@Article{or.2026.080228,
AUTHOR = {Shangjian Li, Qipeng Han, Xinying Sun, Rongrong Yu},
TITLE = {Promoter Hypermethylation-Driven NPHS2 Silencing Promotes Immune Escape and Sunitinib Resistance in Clear Cell Renal Cell Carcinoma},
JOURNAL = {Oncology Research},
VOLUME = {},
YEAR = {},
NUMBER = {},
PAGES = {{pages}},
URL = {http://www.techscience.com/or/online/detail/28042},
ISSN = {1555-3906},
ABSTRACT = {<b>Objective:</b> Renal cell carcinoma is a common malignancy of the urinary system. In this study, we analyzed a public clear cell renal cell carcinoma (ccRCC) dataset and identified Nephrosis 2, idiopathic, steroid-resistant (NPHS2) as a candidate gene to investigate whether epigenetic dysregulation of NPHS2 is associated with tumor microenvironment remodeling. <b>Methods:</b> Differential expression analysis was first performed on GSE68417 using GEO2R. In addition, clinical samples and cell-based assays were used to evaluate changes in NPHS2 expression and promoter methylation following 5′-Aza-CdR treatment. Subsequently, 786-O and A498 cells were obtained, and sunitinib-resistant 786-O/R and A498/R sublines were established. Lentiviral vectors with abnormal expression of NPHS2 were transfected into 786-O, A498, 786-O/R, and 498-R cells to detect changes in biological behaviors such as cell activity and epithelial-mesenchymal transition (EMT). Finally, a ccRCC tumor-bearing mouse model was constructed and intervened with lentiviral vectors with abnormal expression of NPHS2. <b>Results:</b> A total of 159 differentially expressed genes (DEGs) were identified in the GSE68417 dataset, and NPHS2 was included in all morphological changes related to cell epigenetic modifications. 5′-Aza-CdR markedly increased NPHS2 protein expression in 786-O cells (<i>p</i> &lt; 0.05). Meanwhile, there was a high methylation phenomenon in the promoter region of the NPHS2 gene in ccRCC tissue (<i>p</i> &lt; 0.05). <i>In vitro</i>, NPHS2 overexpression suppressed malignant cell behavior, attenuated EMT, and weakened immune evasion in ccRCC cells (<i>p</i> &lt; 0.05). Finally, upregulating NPHS2 could inhibit the growth of ccRCC (<i>p</i> &lt; 0.05) without causing significant changes in liver and kidney functions or malignant pathological damage in mice. <b>Conclusion:</b> These findings support an association between promoter hypermethylation and NPHS2 downregulation in ccRCC and suggest that NPHS2 loss may contribute to immune-evasive features and reduced sunitinib sensitivity. Further multicohort and mechanistic studies are warranted.},
DOI = {10.32604/or.2026.080228}
}