Abstract
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.
Highlights
CcRCC is a highly invasive malignancy that accounts for 85–90% of renal cell carcinoma[1]
Procollagen C-Endopeptidase Enhancer (PCOLCE), Prolyl 4-Hydroxylase Subunit Beta (P4HB), COL6A2 and COL6A3 are upregulated in metastatic Clear cell renal cell carcinoma (ccRCC) and might be related to poor prognosis and distant metastases
1, 104 intersected co-expressed differentially expressed genes (DEGs) were screened out from three datasets (GSE85258, GSE105288, GSE22541) to investigate possible pathways related to prognosis and metastasis in clear cell renal cell carcinoma
Summary
CcRCC is a highly invasive malignancy that accounts for 85–90% of renal cell carcinoma[1]. About 17– 30% of ccRCC patients suffered from distant metastasis by the time of diagnosis[2]. Since ccRCC is not sensitive to radiotherapy and chemotherapy, radical or partial nephrectomy is still the main treatment, with 20–40% of local recurrence or distant metastasis[3]. The mechanism of ccRCC metastasis is still unclear. Patients with metastasis cannot get the proper treatment to improve their survival. It is extremely urgent to clarify the mechanism of ccRCC metastasis and obtain effective therapeutic targets. Clear cell renal cell carcinoma (ccRCC) is a tumor with frequent hematogenous metastasis and is usually resistant with radiotherapy and chemotherapy. The mechanism of ccRCC metastasis still needs to be illustrated
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