Association of PON2 and Its S311C Substitution with Tumor Progression and Its Significance as an Immune-Associated Prognostic Indicator in Clear Cell Renal Cell Carcinoma.
- 1Department of Urology & Urology Laboratory, The Third Affiliated Hospital of Nanjing Medical University, 68 Gehu Middle Road, Wujin District, Changzhou 213003, China.
Abstract
Background: Clear cell renal cell carcinoma (ccRCC), the predominant histological subtype of kidney malignancies, is characterized by metabolic dysregulation and therapeutic resistance. Although the intracellular antioxidant paraoxonase 2 (PON2) is frequently dysregulated across multiple cancers, its biological role in ccRCC-particularly the contribution of its enzymatic activity and interplay with the tumor immune microenvironment-remains poorly defined. Methods: Multi-cohort analysis integrating TCGA, ICGC, GEO, and CPTAC datasets was combined with single-cell transcriptomic profiling, survival and Cox regression modeling, immune infiltration estimation, and in vitro loss- and gain-of-function experiments in ccRCC cell lines. Results: PON2 was markedly elevated in ccRCC tissues, predominantly localizing to malignant epithelial and endothelial cells as determined by single-cell transcriptomic profiling. High PON2 expression correlated with advanced T/M stages and independently predicted poor prognosis. Functional experiments showed that PON2 silencing was associated with reduced tumor cell proliferation, invasion, and glycolysis, while rescue experiments using wild-type-but not S311C mutant-PON2 partially restored these phenotypes. PON2 expression was associated with glycolysis-related metabolic changes and CEBPB-related expression of downstream glycolytic targets, including LDHA and PGK1. Furthermore, PON2-high tumors showed transcriptomic features consistent with an immunosuppressive microenvironment, with higher computational estimates of CD8⁺ T-cell infiltration accompanied by elevated immune checkpoint expression (PD-L1, CTLA4) and higher estimated abundance of immunosuppressive populations (Tregs, MDSCs). Conclusions: Collectively, our findings identify PON2 as a candidate biomarker associated with ccRCC progression and CEBPB-related glycolysis and features consistent with an immunosuppressive microenvironment.
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BibTeX
@article{liu2026association,
title = {{Association of PON2 and Its S311C Substitution with Tumor Progression and Its Significance as an Immune-Associated Prognostic Indicator in Clear Cell Renal Cell Carcinoma.}},
author = {Zhiyu Liu and Wei Yun and Ting Hong and Chuan Liu and Guangming He and Shenglin Gao and Xiaokai Shi and Li Zuo},
journal = {Cancers},
year = {2026},
month = sep,
doi = {10.3390/cancers18193086},
url = {https://europepmc.org/article/MED/42882781},
note = {CC BY},
}
RIS
TY - JOUR
TI - Association of PON2 and Its S311C Substitution with Tumor Progression and Its Significance as an Immune-Associated Prognostic Indicator in Clear Cell Renal Cell Carcinoma.
AU - Zhiyu Liu
AU - Wei Yun
AU - Ting Hong
AU - Chuan Liu
AU - Guangming He
AU - Shenglin Gao
AU - Xiaokai Shi
AU - Li Zuo
PY - 2026
DA - 2026/09/23
JO - Cancers
DO - 10.3390/cancers18193086
UR - https://europepmc.org/article/MED/42882781
AB - Background: Clear cell renal cell carcinoma (ccRCC), the predominant histological subtype of kidney malignancies, is characterized by metabolic dysregulation and therapeutic resistance. Although the intracellular antioxidant paraoxonase 2 (PON2) is frequently dysregulated across multiple cancers, its biological role in ccRCC-particularly the contribution of its enzymatic activity and interplay with the tumor immune microenvironment-remains poorly defined. Methods: Multi-cohort analysis integrating TCGA, ICGC, GEO, and CPTAC datasets was combined with single-cell transcriptomic profiling, survival and Cox regression modeling, immune infiltration estimation, and in vitro loss- and gain-of-function experiments in ccRCC cell lines. Results: PON2 was markedly elevated in ccRCC tissues, predominantly localizing to malignant epithelial and endothelial cells as determined by single-cell transcriptomic profiling. High PON2 expression correlated with advanced T/M stages and independently predicted poor prognosis. Functional experiments showed that PON2 silencing was associated with reduced tumor cell proliferation, invasion, and glycolysis, while rescue experiments using wild-type-but not S311C mutant-PON2 partially restored these phenotypes. PON2 expression was associated with glycolysis-related metabolic changes and CEBPB-related expression of downstream glycolytic targets, including LDHA and PGK1. Furthermore, PON2-high tumors showed transcriptomic features consistent with an immunosuppressive microenvironment, with higher computational estimates of CD8⁺ T-cell infiltration accompanied by elevated immune checkpoint expression (PD-L1, CTLA4) and higher estimated abundance of immunosuppressive populations (Tregs, MDSCs). Conclusions: Collectively, our findings identify PON2 as a candidate biomarker associated with ccRCC progression and CEBPB-related glycolysis and features consistent with an immunosuppressive microenvironment.
SN - 2072-6694
ER -