable for SREBPs activation and lipogenesis. Notably, GP73 overexpression enhanced SCAP-SREBPs binding and its Golgi trafficking even under cholesterol sufficiency. Consistent with these functional findings, GP73 blockage could alleviate tunicamycin-induced liver steatosis by reducing SREBPs activation. A significant positive correlation of GP73 with genes in lipid metabolism pathway was also identified in liver cancer based on data from The Cancer Genome Atlas (TCGA) dataset. Our findings revealed previously unrecognized role of GP73 in lipid metabolism.

BACKGROUND: Immunotherapy that targets immune checkpoints has achieved revolutionary success, but its application in solid tumors remains limited, highlighting the need for reliable enhancement of the efficacy of immunotherapy. Golgi protein 73 (GP73), a Golgi membrane protein, has been implicated in various cellular processes, including immune regulation. Recent studies suggested that GP73 may play a role in modulating the immune response in patients with cancer. In this study, we investigated the mechanism by which GP73 regulates T-cell-mediated antitumor immunity within the tumor microenvironment. METHODS: We used T-cell specific GP73 knockout mice to establish MC38 and B16 tumor models to investigate the impact of GP73-deficient T cells on tumor growth. Single-cell sequencing was subsequently employed to classify tumor-infiltrating immune cells and assess changes in cytokines and metabolic genes. Through RNA sequencing, real-time quantitative PCR, western blotting, flow cytometry, seahorse analysis, glucose uptake, and L-lactic acid secretion assays, we explored how GP73 regulates hypoxia-inducible factor 1α (HIF-1α) to influence T-cell antitumor functionality. Furthermore, we established adoptive transfer experiments to study the ability of GP73-overexpressing T cells to combat tumors. Blood samples of patient with clinical tumor were collected to assess the relationship between immunotherapy efficacy and T-cell GP73 levels. RESULTS: In this study, the absence of GP73 in mouse T cells promoted tumor growth and metastasis, accompanied by a decrease in the proportion of cytotoxic CD8+T cell subsets infiltrating the tumor and an increase in exhausted CD8+ T-cell subsets. Further analysis revealed that the effector function of CD8+T cells in tumors relies on glycolysis regulated by HIF-1α rather than immune checkpoints. GP73-deficient T cells exhibit severely impaired glycolysis in hypoxic environments, whereas ectopic GP73 expression restores HIF-1α levels. In adoptive immunotherapy, overexpression of GP73 in T cells inhibits tumor growth. In cytotoxicity assays, knockdown of GP73 affected the ability of CD8+T cells to kill target cells. Clinically, tumor immunotherapy partial response patients present significantly elevated levels of GP73 expression in T cells. CONCLUSIONS: These findings reveal the role of GP73 in regulating T-cell glycolysis and may lead to new therapeutic strategies for the prognosis and treatment of clinical tumor immunotherapy.

BACKGROUND: Retinoblastoma (RB) is a common intraocular malignant tumor in infants and young children. However, reports on the morphological descriptions of RB tumor cells from native and foreign scholars are rare. OBJECTIVES: To investigate the myelogram characteristics of RB with extraocular tumor extension and the morphological characteristics of tumor cells in the bone marrow and cerebrospinal fluid. METHODS: For the period from May 2011 to February 2015, we analyzed clinical data on 18 patients in our hospital diagnosed as having metastatic RB in the extraocular and other distant regions associated with clear bone marrow metastasis. The morphology of tumor cells in the bone marrow and cerebrospinal fluid was retrospectively analyzed after staining with Wright-Giemsa stain. A summary of the cytological characteristics was also presented. RESULTS: RB tumor cells in the bone marrow and cerebrospinal fluid not only appeared as aggregated clumps, but were distributed in a scattered manner. The tumor cells may present different characteristic morphologies in different cases, with different tumor cell smears from the same tumor mass even showing different features. According to the degree of tumor metastasis, changes in myelogram were significantly different. CONCLUSION: The tumor cells of RB patients show unique morphological characteristics in the bone marrow and cerebrospinal fluid. Therefore, correct identification of the cells is of great value in the diagnosis, staging, and prognosis of RB.