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Transmembrane Transporter Sema3D Serves as a Tumor Suppressor in Localized Clear Cell Renal Cell Carcinoma
Ruiyang Xie1, Jie Wu1, Bingqing Shang1
1Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Chaoyang District, Beijing, China.
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.
Insights
Sema3D, a transmembrane transporter, is downregulated in clear cell renal cell carcinoma (ccRCC). Low Sema3D expression indicates poor prognosis, suggesting its role as a tumor suppressor and potential therapeutic target in ccRCC.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Sema3D is a transmembrane transporter crucial for axon guidance and cancer development.
- Its role in clear cell renal cell carcinoma (ccRCC) is largely unexplored.
- Understanding Sema3D's function in ccRCC is vital for potential therapeutic strategies.
Purpose of the Study:
- To investigate the expression of Sema3D in ccRCC.
- To analyze the correlation between Sema3D expression and clinical/histological features.
- To evaluate the prognostic value and potential mechanisms of Sema3D in ccRCC.
Main Methods:
- Transcriptome data analysis from TCGA repository.
- Immunofluorescence staining for Sema3D protein expression in ccRCC tissues.
- Cox proportional hazard analysis for prognostic evaluation.
- Gene set enrichment analysis (GSEA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) for mechanistic insights.
- ssGSEA for correlation with tumor-infiltrating lymphocytes.
Main Results:
- Sema3D mRNA and protein were significantly downregulated in ccRCC tumor tissues compared to adjacent tissues.
- Low Sema3D expression correlated with advanced tumor stage, higher histological grade, and poorer prognosis.
- Sema3D served as an independent protective prognostic factor for overall survival in localized ccRCC.
- Sema3D expression was linked to specific signaling pathways (coagulation, complement, estrogen response, KRAS) and immune cell infiltration.
Conclusions:
- Sema3D acts as a tumor suppressor in ccRCC.
- Downregulated Sema3D is an effective prognostic biomarker for localized ccRCC.
- Sema3D represents a potential novel therapeutic target for ccRCC treatment.
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