AccScience Publishing / CP / Online First / DOI: 10.36922/CP026060008
Submit to CP
Cite this article
7
Download
53
Views
Journal Browser
Volume | Year
Issue
Search
Forthcoming Issue
Current Issue
View All
News and Announcements
View All
ORIGINAL RESEARCH ARTICLE

Integrated bioinformatics-based identification of shared immune-related biomarkers in hepatocellular carcinoma and major depressive disorder

Shasha Wu1 ,  Xiaofen Fan1 ,  Renhou Zhi2* ,  Huijun Duan1*
Show Less
1 Department of Psychiatry, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, Shanxi, China
2 Department of General Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
CP, 026060008 https://doi.org/10.36922/CP026060008
Received: 5 February 2026 | Revised: 23 March 2026 | Accepted: 24 March 2026 | Published online: 24 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 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Download PDF
XML
Cite
Abstract

Hepatocellular carcinoma (HCC) and major depressive disorder (MDD) are characterized by shared pathophysiological mechanisms. However, the specific molecular indicators and the fundamental biological pathways driving this connection have yet to be fully elucidated. This study aims to identify immune-related molecular signatures shared by HCC and MDD using a systems biology approach and to evaluate their potential prognostic and immune-related relevance. By integrating MDD transcriptomic data from the Gene Expression Omnibus with HCC transcriptomic and clinical data from The Cancer Genome Atlas-Liver Hepatocellular Carcinoma repository, we performed weighted gene co-expression network analysis, Gene Ontology/Kyoto Encyclopedia of Genes and Genomes functional enrichment, Gene Set Enrichment Analysis, and least absolute shrinkage and selection operator-Cox regression to construct a prognostic model. The model was internally evaluated using survival analysis and time-dependent receiver operating characteristic analyses. Furthermore, to quantify the relative abundance of tumor-infiltrating immune cells and verify target mRNA levels, the CIBERSORT algorithm and quantitative reverse transcription polymerase chain reaction assays were implemented, respectively. Among the differentially expressed genes, NIN was identified as a candidate immune-related biomarker associated with HCC and MDD in separate transcriptomic analyses and validation cohorts, offering a crucial target for future research and potential development of early diagnostic tools and therapeutic strategies for this patient population.

Keywords
Major depressive disorder
Hepatocellular carcinoma
Hub genes
Immune cell infiltration
Clinical features
Prognosis
Molecular mechanism
Funding
This work was supported by the Science Foundation of Shanxi Bethune Hospital (no. 2023RC52), the 2024 Annual “Promising Candidates” Cultivation Project for National Natural Science Foundation at Shanxi Bethune Hospital (no. 2024GZRZ12), and Clinical Key Specialty Program of Shanxi Bethune Hospital.
Conflict of interest
The authors declare that they have no competing interests.
References
  1. Liu Q, He H, Yang J, Feng X, Zhao F, Lyu J. Changes in the global burden of depression from 1990 to 2017: Findings from the Global Burden of Disease study. J Psychiatr Res. 2020;126:134-140. doi: 10.1016/j.jpsychires.2019.08.002

 

  1. Oh HM, Son CG. The Risk of Psychological Stress on Cancer Recurrence: A Systematic Review. Cancers (Basel). 2021;13(22):5816. doi: 10.3390/cancers13225816

 

  1. Calderaro J, Seraphin TP, Luedde T, Simon TG. Artificial intelligence for the prevention and clinical management of hepatocellular carcinoma. J Hepatol. 2022;76(6):1348-1361. doi: 10.1016/j.jhep.2022.01.014

 

  1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-249. doi: 10.3322/caac.21660

 

  1. Han T, Zhou Y, Li D. Relationship between hepatocellular carcinoma and depression via online database analysis. Bioengineered. 2021;12(1):1689-1697. doi: 10.1080/21655979.2021.1921552

 

  1. Sun V, Ferrell B, Juarez G, Wagman LD, Yen Y, Chung V. Symptom concerns and quality of life in hepatobiliary cancers. Oncol Nurs Forum. 2008;35(3):E45-E52. doi: 10.1188/08.onf.e45-e52

 

  1. Pu C, Tian S, He S, et al. Depression and stress levels increase risk of liver cancer through epigenetic downregulation of hypocretin. Genes Dis. 2022;9(4):1024-1037. doi: 10.1016/j.gendis.2020.11.013

 

  1. Tang PL, Wang HH, Chou FH. A systematic review and meta-analysis of demoralization and depression in patients with cancer. Psychosomatics. 2015;56(6):634-643. doi: 10.1016/j.psym.2015.06.005

 

  1. Lloyd-Williams M. Difficulties in diagnosing and treating depression in the terminally ill cancer patient. Postgrad Med J. 2000;76(899):555-558. doi: 10.1136/pmj.76.899.555

 

  1. Chen JJ, Huang SS, Li IF, Lin KP, Tsay SL. Prognostic association of demographic and clinical factors with the change rates of symptoms and depression among patients with hepatocellular carcinoma. Support Care Cancer. 2019;27:4665-4674. doi: 10.1007/s00520-019-04776-3

 

  1. Tan DJH, Quek SXZ, Yong JN, et al. Global prevalence of depression and anxiety in patients with hepatocellular carcinoma: Systematic review and meta-analysis. Clin Mol Hepatol. 2022;28(4):864. doi: 10.3350/cmh.2022.0136

 

  1. Wang HJ, Zakhari S, Jung MK. Alcohol, inflammation, and gut-liver-brain interactions in tissue damage and disease development. World J Gastroenterol. 2010;16(11):1304-1313. doi: 10.3748/wjg.v16.i11.1304

 

  1. Valenzuela R, Farías C, Muñoz Y, Zúñiga-Hernández J, Videla LA. Interrelationship between alcohol consumption, overnutrition, and pharmacotherapy for liver steatosis: Considerations and proposals. Mol Cell Endocrinol. 2026;611:112676. doi: 10.1016/j.mce.2025.112676

 

  1. Jia Y, Li F, Liu YF, Zhao JP, Leng MM, Chen L. Depression and cancer risk: a systematic review and meta-analysis. Public Health. 2017;149:138-148. doi: 10.1016/j.puhe.2017.04.026

 

  1. Nikendei C, Terhoeven V, Ehrenthal JC, et al. Depression profile in cancer patients and patients without a chronic somatic disease. Psychooncology. 2018;27(1):83-90. doi: 10.1002/pon.4465

 

  1. Spiegel D, Giese-Davis J. Depression and cancer: mechanisms and disease progression. Biol Psychiatry. 2003;54(3):269- 282. doi: 10.1016/S0006-3223(03)00566-3

 

  1. Liu YZ, Wang YX, Jiang CL. Inflammation: the common pathway of stress-related diseases. Front Hum Neurosci. 2017;11:316. doi: 10.3389/fnhum.2017.00316

 

  1. Hughes MM, Connor TJ, Harkin A. Stress-related immune markers in depression: implications for treatment. Int J Neuropsychopharmacol. 2016;19(6):pyw001. doi: 10.1093/ijnp/pyw001

 

  1. Zhang L, Pan J, Chen W, Jiang J, Huang J. Chronic stress-induced immune dysregulation in cancer: implications for initiation, progression, metastasis, and treatment. Am J Cancer Res. 2020;10(5):1294-1307.

 

  1. Jin Shin K, Jin Lee Y, Ryoul Yang Y, et al. Molecular mechanisms underlying psychological stress and cancer. Curr Pharm Des. 2016;22(16):2389-2402. doi: 10.2174/1381612822666160226144025

 

  1. Menke A, Binder EB. Epigenetic alterations in depression and antidepressant treatment. Dialogues Clin Neurosci. 2014;16(3):395-404. doi: 10.31887/DCNS.2014.16.3/amenke

 

  1. Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics. 2008;9(1):559. doi: 10.1186/1471-2105-9-559

 

  1. Jiao X, Sherman BT, Huang da W, et al. DAVID-WS: a stateful web service to facilitate gene/protein list analysis. Bioinformatics. 2012;28(13):1805-1806. doi: 10.1093/bioinformatics/bts251

 

  1. Newman AM, Liu CL, Green MR, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12(5):453-457. doi: 10.1038/nmeth.3337

 

  1. Pitman A, Suleman S, Hyde N, Hodgkiss A. Depression and anxiety in patients with cancer. BMJ. 2018;361:k1415. doi: 10.1136/bmj.k1415

 

  1. Rice DR, Dalmacy D, Hyer JM, Diaz A, Tsilimigras DI, Pawlik TM. Impact of psychiatric illness on survival among patients with hepatocellular carcinoma. J Gastrointest Surg. 2021;25(12):3242-3243. doi: 10.1007/s11605-021-05029-7

 

  1. Ingelman-Sundberg M. Polymorphism of cytochrome P450 and xenobiotic toxicity. Toxicology. 2002;181-182:447-452. doi: 10.1016/S0300-483X(02)00492-4

 

  1. Ho JC, Cheung ST, Leung KL, Ng IO, Fan ST. Decreased expression of cytochrome P450 2E1 is associated with poor prognosis of hepatocellular carcinoma. Int J Cancer. 2004;111(4):494-500. doi: 10.1002/ijc.20282

 

  1. Zhou Y, Li X, Long G, Tao Y, Zhou L, Tang J. Identification and validation of a tyrosine metabolism-related prognostic prediction model and characterization of the tumor microenvironment infiltration in hepatocellular carcinoma. Front Immunol. 2022;13:994259. doi: 10.3389/fimmu.2022.994259

 

  1. Watanabe A, Higashi T, Sakata T, Nagashima H. Serum amino acid levels in patients with hepatocellular carcinoma. Cancer. 1984;54(9):1875-1882. doi: 10.1002/1097-0142(19841101)54:9<1875::AID-CNCR2820540918>3.0.CO;2-O

 

  1. Mhaidly R, Mechta-Grigoriou F. Fibroblast heterogeneity in tumor microenvironment: Role in immunosuppression and new therapies. Semin Immunol. 2020;49:101417. doi: 10.1016/j.smim.2020.101417

 

  1. Galasso L, Cerrito L, Maccauro V, et al. Inflammatory Response in the Pathogenesis and Treatment of Hepatocellular Carcinoma: A Double-Edged Weapon. Int J Mol Sci. 2024;25(13):7191. doi: 10.3390/ijms25137191

 

  1. Sonali S, Ray B, Ahmed Tousif H, et al. Mechanistic Insights into the Link between Gut Dysbiosis and Major Depression: An Extensive Review. Cells. 2022;11(8):1362. doi: 10.3390/cells11081362

 

  1. Ji Y, Li M, Chang M, et al. Inflammation: Roles in Skeletal Muscle Atrophy. Antioxidants. 2022;11(9):1686. doi: 10.3390/antiox11091686

 

  1. Zheng D, Liwinski T, Elinav E. Interaction between microbiota and immunity in health and disease. Cell Res. 2020;30(6):492-506. doi: 10.1038/s41422-020-0332-7

 

  1. Wu Z, Li S, Zhu X. The mechanism of stimulating and mobilizing the immune system enhancing the anti-tumor immunity. Front Immunol. 2021;12:682435. doi: 10.3389/fimmu.2021.682435

 

  1. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132(7):2557-2576. doi: 10.1053/j.gastro.2007.04.061

 

  1. Yan D, Hou Y, Lei X, et al. The Impact of Polyunsaturated Fatty Acids in Cancer and Therapeutic Strategies. Curr Nutr Rep. 2025;14(1):46. doi: 10.1007/s13668-025-00639-y

 

  1. Colognesi M, Gabbia D, De Martin S. Depression and Cognitive Impairment-Extrahepatic Manifestations of NAFLD and NASH. Biomedicines. 2020;8(7):229. doi: 10.3390/biomedicines8070229

 

  1. Cui S, Lin H, Cui Y, et al. Depression promotes lung carcinoma progression by regulating the tumor microenvironment in tumor-bearing models of C57BL/6J mice. Neurosci Lett. 2021;754:135851. doi: 10.1016/j.neulet.2021.135851

 

  1. Zhao Y, Jia Y, Shi T, et al. Depression promotes hepatocellular carcinoma progression through a glucocorticoid-mediated upregulation of PD-1 expression in tumor-infiltrating NK cells. Carcinogenesis. 2019;40(9):1132-1141. doi: 10.1093/carcin/bgz017

 

  1. Eckerling A, Ricon-Becker I, Sorski L, Sandbank E, Ben- Eliyahu S. Stress and cancer: mechanisms, significance and future directions. Nat Rev Cancer. 2021;21(12):767-785. doi: 10.1038/s41568-021-00395-5

 

  1. Liu Y, Tian S, Ning B, Huang T, Li Y, Wei Y. Stress and cancer: The mechanisms of immune dysregulation and management. Front Immunol. 2022;13:1032294. doi: 10.3389/fimmu.2022.1032294

 

  1. Huakan Z, Wu L, Guifang Y, et al. Inflammation and tumor progression: signaling pathways and targeted intervention. Signal Transduct Target Ther. 2021;6(1):263. doi: 10.1038/s41392-021-00658-5

 

  1. Irwin MR. Sleep and inflammation: partners in sickness and in health. Nat Rev Immunol. 2019;19(11):702-715. doi: 10.1038/s41577-019-0190-z

 

  1. Mogensen MM, Malik A, Piel M, Bouckson-Castaing V, Bornens M. Microtubule minus-end anchorage at centrosomal and non-centrosomal sites: the role of ninein. J Cell Sci. 2000;113(17):3013-3023. doi: 10.1242/jcs.113.17.3013

 

  1. Montgomery S, Mundy N. Positive selection on NIN, a gene involved in neurogenesis, and primate brain evolution. Genes Brain Behav. 2012;11(8):903-910. doi: 10.1111/j.1601-183X.2012.00844.x

 

  1. Ohama Y, Hayashi K. Relocalization of a microtubule-anchoring protein, ninein, from the centrosome to dendrites during differentiation of mouse neurons. Histochem Cell Biol. 2009;132:515-524. doi: 10.1007/s00418-009-0631-z

 

  1. Wang X, Tsai JW, Imai JH, Lian WN, Vallee RB, Shi SH. Asymmetric centrosome inheritance maintains neural progenitors in the neocortex. Nature. 2009;461(7266):947- 955. doi: 10.1038/nature08435

 

  1. Miguel-Hidalgo JJ, Baucom C, Dilley G, et al. Glial fibrillary acidic protein immunoreactivity in the prefrontal cortex distinguishes younger from older adults in major depressive disorder. Biol Psychiatry. 2000;48(8):861-873. doi: 10.1016/S0006-3223(00)00999-9

 

  1. Choi J, Crotty S. Bcl6-mediated transcriptional regulation of follicular helper T cells (TFH). Trends Immunol. 2021;42(4):336-349. doi: 10.1016/j.it.2021.02.002

 

  1. Bian J, Lin J, Long J, et al. T lymphocytes in hepatocellular carcinoma immune microenvironment: insights into human immunology and immunotherapy. Am J Cancer Res. 2020;10(12):4585-4606.

 

  1. Chen MM, Xiao X, Lao XM, et al. Polarization of tissue-resident TFH-like cells in human hepatoma bridges innate monocyte inflammation and M2b macrophage polarization. Cancer Discov. 2016;6(10):1182-1195. doi: 10.1158/2159-8290.CD-16-0329

 

  1. Zongyi Y, Xiaowu L. Immunotherapy for hepatocellular carcinoma. Cancer Lett. 2020;470:8-17. doi: 10.1016/j.canlet.2019.12.002

 

  1. Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, Ley K. Development of monocytes, macrophages, and dendritic cells. Science. 2010;327(5966):656-661. doi: 10.1126/science.1178331

 

  1. Lewis M, Merched A. Tumor-Associated Macrophages, Inflammation and Pathogenesis of Hepatocellular Carcinoma. J Mol Genet Med. 2014;8(3):132. doi: 10.4172/1747-0862.1000132

 

  1. Xu W, Cheng Y, Guo Y, Yao W, Qian H. Targeting tumor associated macrophages in hepatocellular carcinoma. Biochem Pharmacol. 2022;199:114990. doi: 10.1016/j.bcp.2022.114990

 

  1. Li S, Zhou C, Xu Y, et al. Similarity and potential relation between periimplantitis and rheumatoid arthritis on transcriptomic level: results of a bioinformatics study. Front Immunol. 2021;12:702661. doi: 10.3389/fimmu.2021.702661
Next article in this issue
Share
Back to top
Cancer Plus, Electronic ISSN: 2661-3840 Print ISSN: 2661-3832, Published by AccScience Publishing
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here
Accept