Claudin-9 (CLDN9) promotes gastric cancer progression by enhancing the glycolysis pathway and facilitating PD-L1 lactylation to suppress CD8+ T cell anti-tumor immunity

作者：Xingbin Hu, Wenhao Ouyang, Haizhu Chen, Zhihong Liu, Zijia Lai, Herui Yao · 发表于：Cancer Pathogenesis and Therapy · 年份：2024 · DOI：10.1016/j.cpt.2024.09.006 · 被引用次数：16 · 研究领域：Cancer, Stress, Anesthesia, and Immune Response、Immune cells in cancer、Cancer Immunotherapy and Biomarkers

Gastric cancer (GC) is a common malignancy characterized by the absence of reliable prognostic indicators and effective therapeutic targets. Claudin-9 (CLDN9) has been demonstrated to be upregulated in various cancers. However, its prognostic value, biological function, and regulatory mechanisms in GC remain unclear. Therefore, this study aimed to elucidate the role of CLDN9 in GC progression and its underlying mechanisms. We utilized consensus cluster, random survival forest, and multivariate Cox regression analyses to identify CLDN9 in GC. Subsequently, we evaluated the mRNA and protein levels of CLDN9 in GC using quantitative real-time polymerase chain reaction (PCR) (qRT-PCR), Western blotting (WB), and immunohistochemistry (IHC). Furthermore, the role of CLDN9 in GC progression was investigated using a series of functional in vivo and in vitro experiments. Finally, we elucidated the molecular mechanisms of CLDN9 using bioinformatics, molecular biology, animal models, and patient tissue specimens. Two GC subtypes with survival and functional differences were identified based on glycolytic metabolic genes in the Cancer Genome Atlas (TCGA)- Stomach adenocarcinoma (STAD) dataset. A prognostic risk score was calculated using seven genes to assess the overall survival (OS) in GC. Using random survival forest and multivariate Cox analyses, we identified CLDN9 as the key gene linked to the glycolytic subtype and prognosis of GC. CLDN9 expression was significantly upregulated in ...