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A Zic2/Runx2/NOLC1 signaling axis mediates tumor growth and metastasis in clear cell renal cell carcinoma.

ABSTRACT: Clear cell renal cell carcinoma (ccRCC) is one of the most common malignancies with rapid growth and high metastasis, but lacks effective therapeutic targets. Here, using public sequencing data analyses, quantitative real-time PCR assay, western blotting, and IHC staining, we characterized that runt-related transcription factor 2 (Runx2) was significantly upregulated in ccRCC tissues than that in normal renal tissues, which was associated with the worse survival of ccRCC patients. Overexpression of Runx2 promoted malignant proliferation and migration of ccRCC cells, and inversely, interfering Runx2 with siRNA attenuates its oncogenic ability. RNA sequencing and functional studies revealed that Runx2 enhanced ccRCC cell growth and metastasis via downregulation of tumor suppressor nucleolar and coiled-body phosphoprotein 1 (NOLC1). Moreover, increased Zic family member 2 (Zic2) was responsible for the upregulation of Runx2 and its oncogenic functions in ccRCC. Kaplan-Meier survival analyses indicated that ccRCC patients with high Zic2/Runx2 and low NOLC1 had the worst outcome. Therefore, our study demonstrates that Zic2/Runx2/NOLC1 signaling axis promotes ccRCC progression, providing a set of potential targets and prognostic indicators for patients with ccRCC.

SUBMITTER: Wu CY

PROVIDER: S-EPMC7994417 | 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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A Zic2/Runx2/NOLC1 signaling axis mediates tumor growth and metastasis in clear cell renal cell carcinoma.

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