AccScience Publishing / TD / Online First / DOI: 10.36922/TD026120026
ORIGINAL RESEARCH ARTICLE

Integrated bioinformatic analysis of RNH1 role in cervical cancer: Methylation, expression, prognostic value, diagnostic value, and association with immune infiltration

Julio Ortiz-Ortiz1† Hilda Jiménez-Wences1† Adán Arizmendi-Izazaga1 Ramón Antaño-Arias2 Francisco I. Torres-Rojas2 Paola Briseño-Díaz3 Eric. G. Salmerón-Bárcenas4*
Show Less
1 Laboratory of Research in Metabolism and Cancer, Faculty of Chemical-Biological Sciences, Autonomous University of Guerrero, Chilpancingo, Guerrero, Mexico
2 Laboratory of Molecular Biomedicine, Faculty of Chemical-Biological Sciences, Autonomous University of Guerrero, Chilpancingo, Guerrero, Mexico
3 Department of Genetics and Molecular Biology, Center for Research and Advanced Studies of the National Polytechnic Institute (CINVESTAV), Mexico City, Mexico
4 Department of Molecular Biomedicine, Center for Research and Advanced Studies of the National Polytechnic Institute (CINVESTAV), Mexico City, Mexico
†These authors contributed equally to this work.
Tumor Discovery, 026120026 https://doi.org/10.36922/TD026120026
Received: 20 March 2026 | Revised: 27 April 2026 | Accepted: 6 May 2026 | Published online: 26 May 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Abstract

Cervical cancer (CC) is the fourth leading cause of cancer incidence and mortality among women worldwide. Currently, the survival rate in patients with advanced CC remains low. Thus, it is necessary to investigate the molecular mechanisms involved in CC. RNH1 has been reported as a tumor suppressor gene in several cancer types; its role in CC remains unclear. In this study, we analyzed the role of RNH1 in CC using a bioinformatics approach. Methylation of the RNH1 promoter was investigated using data from the Cancer Genome Atlas (TCGA) and GSE30760 datasets in the DiseaseMeth and Gene Expression Omnibus (GEO) databases. RNH1 expression was evaluated in samples from TCGA, GSE9750, GSE7803, GSE67522, and the Human Protein Atlas (HPA) datasets in the University of Alabama at Birmingham Cancer Data Analysis Portal, GEO, and HPA platforms. The prognostic and diagnostic value of RNH1 expression was assessed using Kaplan–Meier and receiver operating characteristic curves. Genes correlated with RNH1 expression in CC were identified using the cBioPortal database. Pathway and Gene Ontology (GO) enrichment analyses were performed using Enrichr. Finally, immune infiltration analysis was conducted using the Tumor Immune Estimation Resource database. Our results showed that the RNH1 promoter is aberrantly methylated in CC. Decreased RNH1 expression could be used as a prognostic and diagnostic biomarker in CC. Pathway and GO analyses identified terms associated with CC pathways and biological processes related to immune response. Furthermore, immune infiltration analysis demonstrated that RNH1 expression correlates with the presence of various immune cell types. In conclusion, our findings indicate that RNH1 plays a key role in CC.

Keywords
RNH1
Methylation
Biomarker
Immune infiltration
Cervical cancer
Bioinformatic analysis
Funding
None.
Conflict of interest
The authors declare they have no competing interests.
References
  1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229–263. doi: 10.3322/caac.21834
  2. Siegel RL, Kratzer TB, Giaquinto AN, et al. Cancer statistics, 2025. CA Cancer J Clin. 2025;75(1):10–45. doi: 10.3322/caac.21871
  3. Woodman CB, Collins S, Winter H, et al. Natural history of cervical human papillomavirus infection in young women: a longitudinal cohort study. Lancet. 2001;357(9271):1831– 1836. doi: 10.1016/s0140-6736(00)04956-4
  4. Perkins RB, Wentzensen N, Guido RS, et al. Cervical Cancer Screening: A Review. Jama. 2023;330(6):547–558. doi: 10.1001/jama.2023.13174
  5. Lin H, Wu CH, Fu HC, et al. Recent advances in cervical cancer treatment: Innovations from early-stage to advanced disease. Taiwan J Obstet Gynecol. 2025;64(4):608–615. doi: 10.1016/j.tjog.2025.04.006
  6. Xu M, Cao C, Wu P, et al. Advances in cervical cancer: current insights and future directions. Cancer Commun. 2025;45(2):77–109. doi: 10.1002/cac2.12629
  7. American Cancer Society. Cancer Facts & Figures 2026. Atlanta Am. Cancer Soc. 2026.
  8. Dickson KA, Haigis MC, Raines RT. Ribonuclease inhibitor: structure and function. Prog Nucleic Acid Res Mol Biol. 2005;80:349–374. doi: 10.1016/s0079-6603(05)80009-1
  9. Sarangdhar MA, Allam R. Angiogenin (ANG)-Ribonuclease Inhibitor (RNH1) System in Protein Synthesis and Disease. Int J Mol Sci. 2021;22(3):1287. doi: 10.3390/ijms22031287
  10. Chen S, Ran J, Fan Z, et al. Functional status analysis of RNH1 in bladder cancer for predicting immunotherapy response. Sci Rep. 2023;13(1):12625. doi: 10.1038/s41598-023-39827-7
  11. Zhao W, Liu Y, Yang Y, et al. New link between RNH1 and E2F1: regulates the development of lung adenocarcinoma. BMC Cancer. 2024;24(1): 635. doi: 10.1186/s12885-024-12392-6
  12. Chen JX, Gao Y, Liu JW, et al. Antitumor effects of human ribonuclease inhibitor gene transfected on B16 melanoma cells. Int J Biochem Cell Biol. 2005;37(6):1219–1231. doi: 10.1016/j.biocel.2004.11.020
  13. Tang Y, Ren F, Cong X, et al. Overexpression of ribonuclease inhibitor induces autophagy in human colorectal cancer cells via the Akt/mTOR/ULK1 pathway. Mol Med Rep. 2019;19(5):3519–3526. doi: 10.3892/mmr.2019.10030
  14. Tian YX, Wang DM, Cui XY. Rén rǔxiàn ái zǔzhī zhōng hétáng hésuān méi yìzhì jì jīyīn biǎodá fēnxī. [Analysis of gene expression of ribonuclease inhibitor in human breast cancer tissue]. Ai Zheng. 2004;23(3):269–272. [In Chinese]
  15. Dreos R, Ambrosini G, Perier RC, et al. The Eukaryotic Promoter Database: expansion of EPDnew and new promoter analysis tools. Nucleic Acids Res. 2015;43(Database issue):D92–96. doi: 10.1093/nar/gku1111
  16. Gasteiger E, Gattiker A, Hoogland C, et al. ExPASy: The proteomics server for in-depth protein knowledge and analysis. Nucleic Acids Res 2003;31(13):3784–3788. doi: 10.1093/nar/gkg563
  17. Li LC, Dahiya R. MethPrimer: designing primers for methylation PCRs. Bioinformatics 2002;18(11):1427–1431. doi: 10.1093/bioinformatics/18.11.1427
  18. Teschendorff AE, Jones A, Fiegl H, et al. Epigenetic variability in cells of normal cytology is associated with the risk of future morphological transformation. Genome Med. 2012;4(3):24. doi: 10.1186/gm323
  19. Xing J, Zhai R, Wang C, et al. DiseaseMeth version 3.0: a major expansion and update of the human disease methylation database. Nucleic Acids Res. 2022;50(D1):D1208–D1215. doi: 10.1093/nar/gkab1088
  20. Edgar R, Domrachev M, Lash AE. Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 2002;30(1):207–210. doi: 10.1093/nar/30.1.207
  21. Barrett T, Wilhite SE, Ledoux P, et al. NCBI GEO: archive for functional genomics data sets--update. Nucleic Acids Res. 2013;41(Database issue):D991–995. doi: 10.1093/nar/gks1193
  22. Cerami E, Gao J, Dogrusoz U, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401–404. doi: 10.1158/2159-8290.CD-12-0095
  23. Gao J, Aksoy BA, Dogrusoz U, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6(269):pl1. doi: 10.1126/scisignal.2004088
  24. Scotto L, Narayan G, Nandula SV, et al. Identification of copy number gain and overexpressed genes on chromosome arm 20q by an integrative genomic approach in cervical cancer: potential role in progression. Genes Chromosomes Cancer. 2008;47(9):755–765. doi: 10.1002/gcc.20577
  25. Zhai Y, Kuick R, Nan B, et al. Gene expression analysis of preinvasive and invasive cervical squamous cell carcinomas identifies HOXC10 as a key mediator of invasion. Cancer Res. 2007;67(21):10163–10172. doi: 10.1158/0008-5472.CAN-07-2056
  26. Sharma S, Mandal P, Sadhukhan T, et al. Bridging Links between Long Noncoding RNA HOTAIR and HPV Oncoprotein E7 in Cervical Cancer Pathogenesis. Sci Rep. 2015;5(1):11724. doi: 10.1038/srep11724
  27. Saha SS, Chowdhury RR, Mondal NR, et al. Expression signatures of HOX cluster genes in cervical cancer pathogenesis: Impact of human papillomavirus type 16 oncoprotein E7. Oncotarget. 2017;8(22):36591–36602. doi: 10.18632/oncotarget.16619
  28. Uhlén M, Fagerberg L, Hallström BM, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015;347(6220):1260419. doi: 10.1126/science.1260419
  29. Chandrashekar DS, Karthikeyan SK, Korla PK, et al. UALCAN: An update to the integrated cancer data analysis platform. Neoplasia. 2022;25:18–27. doi: 10.1016/j.neo.2022.01.001
  30. Chandrashekar DS, Bashel B, Balasubramanya SAH, et al. UALCAN: A Portal for Facilitating Tumor Subgroup Gene Expression and Survival Analyses. Neoplasia. 2017;19(8):649–658. doi: 10.1016/j.neo.2017.05.002
  31. Tang Z, Li C, Kang B, et al. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017;45(W1):W98–w102. doi: 10.1093/nar/gkx247
  32. Çorbacıoğlu Ş K, Aksel G. Receiver operating characteristic curve analysis in diagnostic accuracy studies: A guide to interpreting the area under the curve value. Turk J Emerg Med. 2023;23(4):195–198. doi: 10.4103/tjem.tjem_182_23
  33. Youden WJ. Index for rating diagnostic tests. Cancer. 1950;3(1):32–35. doi: 10.1002/1097-0142(1950)3:1<32::aid-cncr2820030106>3.0.co;2-3
  34. Chen EY, Tan CM, Kou Y, et al. Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinform. 2013;14(1):128. doi: 10.1186/1471-2105-14-128
  35. Li B, Severson E, Pignon JC, et al. Comprehensive analyses of tumor immunity: implications for cancer immunotherapy. Genome Biol. 2016;17(1):174. doi: 10.1186/s13059-016-1028-7
  36. Li T, Fan J, Wang B, et al. TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells. Cancer Res. 2017;77(21):e108–e110. doi: 10.1158/0008-5472.Can-17-0307
  37. Almazrouei KM, Mishra V, Pandya H, et al. Tumor Microenvironment and Its Role in Cancer Progression: An Integrative Review. Cureus. 2025;17(9):e92707. doi: 10.7759/cureus.92707
  38. Arneth B. Tumor Microenvironment. Medicina. 2019;56(1):15. doi: 10.3390/medicina56010015
  39. Zhang Z, Liu M, An Y, et al. Targeting immune microenvironment in cervical cancer: current research and advances. J Transl Med. 2025;23(1):888. doi: 10.1186/s12967-025-06896-3
  40. Ma B, Ren C, Yin Y, et al. Immune cell infiltration and prognostic index in cervical cancer: insights from metabolism-related differential genes. Front Immunol. 2024;15:1411132. doi: 10.3389/fimmu.2024.1411132
  41. Petignat P, Roy M. Diagnosis and management of cervical cancer. BMJ. 2007;335(7623):765–768. doi: 10.1136/bmj.39337.615197.80
  42. Zhu H, Zhu H, Tian M, et al. DNA Methylation and Hydroxymethylation in Cervical Cancer: Diagnosis, Prognosis and Treatment. Front Genetics. 2020;11. doi: 10.3389/fgene.2020.00347
  43. Yang C, Zhang ZC, Liu TB, et al. E2F1/2/7/8 as independent indicators of survival in patients with cervical squamous cell carcinoma. Cancer Cell Int. 2020;20(1):500. doi: 10.1186/s12935-020-01594-0
  44. Wang Y, He M, He T, et al. Integrated genomic and transcriptomic analysis reveals the activation of PI3K signaling pathway in HPV-independent cervical cancers. Br J Cancer. 2024;130(6):987–1000. doi: 10.1038/s41416-023-02555-w
  45. Neu C, Beckers C, Frank N, et al. Ribonuclease inhibitor 1 emerges as a potential biomarker and modulates inflammation and iron homeostasis in sepsis. Sci Rep. 2024;14(1):14972. doi: 10.1038/s41598-024-65778-8
  46. Saha D, Angelillo-Scherrer A, Allam R. Ribonuclease Inhibitor (RNH1) Is a Novel Regulator in Myelopoiesis and Resolves Differentiation Blockade in Acute Myeloid Leukemia. Blood. 2024;144(Suppl. 1):4111–4111. doi: 10.1182/blood-2024-202479 (accessed 3/6/2026)
  47. Templeton CW, Laimins LA. p53-dependent R-loop formation and HPV pathogenesis. Proc Natl Acad Sci USA. 2023;120(35):e2305907120. doi: 10.1073/pnas.2305907120
  48. Kind B, Schmidt F, Kretschmer S, et al. Role of RNH1 in the regulation of RNase H2 function. Pediatric Rheumatol. 2015;13(1):O3. doi: 10.1186/1546-0096-13-S1-O3
  49. Chen C, Chen X, Yang Y, et al. Exploring the pathogenic mechanism of RNH1 in colorectal cancer based on eQTL, Multi-omics and deep learning. J Appl Genet. 2025. doi: 10.1007/s13353-025-01029-4
  50. Melssen MM, Sheybani ND, Leick KM, et al. Barriers to immune cell infiltration in tumors. J Immunother Cancer. 2023;11(4):e006401. doi: 10.1136/jitc-2022-006401
  51. Ogasawara A, Hasegawa K. Recent advances in immunotherapy for cervical cancer. Int J Clin Oncol. 2025;30(3):434–448. doi: 10.1007/s10147-025-02699-0
Share
Back to top
Tumor Discovery, Electronic ISSN: 2810-9775 Print ISSN: 3060-8597, Published by AccScience Publishing