Tumor Microenvironment in Clear Cell Renal Cell Carcinoma: A Comprehensive Analysis
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Abstract
Background: M6A RNA methylation and the tumor microenvironment (TME) have been reported to play important roles in the progression and prognosis of clear cell renal cell carcinoma (ccRCC). However, whether m6A RNA methylation regulators affect the TME in ccRCC remains unknown. Thus, we aimed to evaluate comprehensively the effect of m6A RNA methylation regulators on the TME in ccRCC.
Methods: Transcriptome data of ccRCC were obtained from TCGA database. Consensus clustering analysis was conducted based on the expression of m6A RNA methylation regulators. Survival differences were evaluated by Kaplan–Meier analysis between the clusters. The DESeq2 package was used to analyze the differentially expressed genes (DEGs) between the clusters. GO and KEGG pathway analyses were performed by the ClusterProfiler R package. The CIBERSORT algorithm was used to evaluate immune infiltration.
Results: The expression of 15 m6A regulators significantly differed between ccRCC and normal kidney tissues. Based on the expression of these 15 m6A regulators, two clusters were identified by consensus clustering, in which cluster 1 had better overall survival (OS). Overall, 4,429 DEGs were identified between the two clusters and were enriched in immune-related biological processes. Cluster 1 had lower immune and ESTIMATE scores, higher expression of HLA and lower expression of immune checkpoint molecules. Moreover, immune infiltration and expressions of Th1/IFNγ gene signature were also significantly different between the two clusters.
Conclusion: Our study revealed m6A regulators were important participants in the development of ccRCC, with a close relationship with the TME.
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32. Huang H, Han Y, Zhang C, et al (2016). HNRNPC as a candidate biomarker for chemoresistance in gastric cancer. Tumour Biol, 37(3): 3527-34.
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34. Pitt JM, Vetizou M, Daillere R, et al (2016). Resistance Mechanisms to Immune-Checkpoint Blockade in Cancer: Tumor-Intrinsic and -Extrinsic Factors. Immunity, 44(6): 1255-69.
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36. Xu S, Tang L, Dai G, Luo C, Liu Z (2020). Expression of m6A Regulators Correlated With Immune Microenvironment Predicts Therapeutic Efficacy and Prognosis in Gliomas. Front Cell Dev Biol, 8: 594112.
37. Liu J, Nie S, Wu Z, et al (2020). Exploration of a novel prognostic risk signatures and immune checkpoint molecules in endometrial carcinoma microenvironment. Genomics, 112(5): 3117-3134.
38. Chon HJ, Lee WS, Yang H, et al (2019). Tumor Microenvironment Remodeling by Intratumoral Oncolytic Vaccinia Virus Enhances the Efficacy of Immune-Checkpoint Blockade. Clin Cancer Res, 25(5): 1612-1623.
2. Rini BI, Campbell SC, Escudier B (2009). Renal cell carcinoma. Lancet, 373(9669): 1119-32.
3. Greef B,Eisen T (2016). Medical treatment of renal cancer: new horizons. Br J Cancer, 115(5): 505-16.
4. Stewart SB, Thompson RH, Psutka SP, et al (2014). Evaluation of the National Comprehensive Cancer Network and American Urological Association renal cell carcinoma surveillance guidelines. J Clin Oncol, 32(36): 4059-65.
5. Caceres W, Cruz-Chacon A (2011). Renal cell carcinoma: molecularly targeted therapy. P R Health Sci J, 30(2): 73-7.
6. Wang S, Sun C, Li J, et al (2017). Roles of RNA methylation by means of N(6)-methyladenosine (m(6)A) in human cancers. Cancer Lett, 408: 112-120.
7. Du K, Zhang L, Lee T,Sun T (2019). m(6)A RNA Methylation Controls Neural Development and Is Involved in Human Diseases. Mol Neurobiol, 56(3): 1596-1606.
8. Chen M,Wong CM (2020). The emerging roles of N6-methyladenosine (m6A) deregulation in liver carcinogenesis. Mol Cancer, 19(1): 44.
9. Cao G, Li HB, Yin Z, Flavell RA (2016). Recent advances in dynamic m6A RNA modification. Open Biol, 6(4): 160003.
10. Qin Y, Li L, Luo E, et al (2020). Role of m6A RNA methylation in cardiovascular disease (Review). Int J Mol Med, 46(6): 1958-1972.
11. Chen J, Yu K, Zhong G, Shen W (2020). Identification of a m (6) A RNA methylation regulators-based signature for predicting the prognosis of clear cell renal carcinoma. Cancer Cell Int, 20: 157.
12. Zhang QJ, Luan JC, Song LB, et al (2020). m6A RNA methylation regulators correlate with malignant progression and have potential predictive values in clear cell renal cell carcinoma. Exp Cell Res, 392(1): 112015.
13. Liu T, Li C, Jin L, Li C, Wang L (2019). The Prognostic Value of m6A RNA Methylation Regulators in Colon Adenocarcinoma. Med Sci Monit, 25: 9435-9445.
14. Chen M, Nie ZY, Wen XH, Gao YH, Cao H, Zhang SF (2019). m6A RNA methylation regulators can contribute to malignant progression and impact the prognosis of bladder cancer. Biosci Rep, 39(12): BSR20192892.
15. Lei X, Lei Y, Li JK, et al (2020). Immune cells within the tumor microenvironment: Biological functions and roles in cancer immunotherapy. Cancer Lett, 470: 126-133.
16. Lee YS,Cho YB (2020). CCL7 Signaling in the Tumor Microenvironment. Adv Exp Med Biol, 1231: 33-43.
17. Senbabaoglu Y, Gejman RS, Winer AG, et al (2016). Tumor immune microenvironment characterization in clear cell renal cell carcinoma identifies prognostic and immunotherapeutically relevant messenger RNA signatures. Genome Biol, 17(1): 231.
18. Wang L, Hui H, Agrawal K, et al (2020). m(6) A RNA methyltransferases METTL3/14 regulate immune responses to anti-PD-1 therapy. EMBO J, 39(20): e104514.
19. Li N, Kang Y, Wang L, et al (2020). ALKBH5 regulates anti-PD-1 therapy response by modulating lactate and suppressive immune cell accumulation in tumor microenvironment. Proc Natl Acad Sci U S A, 117(33): 20159-20170.
20. Zhang B, Wu Q, Li B, Wang D, Wang L, Zhou YL (2020). m(6)A regulator-mediated methylation modification patterns and tumor microenvironment infiltration characterization in gastric cancer. Mol Cancer, 19(1): 53.
21. Zhou GQ, Lv JW, Tang LL, et al (2020). Evaluation of the National Comprehensive Cancer Network and European Society for Medical Oncology Nasopharyngeal Carcinoma Surveillance Guidelines. Front Oncol, 10: 119.
22. Xu Z, Chen Q, Shu L, Zhang C, Liu W, Wang P. (2022). Expression profiles of m6A RNA methylation regulators, PD-L1 and immune infiltrates in gastric cancer. Front Oncol, 12: 970367.
23. Zheng Z, Mao S, Guo Y, et al (2020). N6methyladenosine RNA methylation regulators participate in malignant progression and have prognostic value in clear cell renal cell carcinoma. Oncol Rep, 43(5): 1591-1605.
24. Gao W, Cheng L, He S, et al (2020). Multiomics integrative analysis for gene signatures and prognostic values of m(6)A regulators in pancreatic adenocarcinoma: a retrospective study in The Cancer Genome Atlas project. Aging (Albany NY), 12(20): 20587-20610.
25. Zhou X, Han J, Zhen X, et al (2020). Analysis of Genetic Alteration Signatures and Prognostic Values of m6A Regulatory Genes in Head and Neck Squamous Cell Carcinoma. Front Oncol, 10: 718.
26. Liu L, Liu X, Dong Z, et al (2019). N6-methyladenosine-related Genomic Targets are Altered in Breast Cancer Tissue and Associated with Poor Survival. J Cancer, 10(22): 5447-5459.
27. Cui XH, Hu SY, Zhu CF, Qin XH (2020). Expression and prognostic analyses of the insulin-like growth factor 2 mRNA binding protein family in human pancreatic cancer. BMC Cancer, 20(1): 1160.
28. Li J, Rao B, Yang J, et al (2020). Dysregulated m6A-Related Regulators Are Associated With Tumor Metastasis and Poor Prognosis in Osteosarcoma. Front Oncol, 10: 769.
29. Niu Y, Lin Z, Wan A, et al (2019). RNA N6-methyladenosine demethylase FTO promotes breast tumor progression through inhibiting BNIP3. Mol Cancer, 18(1): 46.
30. Chen Y, Zhao Y, Chen J, et al (2020). ALKBH5 suppresses malignancy of hepatocellular carcinoma via m(6)A-guided epigenetic inhibition of LYPD1. Mol Cancer, 19(1): 123.
31. Zhang Y, Liu X, Liu L, Li J, Hu Q,Sun R (2020). Expression and Prognostic Significance of m6A-Related Genes in Lung Adenocarcinoma. Med Sci Monit, 26: e919644.
32. Huang H, Han Y, Zhang C, et al (2016). HNRNPC as a candidate biomarker for chemoresistance in gastric cancer. Tumour Biol, 37(3): 3527-34.
33. Zhao X, Cui L (2019). Development and validation of a m(6)A RNA methylation regulators-based signature for predicting the prognosis of head and neck squamous cell carcinoma. Am J Cancer Res, 9(10): 2156-2169.
34. Pitt JM, Vetizou M, Daillere R, et al (2016). Resistance Mechanisms to Immune-Checkpoint Blockade in Cancer: Tumor-Intrinsic and -Extrinsic Factors. Immunity, 44(6): 1255-69.
35. Popovic A, Jaffee EM,Zaidi N (2018). Emerging strategies for combination checkpoint modulators in cancer immunotherapy. J Clin Invest, 128(8): 3209-3218.
36. Xu S, Tang L, Dai G, Luo C, Liu Z (2020). Expression of m6A Regulators Correlated With Immune Microenvironment Predicts Therapeutic Efficacy and Prognosis in Gliomas. Front Cell Dev Biol, 8: 594112.
37. Liu J, Nie S, Wu Z, et al (2020). Exploration of a novel prognostic risk signatures and immune checkpoint molecules in endometrial carcinoma microenvironment. Genomics, 112(5): 3117-3134.
38. Chon HJ, Lee WS, Yang H, et al (2019). Tumor Microenvironment Remodeling by Intratumoral Oncolytic Vaccinia Virus Enhances the Efficacy of Immune-Checkpoint Blockade. Clin Cancer Res, 25(5): 1612-1623.
| Files | ||
| Issue | Vol 53 No 11 (2024) | |
| Section | Original Article(s) | |
| Keywords | ||
| M6A RNA methylation regulator Tumor microenvironment Clear cell renal cell carcinoma | ||
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How to Cite
1.
Guo Z, Wang X, Huang S, Weng G. Tumor Microenvironment in Clear Cell Renal Cell Carcinoma: A Comprehensive Analysis. Iran J Public Health. 2024;53(11):2538-2550.
