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S1PR1 suppresses lung adenocarcinoma progression through p-STAT1/miR-30c-5 p/FOXA1 pathway
Yanfei Chai1,2,3, Hong Xiang1,4, Yuchao Ma2
1Department of Health Management Center, The Third Xiangya Hospital of Central South University, Changsha, China.
Background:
Sphingosine-1-phosphate receptor 1 (S1PR1) is considered to be closely related to a variety of malignant tumors, but the role and mechanism of S1PR1 in lung adenocarcinoma are not fully understood. In this study, we aim to explore the role and downstream signaling pathways of S1PR1 in the malignant biological functions of lung adenocarcinoma (LUAD).
Methods:
Bioinformatics analysis, RT-qPCR, western blot and immunohistochemistry (IHC) were was used to investigate the expression of S1PR1 in LUAD. The prognosis of S1PR1 was also analyzed. CCK-8 assay, colony formation assay, scratch assay, transwell migration and invasion assay, cell adhesion assay were performed to examine the effect of S1PR1 on LUAD. RNA sequencing was employed to analyze the DEGs in LUAD cells overexpressing S1PR1. Enrichment pathway analysis using KEGG, GO, and GSEA was conducted to predict potential signaling pathways and downstream targets. chromatin immunoprecipitation (ChIP) and dual luciferase reporter assay were performed to verify the direct regulation between FOXA1 and the target genes. Then FOXA1 overexpression were performed to functional rescue experiments. miRNA-30c-5p was identified as a microRNA regulating FOXA1 by dual luciferase reporter assay. The downstream signaling pathways of S1PR1 was detected to clarify the specific pathways to regulates miR-30c-5p.
Results:
S1PR1 is significantly decreased in LUAD and is positively correlated with the prognosis. Overexpression of S1PR1 inhibits the proliferation, migration, invasion and adhesion function of LUAD cells by suppressing the expression of COL5A1, MMP1, and SERPINE1. FOXA1 is a key transcription factor regulating the expression of MMP1, COL5A1 and SERPINE1. S1PR1 inhibits the expression of FOXA1 through p-STAT1/miR-30c-5p, thereby suppressing the malignant function of LUAD cells.
Conclusions:
The expression of S1PR1 is downregulated in LUAD, which is positively correlated with prognosis. S1PR1 regulates the malignant function of LUAD cells by inhibiting the expression of COL5A1, MMP1 and SERPINE1 through the p-STAT1/miR-30c-5p/FOXA1 signaling pathway.
Insights
Sphingosine-1-phosphate receptor 1 (S1PR1) is downregulated in lung adenocarcinoma (LUAD), inhibiting cancer progression. S1PR1 suppresses tumor growth by regulating the miR-30c-5p/FOXA1 pathway, improving patient prognosis.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Lung adenocarcinoma (LUAD) progression is linked to Sphingosine-1-phosphate receptor 1 (S1PR1), but its precise role remains unclear.
- Investigating S1PR1's function and downstream pathways in LUAD is crucial for understanding tumorigenesis.
Purpose of the Study:
- To elucidate the role and molecular mechanisms of S1PR1 in LUAD.
- To identify downstream signaling pathways regulated by S1PR1 in LUAD progression.
Main Methods:
- Bioinformatics, RT-qPCR, Western blot, and IHC assessed S1PR1 expression and prognosis in LUAD.
- Functional assays (CCK-8, colony formation, migration, invasion, adhesion) evaluated S1PR1's impact on LUAD cells.
- RNA sequencing, KEGG, GO, GSEA, ChIP, and dual luciferase reporter assays identified S1PR1-regulated pathways and targets, including FOXA1 and miR-30c-5p.
Main Results:
- S1PR1 expression is decreased in LUAD and correlates positively with patient prognosis.
- S1PR1 overexpression suppressed LUAD cell proliferation, migration, invasion, and adhesion by reducing COL5A1, MMP1, and SERPINE1 expression.
- S1PR1 inhibits FOXA1 expression via the p-STAT1/miR-30c-5p axis, thereby suppressing LUAD malignancy.
Conclusions:
- Downregulation of S1PR1 in LUAD is associated with poorer prognosis.
- S1PR1 inhibits LUAD cell malignancy by suppressing COL5A1, MMP1, and SERPINE1 through the p-STAT1/miR-30c-5p/FOXA1 signaling pathway.
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