Discussion
Molecular mechanisms involved in leukemogenesis, such as structural chromosomal rearrangements, alternative splicing, and epigenetic deregulation can alter the expression of transcripts that are associated with the B-ALL development. Identifying these mechanisms through molecular diagnostic technologies will provide a better understanding of the disease pathogenesis, leading to the rapid expansion of molecular biomarkers related to B-ALL. Identification of these novel biomarkers can improve the precision of risk diagnosis, personalized treatment, better monitoring of treatment response, development of new risk-adapted targeted therapies, and patient outcome .
This study aimed to evaluate the transcriptome profile of B-ALL patients to find a novel diagnostic or prognostic biomarker through RNA-seq data analysis. The differential expression analysis, WGCNA, and GO analysis was performed to identify patterns of gene expression alterations and biological pathways related to DEGs. Our first findings demonstrated the SPRING1 upregulation in B-ALL patients based on WGCNA analysis and qRT-PCR. Moreover, there was a positive correlation between the lipopolysaccharide-mediated signaling pathway andSPRING1 activity based on GO enrichment analysis. These data propose that SPRING1 has an imminent role in B-ALL tumorigenesis and can be a potential diagnostic marker for this disease. This integrated approach which includes a combination of bioinformatics and experimental validation, could be a powerful strategy to identify potential biomarkers and increase our understanding of the underlying biology of B-ALL.
Lipid rafts serve as a principal modality for signaling in cancer cells, where cholesterol assumes a pivotal function in this context. Accordingly, targeting cholesterol metabolism may be used as a viable therapeutic approach for the treatment of B-ALL . It is noteworthy that the disruption of cholesterol metabolism may lead to the formation of malignancy, such as breast, prostate, and colorectal cancers; consequently, there is a positive correlation between the cholesterol levels and cancer incidence . SPRING1 protein (or C12orf49) is localized in the Golgi and plays a crucial role in regulation of fatty acid metabolism and tumor pathogenesis (18,19). SPRING1 binds to the peptidase-site membrane-bound transcription factor 1 (MBTPS1) and triggers the cleavage of its substrate, specifically sterol regulatory element binding protein (SREBP) transcription factors (19,21,22).SPRING1 plays a key role in the activation and cleavage of the SREBP precursor protein through the protease activity and maturation of S1P during its transport from the endoplasmic reticulum to the Golgi . Therefore, SPRING1 is essential for maintaining both precursor and mature SREBP protein levels . SREBPs, as a large class of transcription factors, regulate lipid homeostasis by modulating the expression of enzymes necessary for endogenous cholesterol, fatty acid (FA), triacylglycerol, and phospholipid synthesis . Activation of SREBP occurs through its transport from the endoplasmic reticulum to the Golgi, where the S1P enzyme cleaves the endoplasmic reticulum loop of SREBP . It has been reported that S1P cleavage activity depends on its interaction with SPRING1 . Moreover, SREBPs transcription factors regulate cholesterol biosynthesis and uptake for cellular function . Cholesterol is a major component of membrane lipids, which plays a critical role in cancer development as the primary platform in the membrane for signaling regulation in cancer . Consequently, regulation of membrane cholesterol balance is essential to maintain cellular homeostasis. Dysregulation of SPRING1 leads to unbalanced cholesterol metabolism and the possibility of some disorders, such as tumor formation, cardiovascular, and neurodegenerative diseases .
It has been reported that the function of SPRING1 is associated with divergent prognostic outcomes across various tumor types, including kidney, breast, liver, and sarcoma by The Cancer Genome Atlas (TCGA) database analysis . The upregulation of SPRING1 was indicated in CRC tissues compared to non-cancerous tissue samples that correlated to tumor growth. Therefore, SPRING1 was identified as a potential biomarker that provides therapeutic benefits for CRC patients . Moreover, the overexpression of SPRING1 in breast cancer tissues was associated with significantly reduced survival rates of the patients as demonstrated by TCGA database analysis . Additionally, the significant upregulation of SPRING1 was confirmed in clear cell renal cell carcinoma-small renal masses (ccRCC-SRMs) compared to renal oncocytoma, which was associated with decreased overall survival rate of patients based on proteome analysis . Consistent with previous studies, our data showed significant overexpression of SPRING1 in B-ALL patients. Taken together, our data propound that the SPRING1dysregulation can impact the lipopolysaccharide-mediated signaling pathway and the downstream genes, which can correlate to B-ALL formation and development.