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Prognostic value of inflammation and immune-related gene NOD2 in clear cell renal cell carcinoma

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Abstract

Inflammation and immune responses play important roles in cancer development and prognosis. We identified 59 upregulated inflammation- and immune-related genes (IIRGs) in clear cell renal cell carcinoma (ccRCC) from The Cancer Genome Atlas database. Among the upregulated IIRGs, nucleotide binding oligomerization domain 2 (NOD2), PYD and CARD domain (PYCARD) were also confirmed to be upregulated in the Oncomine database and in three independent GEO data sets. Tumor immune infiltration resource database analysis revealed that NOD2 and PYCARD levels were significantly positively correlated with infiltration levels of B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages and dendritic cells. Multivariate Cox hazards regression analysis indicated that based on clinical variables (age, gender, tumor grade, pathological TNM stage), NOD2, but not PYCARD, was an independent, unfavorable ccRCC prognostic biomarker. Functional enrichment analyses (GSEA) showed that NOD2 was involved in innate immune responses, inflammatory responses, and regulation of cytokine secretion. Meanwhile, mRNA and protein levels of NOD2 were elevated in four ccRCC cell lines (786-O, ACHN, A498 and Caki-1), and its knockdown significantly inhibited IL-8 secretion, thereby inhibiting ccRCC cell proliferation and invasion. Furthermore, results showed that miR-20b-5p targeted NOD2 to alleviate NOD2-mediated IL-8 secretion. In conclusion, NOD2 is a potential prognostic biomarker for ccRCC and the miR-20b-5p/NOD2/IL-8 axis may regulate inflammation- and immune-mediated tumorigenesis in ccRCC.

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The data used to support the findings of this study are available from the corresponding author upon request.

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Funding

This study was supported in part by the National Natural Science Foundation of China (81902593, 82002708), Hubei Province Nature Science Foundation of China (2020CFB732, 2019CFB279) and Wuhan Science and Technology Project of China (2020020601012325).

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Author notes

  1. Lei Lyu, Rui Min and Fuxin Zheng have contributed equally to this work as co-first authors.

Authors and Affiliations

  1. Department of Urology, Wuhan No.1 Hospital (Traditional Chinese and Western Medicine Hospital of Wuhan), Tongji Medical College, Huazhong University of Science and Technology, Hubei, Wuhan, 430022, People’s Republic of China

    Lei Lyu, Rui Min, Fuxin Zheng, Wei Xiang, Tao Huang, Chuanhua Zhang & Jingdong Yuan

  2. Department of PathologyWuhan No.1 Hospital (Traditional Chinese and Western Medicine Hospital of Wuhan), Tongji Medical College, Huazhong University of Science and Technology, Hubei, Wuhan, 430022, People’s Republic of China

    Yan Feng

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Contributions

Lei Lyu and Jingdong Yuan designed the experiments. Rui Min, Fuxin Zheng and Tao Huang performed the experiments. Lei Lyu and Tao Huang drafted the manuscript. Wei Xiang, Yan Feng and Chuanhua Zhang conducted data analysis and interpreted the results. Lei Lyu, Rui Min, Fuxin Zheng and Jingdong Yuan revised the manuscript. Lei Lyu, Rui Min and Fuxin Zheng contributed equally to this work as co-first authors. All authors reviewed and approved the manuscript.

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Correspondence to Jingdong Yuan.

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The authors declare no competing interests or conflict of interests.

Ethics approval and consent to participate

This study was performed in line with the principles of the Declaration of Helsinki and was approved by the Ethics Committee of Wuhan No.1 Hospital, Tongji Medical College, Huazhong University of Science and Technology (Ethics Approval Number: 2020IECA255). Informed consent was obtained from all participating patients.

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Supplementary Information

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Supplementary file1 (XLSX 10 kb)

Supplementary file2 (XLSX 12 kb)

13577_2024_1045_MOESM3_ESM.pdf

Figure S1: Box plot of the 59 upregulated IIRGs in 72 normal renal tissue samples and 537 ccRCC tissue samples. (PDF 256 kb)

13577_2024_1045_MOESM4_ESM.pdf

Figure S2: Forest map of univariate and multivariate Cox regression analysis of OS outcomes for ccRCC patients. (PDF 222 kb)

13577_2024_1045_MOESM5_ESM.pdf

Figure S3: The efficacy of individual inhibitory RNAs in down-regulating the expression of NOD2 gene was measured by qRT-PCR. **P<0.05. Data are representative expressed as the mean ± SD of each group from three independent experiments. (PDF 85 kb)

13577_2024_1045_MOESM6_ESM.pdf

Figure S4: RNA immunoprecipitation (RIP) assays were performed to assess the correlation between miR-20b-5p and NOD2 in 786-O cells and ACHN cells. (A and B) In 786-O cells, Ago2 protein expression level and relative enrichment of specific RNAs in immunoprecipitates were determined by Western blot and qRT-PCR, respectively. (C and D) In ACHN cells, Ago2 protein expression level and relative enrichment of specific RNAs in immunoprecipitates were determined by Western blot and qRT-PCR, respectively. **P<0.05. Data are representative images or expressed as the mean ± SD of each group from three independent experiments. (PDF 102 kb)

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Lyu, L., Min, R., Zheng, F. et al. Prognostic value of inflammation and immune-related gene NOD2 in clear cell renal cell carcinoma. Human Cell 37, 782–800 (2024). https://doi.org/10.1007/s13577-024-01045-2

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