Miao Yandong, Gan Jian, Ni Yan-Jing, Zhang Zhao-Nan, Yu Ling-Xia, Quan Wu-Xia, Zhang Zheng-Chao, Wang Hui-Min, Han Shuang, Qu Fan-Yong, Lu Qian-Qian, Ma Rui, Wang Jiang-Tao, Luan Wen-Yu, Lin Si-Xiang, Mi Deng-Hai, Huang Wen-Hua
Guangdong Provincial Key Laboratory of Medical Biomechanics, National Key Discipline of Human Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510000, China.
Cancer Center, Yantai Affiliated Hospital of Binzhou Medical University, The 2nd Medical College of Binzhou Medical University, Yantai 264100, China.
Int J Surg. 2025 Jun 24. doi: 10.1097/JS9.0000000000002506.
Colorectal cancer (CRC) remains a major cause of cancer-related mortality globally, primarily due to its aggressive progression and poor prognosis in many patients. Despite treatment advances, new therapeutic targets are critically needed to enhance patient outcomes. Although sphingosine kinase 1 (SPHK1) has been linked to various cancers, its role in CRC progression, prognosis, and as a therapeutic target is not well understood.
This study aimed to investigate the role and molecular mechanisms through which SPHK1 contributes to CRC progression, with a focus on its potential as a prognostic marker and therapeutic target by bioinformatics and experimental analysis.
Multi-omics analysis was conducted using data from TCGA, GEPIA2, and other publicly available databases, as well as single-cell RNA sequencing data, to assess SPHK1 expression and its correlation with immune infiltration in CRC tissues. A Mendelian Randomization (MR) approach was employed to investigate the causal relationship between sphingomyelin levels and CRC risk. Multiplex Fluorescence Immunohistochemistry was used to analyze the expression levels of SPHK1, E-cadherin, and Vimentin in 90 CRC and corresponding normal tissues. Migration, invasion, and apoptosis assays were performed in CRC cell lines to examine the functional impact of SPHK1 modulation.
SPHK1 expression was significantly elevated in CRC tissues and correlated with poor prognosis. MR analysis confirmed a causal relationship between sphingomyelin levels and increased CRC risk. SPHK1 gene expression was significantly positively related to methylation levels at sites cg11001059 and cg26442874 and significantly negatively associated with methylation levels at cg02028751. SPHK1 expression was associated with immune cell infiltration and sphingolipid metabolism pathways. SPHK1 was found to modulate the expression of E-cadherin, promoting CRC cell migration and invasion, while inhibiting apoptosis.
SPHK1 plays a key role in facilitating the epithelial-to-mesenchymal transition of CRC cells, enhancing their migratory and invasive abilities, and influencing the tumor microenvironment. The findings suggest that SPHK1 could be a potential biomarker and therapeutic target for CRC, with implications for the development of targeted therapies to improve patient outcomes.
结直肠癌（CRC）仍是全球癌症相关死亡的主要原因，主要是因为其进展迅速且许多患者预后不良。尽管治疗取得了进展，但仍迫切需要新的治疗靶点来改善患者预后。虽然鞘氨醇激酶1（SPHK1）已与多种癌症相关联，但其在CRC进展、预后中的作用以及作为治疗靶点的情况尚不清楚。
本研究旨在通过生物信息学和实验分析，探讨SPHK1促进CRC进展的作用及分子机制，重点关注其作为预后标志物和治疗靶点的潜力。
使用来自TCGA、GEPIA2和其他公开可用数据库的数据以及单细胞RNA测序数据进行多组学分析，以评估SPHK1在CRC组织中的表达及其与免疫浸润的相关性。采用孟德尔随机化（MR）方法研究鞘磷脂水平与CRC风险之间 的因果关系。使用多重荧光免疫组织化学分析90例CRC及相应正常组织中SPHK1、E-钙黏蛋白和波形蛋白的表达水平。在CRC细胞系中进行迁移、侵袭和凋亡检测以检查SPHK1调节的功能影响。
SPHK1在CRC组织中的表达显著升高，且与预后不良相关。MR分析证实鞘磷脂水平与CRC风险增加之间存在因果关系。SPHK1基因表达与位点cg11001059和cg26442874处的甲基化水平显著正相关，与cg02028751处 的甲基化水平显著负相关。SPHK1表达与免疫细胞浸润和鞘脂代谢途径相关联，并发现SPHK1调节E-钙黏蛋白的表达，促进CRC细胞迁移和侵袭, 同时抑制凋亡。
SPHK1在促进CRC细胞上皮-间质转化、增强其迁移和侵袭能力以及影响肿瘤微环境方面起关键作用。研究结果表明，SPHK1可能是CRC的潜在生物标志物和治疗靶点, 对开发改善患者预后的靶向治疗具有重要意义。
