Potential of SPHK1 as a prognostic marker and therapeutic target in colorectal cancer: insights from bioinformatics and experimental analysis

Abstract

Background: 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.

Objective: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Mendelian randomization; S1P; SPHK1; bioinformatics; colorectal cancer; multi-omics; sphingolipid metabolism.