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Background <p>Nicotinamide N-methyltransferase (NNMT) is involved in the development of several cancers. Tumor stem cells are present in various cancers and are linked to treatment resistance, tumor recurrence, and metastasis. However, the role of NNMT in regulating the stemness characteristics of clear cell renal cell carcinoma (ccRCC) is not yet fully understood.</p> Methods <p>NNMT expression was identified as differentially expressed through the analysis of TCGA and GEO datasets (GSE105261 and GSE66272). Functional significance was explored using xenograft models. We performed qPCR, western blot, enzyme-linked immunosorbent assay (ELISA) and additional assays to examine the effects of NNMT on ccRCC stem cells. The potential molecular mechanism of ccRCC stem cells in promoting angiogenesis was investigated through RNA-seq analysis. The expression of C-C motif chemokine ligand 20 (CCL20) was validated through western blot and ELISA analyses. Regulation of angiogenesis was assessed using tube formation assays and Matrigel plug assays.</p> Results <p>NNMT was significantly upregulated in ccRCC tumor tissues and impaired the prognosis in ccRCC patients. In vivo studies revealed that NNMT depletion significantly inhibited tumor growth, whereas increased NNMT levels enhanced tumor progression. Additionally, NNMT enhanced the stemness characteristics of ccRCC cells and maintained C-X-C chemokine receptor type 4 (CXCR4) expression through the activation of Signal Transducer and Activator of Transcription 3 (STAT3) phosphorylation. Moreover, NNMT facilitated the recruitment and differentiation of ccRCC stem cells towards endothelial cells via the stromal cell–derived factor 1 (SDF-1)/CXCR4 axis, thereby promoting vessel function and tumor growth.</p> Conclusion <p>NNMT functions as an oncogene, strengthening the stemness properties of ccRCC cells and sustaining angiogenesis. These results indicate that NNMT may be a viable therapeutic target and prognostic biomarker for ccRCC.</p>

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Upregulated NNMT sustains angiogenesis in clear cell renal cell carcinoma through activation of the SDF-1/CXCR4–ERK–CCL20 axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月31日

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  • Wenfu Zhang,
  • Yang Yu,
  • Bo Geng,
  • Xin Shao,
  • Wei Zhang,
  • Zhuolun Li,
  • Yunhui Chan,
  • Nan Zhang,
  • Jinpeng Wang,
  • Yunfeng Nan,
  • Kaifeng Wang,
  • Meng Dong,
  • Weikang Ma,
  • Bosen You,
  • Xuedong Li,
  • Enyang Zhao

摘要

Background

Nicotinamide N-methyltransferase (NNMT) is involved in the development of several cancers. Tumor stem cells are present in various cancers and are linked to treatment resistance, tumor recurrence, and metastasis. However, the role of NNMT in regulating the stemness characteristics of clear cell renal cell carcinoma (ccRCC) is not yet fully understood.

Methods

NNMT expression was identified as differentially expressed through the analysis of TCGA and GEO datasets (GSE105261 and GSE66272). Functional significance was explored using xenograft models. We performed qPCR, western blot, enzyme-linked immunosorbent assay (ELISA) and additional assays to examine the effects of NNMT on ccRCC stem cells. The potential molecular mechanism of ccRCC stem cells in promoting angiogenesis was investigated through RNA-seq analysis. The expression of C-C motif chemokine ligand 20 (CCL20) was validated through western blot and ELISA analyses. Regulation of angiogenesis was assessed using tube formation assays and Matrigel plug assays.

Results

NNMT was significantly upregulated in ccRCC tumor tissues and impaired the prognosis in ccRCC patients. In vivo studies revealed that NNMT depletion significantly inhibited tumor growth, whereas increased NNMT levels enhanced tumor progression. Additionally, NNMT enhanced the stemness characteristics of ccRCC cells and maintained C-X-C chemokine receptor type 4 (CXCR4) expression through the activation of Signal Transducer and Activator of Transcription 3 (STAT3) phosphorylation. Moreover, NNMT facilitated the recruitment and differentiation of ccRCC stem cells towards endothelial cells via the stromal cell–derived factor 1 (SDF-1)/CXCR4 axis, thereby promoting vessel function and tumor growth.

Conclusion

NNMT functions as an oncogene, strengthening the stemness properties of ccRCC cells and sustaining angiogenesis. These results indicate that NNMT may be a viable therapeutic target and prognostic biomarker for ccRCC.