Department of Neurobiology, School of Medicine, South China University of Technology, Guangzhou, China.
Center for Pancreatic Cancer Research, School of Medicine, South China University of Technology, Guangzhou, China.
IUBMB Life. 2024 Mar;76(3):140-160. doi: 10.1002/iub.2785. Epub 2023 Sep 20.
The molecular mechanisms of glioblastoma (GBM) are unclear, and the prognosis is poor. Spinster homolog 2 (SPNS2) is reportedly involved in pathological processes such as immune response, vascular development, and cancer. However, the biological function and molecular role of SPNS2 in GBM are unclear. SPNS2 is aberrantly low expressed in glioma. Survival curves, risk scores, prognostic nomograms, and univariate and multifactorial Cox regression analyses showed that SPNS2 is an independent prognostic indicator significantly associated with glioma progression and prognosis. Cell function assays and in vivo xenograft transplantation were performed that downregulation of SPNS2 promoted GBM cell growth, migration, invasion, epithelial-mesenchymal transition (EMT), anti-apoptosis, drug resistance, and stemness, while overexpression of SPNS2 had the opposite effect. Meanwhile, the functional enrichment and signaling pathways of SPNS2 in the Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and RNA sequencing were analyzed by Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene set enrichment analysis (GSEA). The above results were related to the inhibition of the PTEN/PI3K/AKT pathway by SPNS2. In addition, we predicted that SPNS2 is closely associated with immune infiltration in the tumor microenvironment by four immune algorithms, ESTIMATE, TIMER, CIBERSORT, and QUANTISEQ. In particular, SPNS2 was negatively correlated with the infiltration of most immune cells, immunomodulators, and chemokines. Finally, single-cell sequencing analysis also revealed that SPNS2 was remarkably correlated with macrophages, and downregulation of SPNS2 promotes the expression of M2-like macrophages. This study provides new evidence that SPNS2 inhibits malignant progression, stemness, and immune infiltration of GBM cells through PTEN/PI3K/AKT pathway. SPNS2 may become a new diagnostic indicator and potential immunotherapeutic target for glioma.
胶质母细胞瘤（GBM）的分子机制尚不清楚，预后较差。据报道，旋毛虫同源物 2（SPNS2）参与免疫反应、血管发育和癌症等病理过程。然而，SPNS2 在 GBM 中的生物学功能和分子作用尚不清楚。SPNS2 在神经胶质瘤中表达异常降低。生存曲线、风险评分、预后列线图以及单因素和多因素 Cox 回归分析表明，SPNS2 是与胶质瘤进展和预后显著相关的独立预后指标。进行了细胞功能测定和体内异种移植移植实验，结果表明下调 SPNS2 促进了 GBM 细胞的生长、迁移、侵袭、上皮-间充质转化（EMT）、抗凋亡、耐药性和干性，而上调 SPNS2 则产生相反的效果。同时，通过基因本体论（GO）、京都基因与基因组百科全书（KEGG）和基因集富集分析（GSEA）对 SPNS2 在癌症基因组图谱（TCGA）、中国神经胶质瘤基因组图谱（CGGA）和 RNA 测序中的功能富集和信号通路进行了分析。上述结果与 SPNS2 对 PTEN/PI3K/AKT 通路的抑制作用有关。此外，我们通过四种免疫算法（ESTIMATE、TIMER、CIBERSORT 和 QUANTISEQ）预测，SPNS2 与肿瘤微环境中的免疫浸润密切相关。特别是，SPNS2 与大多数免疫细胞、免疫调节剂和趋化因子的浸润呈负相关。最后，单细胞测序分析也表明 SPNS2 与巨噬细胞显著相关，下调 SPNS2 促进 M2 样巨噬细胞的表达。这项研究提供了新的证据，表明 SPNS2 通过 PTEN/PI3K/AKT 通路抑制 GBM 细胞的恶性进展、干性和免疫浸润。SPNS2 可能成为神经胶质瘤的新诊断指标和潜在的免疫治疗靶点。
