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Identification and Validation of Tumor Microenvironment-Associated Signature in Clear-Cell Renal Cell Carcinoma through Integration of DNA Methylation and Gene Expression.
Ye, Zijian; Xu, Jialiang; Zhang, Xin; Zhang, Yifan; Ivanova, Deyana; Lu, Weiyu; Zhang, Jianning; Li, Fangfang; Chen, Xuemei; Wang, Yingxiong; Wang, Meijiao; Xie, Biao.
Afiliación
  • Ye Z; Department of Physiology, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, China.
  • Xu J; Department of Biostatistics, School of Public Health, Chongqing Medical University, Chongqing 400016, China.
  • Zhang X; Department of Physiology, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, China.
  • Zhang Y; Joint International Research Laboratory of Reproduction, Development of the Ministry of Education of China, School of Public Health and Management, Chongqing Medical University, Chongqing 400016, China.
  • Ivanova D; Department of Physiology, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, China.
  • Lu W; Department of Physiology, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, China.
  • Zhang J; Department of Biostatistics, School of Public Health, Chongqing Medical University, Chongqing 400016, China.
  • Li F; Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Chen X; Department of Physiology, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, China.
  • Wang Y; Department of Physiology, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, China.
  • Wang M; Department of Biostatistics, School of Public Health, Chongqing Medical University, Chongqing 400016, China.
  • Xie B; Joint International Research Laboratory of Reproduction, Development of the Ministry of Education of China, School of Public Health and Management, Chongqing Medical University, Chongqing 400016, China.
Int J Mol Sci ; 25(12)2024 Jun 20.
Article en En | MEDLINE | ID: mdl-38928496
ABSTRACT
The tumor microenvironment (TME) is crucial in tumor development, metastasis, and response to immunotherapy. DNA methylation can regulate the TME without altering the DNA sequence. However, research on the methylation-driven TME in clear-cell renal cell carcinoma (ccRCC) is still lacking. In this study, integrated DNA methylation and RNA-seq data were used to explore methylation-driven genes (MDGs). Immune scores were calculated using the ESTIMATE, which was employed to identify TME-related genes. A new signature connected with methylation-regulated TME using univariate, multivariate Cox regression and LASSO regression analyses was developed. This signature consists of four TME-MDGs, including AJAP1, HOXB9, MYH14, and SLC6A19, which exhibit high methylation and low expression in tumors. Validation was performed using qRT-PCR which confirmed their downregulation in ccRCC clinical samples. Additionally, the signature demonstrated stable predictive performance in different subtypes of ccRCC. Risk scores are positively correlated with TMN stages, immune cell infiltration, tumor mutation burden, and adverse outcomes of immunotherapy. Interestingly, the expression of four TME-MDGs are highly correlated with the sensitivity of first-line drugs in ccRCC treatment, especially pazopanib. Molecular docking indicates a high affinity binding between the proteins and pazopanib. In summary, our study elucidates the comprehensive role of methylation-driven TME in ccRCC, aiding in identifying patients sensitive to immunotherapy and targeted therapy, and providing new therapeutic targets for ccRCC treatment.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Carcinoma de Células Renales / Regulación Neoplásica de la Expresión Génica / Metilación de ADN / Microambiente Tumoral / Neoplasias Renales Límite: Female / Humans / Male Idioma: En Revista: Int J Mol Sci Año: 2024 Tipo del documento: Article País de afiliación: China

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Carcinoma de Células Renales / Regulación Neoplásica de la Expresión Génica / Metilación de ADN / Microambiente Tumoral / Neoplasias Renales Límite: Female / Humans / Male Idioma: En Revista: Int J Mol Sci Año: 2024 Tipo del documento: Article País de afiliación: China