Identification and Validation of Tumor Microenvironment-Associated Signature in Clear-Cell Renal Cell Carcinoma through Integration of DNA Methylation and Gene Expression

作者全名：Ye, Zijian; Xu, Jialiang; Zhang, Xin; Zhang, Yifan; Ivanova, Deyana; Lu, Weiyu; Zhang, Jianning; Li, Fangfang; Chen, Xuemei; Wang, Yingxiong; Wang, Meijiao; Xie, Biao

作者地址：[Ye, Zijian; Xu, Jialiang; Zhang, Xin; Zhang, Yifan; Lu, Weiyu; Zhang, Jianning; Wang, Meijiao] Chongqing Med Univ, Sch Basic Med Sci, Dept Physiol, Chongqing 400016, Peoples R China; [Ye, Zijian; Zhang, Yifan; Zhang, Jianning; Xie, Biao] Chongqing Med Univ, Sch Publ Hlth, Dept Biostat, Chongqing 400016, Peoples R China; [Xu, Jialiang; Li, Fangfang; Chen, Xuemei; Wang, Yingxiong; Wang, Meijiao] Chongqing Med Univ, Sch Publ Hlth & Management, Joint Int Res Lab Reprod, Dev Minist Educ China, Chongqing 400016, Peoples R China; [Ivanova, Deyana] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA

通信作者：Wang, MJ (通讯作者)，Chongqing Med Univ, Sch Basic Med Sci, Dept Physiol, Chongqing 400016, Peoples R China.; Xie, B (通讯作者)，Chongqing Med Univ, Sch Publ Hlth, Dept Biostat, Chongqing 400016, Peoples R China.; Wang, MJ (通讯作者)，Chongqing Med Univ, Sch Publ Hlth & Management, Joint Int Res Lab Reprod, Dev Minist Educ China, Chongqing 400016, Peoples R China.

来源：INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES

ESI学科分类：CHEMISTRY

WOS号：WOS:001256609300001

JCR分区：Q1

影响因子：4.9

年份：2024

卷号：25

期号：12

开始页：　

结束页：　

文献类型：Article

关键词：clear-cell renal cell carcinoma; molecular docking; tumor microenvironment; DNA methylation; prognostic signature

摘要：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.

基金机构：National Natural Science Foundation of China [82171624, 82204159]; Chongqing Natural Science Foundation [cstc2020jcyj-msxmX0294]; Science and Technology Project of Chongqing Yuzhong District [20200103]; Science and Technology Research Program of Chongqing Municipal Education Commission [KJQN202300423]; Chongqing Maternal and Child Disease Prevention and Control and Public Health Research Center Open Project [CQFYJB01001]

基金资助正文：This research was funded by the National Natural Science Foundation of China (Nos.82171624, 82204159), the Chongqing Natural Science Foundation (No. cstc2020jcyj-msxmX0294), the Science and Technology Project of Chongqing Yuzhong District (No. 20200103), the Science and Technology Research Program of Chongqing Municipal Education Commission (KJQN202300423), and the Chongqing Maternal and Child Disease Prevention and Control and Public Health Research Center Open Project (CQFYJB01001).