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ORIGINAL RESEARCH ARTICLE

Pan-cancer characterization of CHP1 identifies its role in tumor progression and immune microenvironment remodeling

Cui-Fang Han1* ,  Ri-Ting Zhu1,2 ,  Xiao-Min Liu1,2
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1 Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, Guangdong Medical University, Dongguan, Guangdong, China
2 Department of Pharmacology, School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong, China
EJMO, 025470489 https://doi.org/10.36922/EJMO025470489
Received: 19 November 2025 | Revised: 1 January 2026 | Accepted: 30 January 2026 | Published online: 27 April 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
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Abstract

Introduction: Calcineurin B homologous protein 1 (CHP1), a crucial cofactor of the sodium–hydrogen exchanger 1 (NHE1), plays a pivotal role in triglyceride synthesis and storage within the endoplasmic reticulum. Increasing evidence suggests that CHP1 participates in biological processes central to tumorigenesis.

Objective: This study aims to systematically investigate the expression profile of CHP1 across multiple human cancers through a pan-cancer analysis and evaluate its associations with clinical outcomes and immune cell infiltration through integrated bioinformatics approaches.

Methods: Expression and clinical data from 33 cancer types were obtained from The Cancer Genome Atlas and Genotype-Tissue Expression (GTEx) databases. Analyses of CHP1 expression levels, tissue distribution, stage-specific variation, prognostic value, diagnostic performance, gene alterations, immune infiltration, protein–protein interactions, and enrichment pathways were performed using the Human Protein Atlas, Gene Expression Profiling Interactive Analysis 2, Tumor Immune Estimation Resource 2, and Search Tool for the Retrieval of Interacting Genes/Proteins platforms.

Results: CHP1 expression was significantly downregulated in 11 tumor types compared with corresponding adjacent normal tissues. Higher CHP1 expression was associated with a favorable prognosis in several cancer types and demonstrated high diagnostic accuracy.

Conclusion: CHP1 is frequently downregulated across multiple cancers and is closely linked to patient survival, supporting its potential as a prognostic biomarker. Its significant association with immune infiltration suggests a potential role in modulating the tumor immune microenvironment, highlighting CHP1 as a promising therapeutic target in pan-cancer settings.

Keywords
Calcineurin B homologous protein 1
Pan-cancer analysis
Prognosis
Immune infiltration
Funding
This research was funded by the National Natural Science Foundation of China (grant number 81902855) and the Guangdong Basic and Applied Basic Research Foundation (grant number 2023A1515140151)..
Conflict of interest
The authors declare that they have no competing interests.
References
  1. Sobin L, Barcus M, Branton PA, et al. Histologic and Quality Assessment of Genotype-Tissue Expression (GTEx) Research Samples: A Large Postmortem Tissue Collection. Arch Pathol Lab Med. 2025;149(3):217-232. doi: 10.5858/arpa.2023-0467-OA
  2. Campanharo CV, Dos Santos Silveira LV, Meira DD, et al. Pan-cancer and multiomics: advanced strategies for diagnosis, prognosis, and therapy in the complex genetic and molecular universe of cancer. Clin Transl Oncol. 2024;27(7):2936-2954. doi: 10.1007/s12094-024-03819-4
  3. El-Tanani M, Rabbani SA, Babiker R, et al. Unraveling the tumor microenvironment: Insights into cancer metastasis and therapeutic strategies. Cancer Lett. 2024;591:216894. doi: 10.1016/j.canlet.2024.216894
  4. Lin X, Barber DL. A calcineurin homologous protein inhibits GTPase-stimulated Na-H exchange. Proc Natl Acad Sci USA. 1996;93(22):12631-12636. doi: 10.1073/pnas.93.22.12631
  5. Dong Y, Gao Y, Ilie A, et al. Structure and mechanism of the human NHE1-CHP1 complex. Nat Commun. 2021;12(1):3474. doi: 10.1038/s41467-021-23496-z
  6. Dong Y, Li H, Ilie A, et al. Structural basis of autoinhibition of the human NHE3-CHP1 complex. Sci Adv. 2022;8(21):eabn3925. doi: 10.1126/sciadv.abn3925
  7. Kim BS, Lee K, Jung HJ, Bhattarai D, Kwon HJ. HIF-1α suppressing small molecule, LW6, inhibits cancer cell growth by binding to calcineurin b homologous protein 1. Biochem Biophys Res Commun. 2015;458(1):14-20. doi: 10.1016/j.bbrc.2015.01.031
  8. Ermak G, Morgan TE, Davies KJ. Chronic overexpression of the calcineurin inhibitory gene DSCR1 (Adapt78) is associated with Alzheimer’s disease. J Biol Chem. 2001;276(42):38787-38794. doi: 10.1074/jbc.M102829200
  9. Zhu XG, Puthenveedu SN, Shen Y, et al. CHP1 Regulates Compartmentalized Glycerolipid Synthesis by Activating GPAT4. Mol Cell. 2019;74(1):45-58.e7. doi: 10.1016/j.molcel.2019.01.037
  10. Di Sole F, Vadnagara K, Moe OW, Babich V. Calcineurin homologous protein: a multifunctional Ca2+-binding protein family. Am J Physiol Renal Physiol. 2012;303(2):F165-F179. doi: 10.1152/ajprenal.00628.2011
  11. Xi D, Wang J, Yang Y, Ji F, Li C, Yan X. A novel natural killer-related signature to effectively predict prognosis in hepatocellular carcinoma. BMC Med Genomics. 2023;16(1):211. doi: 10.1186/s12920-023-01638-0
  12. Wu Y, Zhu RT, Chen JR, et al. Targeting Sodium Transport Reveals CHP1 Downregulation as a Novel Molecular Feature of Malignant Progression in Clear Cell Renal Cell Carcinoma: Insights from Integrated Multi-Omics Analyses. Biomolecules. 2025;15(7):1019. doi: 10.3390/biom15071019
  13. Liu J, Lichtenberg T, Hoadley KA, et al. An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics. Cell. 2018;173(2):400-416.e11. doi: 10.1016/j.cell.2018.02.052
  14. Uhlen M, Fagerberg L, Hallstrom BM, et al. Tissue-based map of the human proteome. Science. 2015;347(6220):1260419. doi: 10.1126/science.1260419
  15. Sjostedt E, Zhong W, Fagerberg L, et al. An atlas of the protein-coding genes in the human, pig, and mouse brain. Science. 2020;367(6482):eaay5947. doi: 10.1126/science.aay5947
  16. Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. 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
  17. Lanczky A, Gyorffy B. Web-Based Survival Analysis Tool Tailored for Medical Research (KMplot): Development and Implementation. J Med Internet Res. 2021;23(7):e27633. doi: 10.2196/27633
  18. 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
  19. Thorsson V, Gibbs DL, Brown SD, et al. The Immune Landscape of Cancer. Immunity. 2018;48(4):812-830.e14. doi: 10.1016/j.immuni.2018.03.023
  20. Bonneville R, Krook MA, Kautto EA, et al. Landscape of Microsatellite Instability Across 39 Cancer Types. JCO Precis Oncol. 2017;(1):1-15. doi: 10.1200/po.17.00073
  21. Li T, Fu J, Zeng Z, et al. TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res. 2020;48(W1):W509-W514. doi: 10.1093/nar/gkaa407
  22. He Y, Jiang Z, Chen C, Wang X. Classification of triple-negative breast cancers based on Immunogenomic profiling. J Exp Clin Cancer Res. 2018;37(1):327. doi: 10.1186/s13046-018-1002-1
  23. Banta KL, Xu X, Chitre AS, et al. Mechanistic convergence of the TIGIT and PD-1 inhibitory pathways necessitates co-blockade to optimize anti-tumor CD8(+) T cell responses. Immunity. 2022;55(3):512-526.e9. doi: 10.1016/j.immuni.2022.02.005
  24. Szklarczyk D, Gable AL, Nastou KC, et al. The STRING database in 2021: customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res. 2021;49(D1):D605-D612. doi: 10.1093/nar/gkaa1074
  25. Kanehisa M, Furumichi M, Sato Y, Kawashima M, Ishiguro- Watanabe M. KEGG for taxonomy-based analysis of pathways and genomes. Nucleic Acids Res. 2023;51(D1):D587-D592. doi: 10.1093/nar/gkac963
  26. Ashburner M, Ball CA, Blake JA, et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet. 2000;25(1):25-29. doi: 10.1038/75556
  27. Kanehisa M, Goto S. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 2000;28(1):27-30. doi: 10.1093/nar/28.1.27
  28. Jassal B, Matthews L, Viteri G, et al. The reactome pathway knowledgebase. Nucleic Acids Res. 2020;48(D1):D498-D503. doi: 10.1093/nar/gkz1031
  29. Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102(43):15545-15550. doi: 10.1073/pnas.0506580102
  30. Timm S, Titus B, Bernd K, Barroso M. The EF-hand Ca(2+)-binding protein p22 associates with microtubules in an N-myristoylation-dependent manner. Mol Biol Cell. 1999;10(10):3473-3488. doi: 10.1091/mbc.10.10.3473
  31. Andrade J, Pearce ST, Zhao H, Barroso M. Interactions among p22, glyceraldehyde-3-phosphate dehydrogenase and microtubules. Biochem J. 2004;384(2):327-336. doi: 10.1042/BJ20040622
  32. Zhang X, Kumstel S, Jiang K, et al. LW6 enhances chemosensitivity to gemcitabine and inhibits autophagic flux in pancreatic cancer. J Adv Res. 2019;20:9-21. doi: 10.1016/j.jare.2019.04.006
  33. Lin X, Sikkink RA, Rusnak F, Barber DL. Inhibition of calcineurin phosphatase activity by a calcineurin B homologous protein. J Biol Chem. 1999;274(51):36125- 36131. doi: 10.1074/jbc.274.51.36125
  34. Jimenez-Vidal M, Srivastava J, Putney LK, Barber DL. Nuclear-localized calcineurin homologous protein CHP1 interacts with upstream binding factor and inhibits ribosomal RNA synthesis. J Biol Chem. 2010;285(47):36260- 36266. doi: 10.1074/jbc.M110.165555
  35. Nakamura N, Miyake Y, Matsushita M, Tanaka S, Inoue H, Kanazawa H. KIF1Bbeta2, capable of interacting with CHP, is localized to synaptic vesicles. J Biochem. 2002;132(3):483- 491. doi: 10.1093/oxfordjournals.jbchem.a003246
  36. Matsushita M, Tanaka S, Nakamura N, Inoue H, Kanazawa H. A novel kinesin-like protein, KIF1Bbeta3 is involved in the movement of lysosomes to the cell periphery in non-neuronal cells. Traffic. 2004;5(3):140-151. doi: 10.1111/j.1600-0854.2003.00165.x
  37. Yang SZ, Wang JT, Yu WW, et al. Downregulation of KIF1B mRNA in hepatocellular carcinoma tissues correlates with poor prognosis. World J Gastroenterol. 2015;21(27):8418- 8424. doi: 10.3748/wjg.v21.i27.8418
  38. Xue X, Jaulin F, Espenel C, Kreitzer G. PH-domain-dependent selective transport of p75 by kinesin-3 family motors in non-polarized MDCK cells. J Cell Sci. 2010;123(10):1732-1741. doi: 10.1242/jcs.056366
  39. Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022;12(1):31-46. doi: 10.1158/2159-8290.CD-21-1059
  40. Lenoir WF, Morgado M, DeWeirdt PC, et al. Discovery of putative tumor suppressors from CRISPR screens reveals rewired lipid metabolism in acute myeloid leukemia cells. Nat Commun. 2021;12(1):6506. doi: 10.1038/s41467-021-26867-8
  41. Chen YQ, Kuo MS, Li S, et al. AGPAT6 is a novel microsomal glycerol-3-phosphate acyltransferase. J Biol Chem. 2008;283(15):10048-10057. doi: 10.1074/jbc.M708151200
  42. Matsumoto M, Miyake Y, Nagita M, et al. A serine/threonine kinase which causes apoptosis-like cell death interacts with a calcineurin B-like protein capable of binding Na(+)/H(+) exchanger. J Biochem. 2001;130(2):217-225. doi: 10.1093/oxfordjournals.jbchem.a002975
  43. Nagita M, Inoue H, Nakamura N, Kanazawa H. Two nuclear export signals specify the cytoplasmic localization of calcineurin B homologous protein 1. J Biochem. 2003;134(6):919-925. doi: 10.1093/jb/mvg223
  44. Kuwahara H, Kamei J, Nakamura N, Matsumoto M, Inoue H, Kanazawa H. The apoptosis-inducing protein kinase DRAK2 is inhibited in a calcium-dependent manner by the calcium-binding protein CHP. J Biochem. 2003;134(2):245- 250. doi: 10.1093/jb/mvg137
  45. Kuwahara H, Nakamura N, Kanazawa H. Nuclear localization of the serine/threonine kinase DRAK2 is involved in UV-induced apoptosis. Biol Pharm Bull. 2006;29(2):225-233. doi: 10.1248/bpb.29.225
  46. Mao J, Qiao X, Luo H, Wu J. Transgenic drak2 overexpression in mice leads to increased T cell apoptosis and compromised memory T cell development. J Biol Chem. 2006;281(18):12587-12595. doi: 10.1074/jbc.M600497200
  47. Weist BM, Hernandez JB, Walsh CM. Loss of DRAK2 signaling enhances allogeneic transplant survival by limiting effector and memory T cell responses. Am J Transplant. 2012;12(8):2220-2227. doi: 10.1111/j.1600-6143.2012.04056.x
  48. Yang KM, Kim W, Bae E, et al. DRAK2 participates in a negative feedback loop to control TGF-beta/Smads signaling by binding to type I TGF-beta receptor. Cell Rep. 2012;2(5):1286-1299. doi: 10.1016/j.celrep.2012.09.028
  49. Mendoza-Ferreira N, Coutelier M, Janzen E, et al. Biallelic CHP1 mutation causes human autosomal recessive ataxia by impairing NHE1 function. Neurol Genet. 2018;4(1):e209. doi: 10.1212/NXG.0000000000000209

50. Janzen E, Mendoza-Ferreira N, Hosseinibarkooie S, et al. CHP1 reduction ameliorates spinal muscular atrophy pathology by restoring calcineurin activity and endocytosis. Brain. 2018;141(8):2343-2361. doi: 10.1093/brain/awy167

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Eurasian Journal of Medicine and Oncology, Electronic ISSN: 2587-196X Print ISSN: 2587-2400, Published by AccScience Publishing
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