AccScience Publishing / EJMO / Online First / DOI: 10.36922/EJMO026220241
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ORIGINAL RESEARCH ARTICLE

Nucleolin overexpression correlates with poor prognosis and immune checkpoint regulation across various cancer types: Insights from The Cancer Genome Atlas and GTEx analyses

Kruthika Prakash1 ,  Janani Balaji1 ,  Surya Babu1 ,  Ramya Lakshmi Rajendran2,3,4 ,  Prakash Gangadaran2,3,4* ,  ArulJothi Kandasamy Nagarajan1* ,  Byeong-Cheol Ahn2,3,4,5*
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1 Department of Genetic Engineering, College of Engineering and Technology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu , India
2 BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Sciences, School of Medicine, Kyungpook National University, Daegu , Republic of Korea
3 Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu , Republic of Korea
4 Cardiovascular Research Institute, Kyungpook National University, Daegu , Republic of Korea
5 Department of Nuclear Medicine, Kyungpook National University Hospital, Daegu , Republic of Korea
EJMO, 026220241 https://doi.org/10.36922/EJMO026220241
Received: 27 May 2026 | Revised: 29 July 2026 | Accepted: 17 August 2026 | Published online: 4 September 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: Nucleolin (NCL) is an established cancer target proposed to modulate the tumor immune microenvironment, but has not been systematically tested across cancers.

Objective: To systematically investigate the pan-cancer association of NCL expression with tumor progression, prognosis, and the tumor immune microenvironment, with emphasis on immune infiltration and immune checkpoint genes.

Methods: We analyzed 9,358 TCGA tumors across 33 cancer types against 7,262 GTEx and 727 adjacent normal samples using uniformly reprocessed transcriptomes, assessing differential expression with Wilcoxon tests and Cliff’s delta, and stage association with the Jonckheere–Terpstra trend test. Three survival endpoints were modeled using multivariable Cox regression, adjusting for age, sex, stage, and grade, with proportional hazards checks. Immune infiltration was estimated by seven deconvolution algorithms as purity-adjusted partial correlations, with checkpoint correlations additionally proliferation-adjusted. All test families were Benjamini–Hochberg-corrected, and the findings were validated in nine independent Clinical Proteomic Tumor Analysis Consortium (CPTAC) cohorts.

Results: NCL was overexpressed in 24 of 29 evaluable cancers (Cliff’s delta up to +0.93) and reduced in ovarian carcinoma; 7 of 9 CPTAC cohorts confirmed elevated NCL protein. A stage-ordered increase was present in only 2 of 17 cancers. After covariate adjustment and false discovery rate correction, NCL remained independently prognostic in only two: kidney renal papillary cell carcinoma (overall survival hazard ratio 2.12, 95% CI 1.37–3.29) and adrenocortical carcinoma (progression-free hazard ratio 2.41, 95% CI 1.40–4.16).

Conclusion: NCL correlated negatively with the microenvironment score in every cancer where the association was significant, and positively with B7-H3 in 21 of 33 cancers, whereas CTLA-4, PD-1, and TIM-3 were largely uncorrelated. NCL, therefore, associates with tumor-intrinsic immunosuppressive ligands and an immune-excluded phenotype rather than with T-cell checkpoints, and its transcript-level prognostic value is limited, consistent with prior evidence that this effect is localization-dependent.

Keywords
Nucleolin
The Cancer Genome Atlas
Tumorigenesis
Immune regulation
Prognostic biomarker
Therapeutic target
Funding
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (NRF-2022R1A2C2005057).
Conflict of interest
Prakash Gangadaran is an Editorial Board Member of this journal but was not in any way involved in the editorial and peer-review process conducted for this paper, directly or indirectly. Separately, other authors declared that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.
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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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