Transmembrane Transporter Sema3D Serves as a Tumor Suppressor in Localized Clear Cell Renal Cell Carcinoma

BACKGROUND: The transmembrane transporter Sema3D is a vital molecule involved in axon guidance and carcinogenesis of variant malignancies. However, the relationship between Sema3D and clear cell renal cell carcinoma (ccRCC) is barely reported and remains unclear. METHODS: Sema3D expression and the connection of clinical and histological characteristics were first analyzed with transcriptome data in the TCGA repository. We then located and examined the Sema3D expression in ccRCC patients by using immunofluorescence staining in the tissue microarray. The prognostic value of Sema3D in localized ccRCC was evaluated by Cox proportional hazard analysis. Functional and gene set enrichment analysis (GSEA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed to describe the potential mechanisms of Sema3D in ccRCC. Correlation analysis between Sema3D and tumor-infiltrating lymphocytes was calculated by ssGSEA. RESULTS: In 86 ccRCC patients, Sema3D mRNA and protein expression were downregulated in tumor tissues than the para-tumor tissues, and Sema3D was dominantly expressed in the extracellular space. Low expression of Sema3D was associated with advanced tumor stage, advanced histological grade, and poor prognosis in ccRCC. In the subgroup analysis of 81 localized ccRCC patients, Sema3D expression level was an independent protective prognostic factor for overall survival (OS) (HR = 0.125, p=0.043). Coagulation, complement, estrogen response, and KRAS signaling hallmark gene sets were identified as Sema3D-related signaling pathways. The expression level of Sema3D was significantly correlated with a high abundance of several immune cells (neutrophils, eosinophils, and T helper cells). CONCLUSIONS: Transmembrane transporter Sema3D is an efficient prognostic biomarker for localized ccRCC patients, by playing the role of tumor suppressor in ccRCC. Sema3D can be a novel therapeutic target for ccRCC.