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Fibronectin enhances tumor metastasis through B7-H3 in clear cell renal cell carcinoma.

ABSTRACT: B7 homolog 3 (B7-H3) plays an important role in tumor biology, but the molecular mechanism underlying the role of B7-H3 in tumor metastasis remains unclear. In this article, our analysis of The Cancer Genome Atlas database suggested that B7-H3 expression is associated with poor prognosis of patients with clear cell renal cell carcinoma (ccRCC). B7-H3 knockdown affected the expression of metastasis-related genes and significantly suppressed the metastasis of ccRCC cells, but it had no significant effect on the proliferation of ccRCC cells. Database analysis revealed a strong positive correlation between B7-H3 and fibronectin (FN) in ccRCC cells, and further study also confirmed that FN interacts with B7-H3. Silencing FN expression inhibited the migration and invasion of ccRCC cells, whereas exogenous FN promoted the migration and invasion of ccRCC cells, which was accompanied by activation of kinases [namely, phosphorylated (p)-phosphoinositide 3-kinase, p-protein kinase B, p-p38 and p-extracellular regulated protein kinase]. B7-H3 knockdown abolished the prometastatic effect of FN. In conclusion, our data suggest that B7-H3 binds to exogenous FN and promotes the metastasis of ccRCC cells.

SUBMITTER: Xie J

PROVIDER: S-EPMC8564341 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundClear cell renal cell carcinoma (ccRCC) is a tumor that frequently shows the hematogenous pathway and tends to be resistant to radiotherapy and chemotherapy. However, the exact mechanism of ccRCC metastasis remains unknown.MethodsDifferentially expressed genes (DEGs) of three gene expression profiles (GSE85258, GSE105288 and GSE22541) downloaded from the Gene Expression Omnibus (GEO) database were analyzed by GEO2R analysis, and co-expressed DEGs among the datasets were identified using a Venn drawing tool. The co-expressed DEGs were investigated using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, and hub genes were determined based on the protein-protein interaction network established by STRING. After survival analysis performed on UALCAN website, possible key genes were selected and verified in ccRCC cell lines and ccRCC tissues (n = 44). Statistical analysis was conducted using GraphPad Prism (Version 8.1.1).ResultsA total of 104 co-expressed DEGs were identified in the three datasets. Pathway analysis revealed that these genes were enriched in the extracellular matrix (ECM)-receptor interaction, protein digestion and absorption and focal adhesion. Survival analysis on 17 hub genes revealed that four key genes with a significant impact on survival: procollagen C-endopeptidase enhancer (PCOLCE), prolyl 4-hydroxylase subunit beta (P4HB), collagen type VI alpha 2 (COL6A2) and collagen type VI alpha 3 (COL6A3). Patients with higher expression of these key genes had worse survival than those with lower expression. In vitro experiments revealed that the mRNA expression levels of PCOLCE, P4HB and COL6A2 were three times higher and that of COL6A3 mRNA was 16 times higher in the metastatic ccRCC cell line Caki-1 than the corresponding primary cell line Caki-2. Immunohistochemistry revealed higher expression of the proteins encoded by these four genes in metastatic ccRCC compared with tumors from the corresponding primary sites, with statistical significance.ConclusionPCOLCE, P4HB, COL6A2 and COL6A3 are upregulated in metastatic ccRCC and might be related to poor prognosis and distant metastases.

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Fibronectin enhances tumor metastasis through B7-H3 in clear cell renal cell carcinoma.

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