Gastric cancer, one of the deadliest gastrointestinal tumors, has a high incidence rate worldwide. Many studies show that the glycosyltransferase 8 domain-containing protein 1 (GLT8D1) plays a crucial role in protein glycosylation. However, few scholars have explored the prognostic importance of GLT8D1 in gastric cancer. The purpose of this research is to investigate the clinical value and biological function of GLT8D1 by examining multiple databases and performing relevant experiments. This study obtained the transcriptomic information and clinically relevant data from the cancer genome atlas (TCGA) and evaluated GLT8D1 in pan-cancer and gastric cancer. The prognostic role of GLT8D1 in the TCGA-stomach adenocarcinoma (STAD) dataset and gastric cancer patients was explored. A predictive nomogram was developed based on GLT8D1 mRNA expression level and clinical features. The receiver operating characteristic curve (ROC) values of predicting overall survival probabilities in the training set (TCGA-STAD dataset) and external validation sets (GSE62254 and FAHSYSU's cohort) were investigated to evaluate the performance of the prognostic nomogram. The STRING database and GeneMANIA were used to describe the proteins and genes interacting with GLT8D1. Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene ontology (GO), and gene set enrichment analysis (GSEA) were used to analyze the biological function of GLT8D1 based on the TCGA-STAD dataset. The study also performed in vitro assays to evaluate the proliferation, invasion, and migration abilities of GLT8D1 in gastric cancer cells. The results found that GLT8D1 is upregulated in gastric cancer. In addition, according to the study, those with stomach cancer who had increased GLT8D1 expression had decreased overall survival (OS). Moreover, GLT8D1 was identified as a separate risk factor for OS in gastric cancer by the univariate and multivariate analyses. Nomogram evaluation revealed that the predictive model was reliable for estimating the probability of overall survival over 1, 3, and 5 years. Functional enrichment analysis showed that interferon-gamma response, mTORC1 signaling pathway, glycolysis, and IL6-JAK-STAT3 signaling pathways were enriched in patients with high GLT8D1 expression levels. Our in vitro assay experiment revealed that GLT8D1 promotes gastric cancer cell invasion and migration, which suggests the involvement of activating the IL6/STAT3 signaling pathway. The study concludes that GLT8D1 is a prognostic biomarker that suggests an unfavorable prognosis for gastric cancer.
Icaritin, a natural anti-cancer agent, is known to target STAT3 and inhibit glycolysis in hepatocellular carcinoma (HCC), but the connecting mechanism has been elusive. In this study, we identified the glycolytic enzyme aldolase B (ALDOB) as a key target of icaritin by transcriptome sequencing of icaritin-treated hypoxic HepG2 cells. Icaritin significantly inhibited HCC cell proliferation and glycolysis, and these effects were substantially reversed by overexpression of ALDOB. At the molecular level, icaritin suppressed STAT3 promoter activity and mRNA expression. Crucially, a chromatin immunoprecipitation (ChIP) assay revealed that icaritin reduced the enrichment of histone H3K18 lactylation (H3K18la) and its associated enrichment of p300 on the STAT3 promoter. This suppressive effect was rescued by the addition of exogenous lactate, directly linking lactate's availability to the epigenetic activation of STAT3. These findings revealed that icaritin suppresses STAT3 transcription in HCC through inhibiting ALDOB-mediated glycolysis, ultimately reducing the glycolysisdependent H3K18la modification on the STAT3 promoter. This work identifies a critical metabolism-epigenetics pathway, providing a foundational mechanism for icaritin's anti-tumor effect.
SMARCA4-deficient tumors represent a group of highly aggressive malignancies defined by the loss of SMARCA4 (BRG1) protein expression and have been most frequently described in thoracic and gynecologic organs. Reports of SMARCA4 deficiency in primary hepatocellular carcinoma (HCC) remain exceedingly rare. We describe a case of SMARCA4-deficient hepatocellular carcinoma with extensive metastatic involvement. A 75-year-old man with a prior diagnosis of HCC developed pulmonary nodules following transarterial chemoembolization (TACE). Histopathological evaluation of a lung biopsy demonstrated metastatic hepatocellular carcinoma with complete loss of SMARCA4 expression on immunohistochemistry. The tumor exhibited poorly differentiated morphology and aggressive clinical behavior, with rapid progression despite systemic therapy. This case highlights the clinicopathological features of SMARCA4-deficient hepatocellular carcinoma, underscores the importance of incorporating molecular pathological evaluation into routine liver cancer diagnostics, and provides insight into the implications of SMARCA4 deficiency for therapeutic decision-making.
Chimeric Antigen Receptor T (CAR-T) Cell Therapy has been successful in curing hematologic malignancy but has not shown any results on solid tumors. One big obstacle is lack of dispersal coupled with CAR-T cells remaining undetected in the sick tissue environment. IL-9 (interleukin-9) retains T cells survival and function to improve antitumor immune reactions. This study developed Claudin18.2-targeted CAR-T cells that constantly expressed IL-9. It studied their ability to fight tumors in mice with working immune systems suffering from tumors. In vitro, it was found that the proliferative and chemotactic abilities of IL-9 expressing CAR-T cells are strong, but their cytotoxicity against Claudin18.2+ tumor cells is the same as that of regular CAR-T cells. In vivo, in treatment with IL-9, CAR-T cells showed a much stronger effect on tumor growth with the pancreatic model, melanoma model, and hepatocellular carcinoma model than in vitro, with the therapeutic effects improving, with the number of CAR-T cells getting bigger. With better results, more CAR-T cells are formed with a higher infiltration into the tumor, therefore more IFN-gamma, IL-2, and granzyme B. IL-9 expression gives rise to internal T cell development, which become a central storage, which could potentially retain anti-tumor immunity. IL-9 also has some pretty good results with improving efficiency and half-life of Claudin18.2-specific CAR-T cells, it might also be a good way to make solid cancer CAR-T therapies more effective.
