Identification of Hub Genes Associated with Bile Duct Cancer Using Integrated Gene Expression Data with Protein-Protein Interaction Network
Narmadha Ramasamy 1,
Pogala Hema Vardhan 1,
Kannan Muthu 1 * More Detail
1 Department of Bioinformatics, Saveetha School of Engineering, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, India
* Corresponding Author
J CLIN MED KAZ, Volume 23, Issue 3, pp. 11-23.
https://doi.org/10.23950/jcmk/18500
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Author Contributions: Conceptualization, M. K.; methodology, R. N., P. H. V. and M. K; validation, M. K. and P. H. V; formal analysis, R. N.; investigation, P. H. V.; resources, P. H. V.; data curation, R. N., P. H. V.; writing – original draft preparation, P. H. V. and R. N.; writing – review and editing, R. N. and P. H. V.; visualization, R. N. and P. H. V.; supervision, M. K.; project administration, M. K. All authors have read and agreed to the published version of the manuscript.
Data availability statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.
Artificial Intelligence (AI) Disclosure Statement: The authors declare no AI Tools used for preparation of this work.
ABSTRACT
Introduction: Bile duct cancer (cholangiocarcinoma) is an uncommon but highly aggressive malignancy characterized by late diagnosis and poor prognosis. Molecular profiling is essential to understand its pathogenesis and identify biomarkers for early detection and targeted therapy. This study aimed to identify key regulatory genes and molecular pathways associated with bile duct cancer using an integrated bioinformatics approach.
Methods: Gene expression datasets (GSE131027 and GSE107754) were retrieved from the NCBI Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified after normalization and statistical analysis. Protein–protein interaction (PPI) networks were constructed using the STRING database and visualized in Cytoscape. Hub genes were determined using the Cytohubba plugin based on topological parameters. Functional enrichment and pathway analyses were performed using ClueGO and BiNGO to explore associated biological processes and molecular functions.
Results: A total of over 1,000 DEGs were identified across datasets. Network and enrichment analyses revealed seven major hub genes: TP53, HIST1H3F, H2AFZ, FOS, POLR2B, CAV1, and SMAD3. These genes were strongly linked to tumor suppression, oxidative stress response, miRNA transcription regulation, and DNA repair processes. GO and KEGG analyses highlighted pathways associated with oncogenesis, reactive nitrogen species metabolism, and post-transcriptional gene regulation, emphasizing their relevance in bile duct cancer progression.
Conclusion: This integrative bioinformatics study identified critical hub genes and molecular pathways that may serve as potential biomarkers and therapeutic targets for bile duct cancer. Further validation and molecular docking studies could facilitate the development of targeted drugs and improve treatment outcomes.
CITATION
Ramasamy N, Vardhan PH, Muthu K. Identification of Hub Genes Associated with Bile Duct Cancer Using Integrated Gene Expression Data with Protein-Protein Interaction Network. J CLIN MED KAZ. 2026;23(3):11-23.
https://doi.org/10.23950/jcmk/18500
REFERENCES
- Chun K. Recent Classifications of the Common Bile Duct Injury. Korean J. Hepato-Biliary-Pancreatic Surg. 2014; 18: 69, https://doi.org/10.14701/kjhbps.2014.18.3.69.
- Joo I, Lee JM. Imaging Bile Duct Tumors: Pathologic Concepts, Classification, and Early Tumor Detection. Abdom. Imaging. 2013; 38: 1334–1350. https://doi.org/10.1007/s00261-013-0027-3.
- Lee SH, Song SY. Recent Advancement in Diagnosis of Biliary Tract Cancer through Pathological and Molecular Classifications. Cancers (Basel). 2024; 16: 1761. https://doi.org/10.3390/cancers16091761.
- Oba A, Del Chiaro M, Satoi S, Kim S, Takahashi H, Yu J, Hioki M, Tanaka M, Kato Y, Ariake K, Wu YHA, Inoue Y, Takahashi Y, Hackert T, Wolfgang CL, Besselink MG, Schulick RD, Nagakawa Y, Isaji S, Tsuchida A, Endo I. New Criteria of Resectability for Pancreatic Cancer: A Position Paper by the Japanese Society of Hepato‐Biliary‐Pancreatic Surgery (JSHBPS). J. Hepatobiliary. Pancreat. Sci. 2022; 29: 725–731. https://doi.org/10.1002/jhbp.1049.
- Otsubo T, Kobayashi S, Sano K, Misawa T, Ota T, Katagiri S, Yanaga K, Yamaue H, Kokudo N, Unno M, Fujimoto J, Miura F, Miyazaki M, Yamamoto M. Safety-Related Outcomes of the Japanese Society of Hepato-Biliary-Pancreatic Surgery Board Certification System for Expert Surgeons. J. Hepatobiliary. Pancreat. Sci. 2017; 24: 252–261. https://doi.org/10.1002/jhbp.444.
- Kuroda S, Kobayashi T, Hatano E, Kubo S, Endo I, Ohdan H. Questionnaire on the Surgical Indications for Intrahepatic Cholangiocarcinoma Administered to Japanese Board‐certified Expert Hepatobiliary and Pancreatic Surgeons and Instructors. J. Hepatobiliary. Pancreat. Sci. 2025; 32: 179–193. https://doi.org/10.1002/jhbp.12108.
- Baison GN, Bonds MM, Helton WS, Kozarek RA. Choledochal Cysts: Similarities and Differences between Asian and Western Countries. World J. Gastroenterol. 2019; 25: 3334–3343. https://doi.org/10.3748/wjg.v25.i26.3334.
- Oze I, Ito H, Koyanagi YN, Abe SK, Rahman MS, Islam MR, Saito E, Gupta PC, Sawada N, Tamakoshi A, et al. Obesity Is Associated with Biliary Tract Cancer Mortality and Incidence: A Pooled Analysis of 21 Cohort Studies in the Asia Cohort Consortium. Int. J. Cancer. 2024; 154: 1174–1190. https://doi.org/10.1002/ijc.34794.
- Keane MG, Horsfall L, Rait G, Pereira SP. A Case–Control Study Comparing the Incidence of Early Symptoms in Pancreatic and Biliary Tract Cancer. BMJ Open. 2014; 4: e005720. https://doi.org/10.1136/bmjopen-2014-005720.
- Guo L, Zhou F, Liu H, Kou X, Zhang H, Chen X, Qiu J. Genomic Mutation Characteristics and Prognosis of Biliary Tract Cancer. Am. J. Transl. Res. 2022; 14: 4990–5002.
- Wardell CP, Fujita M, Yamada T, Simbolo M, Fassan M, Karlic R, Polak P, Kim J, Hatanaka Y, Maejima K et al. Genomic Characterization of Biliary Tract Cancers Identifies Driver Genes and Predisposing Mutations. J. Hepatol. 2018; 68: 959–969. https://doi.org/10.1016/j.jhep.2018.01.009.
- Tompkins RK, Saunders K, Roslyn JJ, Longmire WP. Changing Patterns in Diagnosis and Management of Bile Duct Cancer. Ann. Surg. 1990; 211: 614–620, discussion 620–621.
- Tanaka K, Kida M. Role of endoscopy in screening of early pancreatic cancer and bile duct cancer. Dig. Endosc. 2009; 21. https://doi.org/10.1111/j.1443-1661.2009.00856.x.
- Ryan ME. Cytologic Brushings of Ductal Lesions during ERCP. Gastrointest. Endosc. 1991; 37: 139–142. https://doi.org/10.1016/S0016-5107(91)70671-8.
- Seyama Y, Makuuchi M. Current Surgical Treatment for Bile Duct Cancer. World J. Gastroenterol. 2007; 13: 1505–1515. https://doi.org/10.3748/wjg.v13.i10.1505.
- Cowzer D, Harding, JJ. Advanced Bile Duct Cancers: A Focused Review on Current and Emerging Systemic Treatments. Cancers (Basel). 2022; 14: 1800. https://doi.org/10.3390/cancers14071800.
- Huguet JM, Lobo M, Labrador JM, Boix C, Albert C, Ferrer-Barceló L, Durá AB, Suárez P, Iranzo I, Gil-Raga M, Burgos CB, Sempere J. Diagnostic-Therapeutic Management of Bile Duct Cancer. World J. Clin. Cases. 2019; 7: 1732–1752. https://doi.org/10.12998/wjcc.v7.i14.1732.
- Min L, Ziyu D, Xiaofei Z, Shunhe X, Bolin W. Analysis of Levels and Clinical Value of CA19-9, NLR and SIRI in Patients with Pancreatic Cancer with Different Clinical Features. Cell. Mol. Biol. 2022; 67: 302–308. https://doi.org/10.14715/cmb/2021.67.4.41.
- Liu J, Gao J, Du Y, Li Z, Ren Y, Gu J, Wang X, Gong Y, Wang W, Kong X. Combination of Plasma MicroRNAs with Serum CA19‐9 for Early Detection of Pancreatic Cancer. Int. J. Cancer. 2012; 131: 683–691. https://doi.org/10.1002/ijc.26422.
- Liao B. Research on the Factors That Affecting the Occurrence of Gastric Cancer Based on NCBI Gene Expression Omnibus Database. AIP Conference Proceedings. 2020; 2208 (1): 020007. https://doi.org/10.1063/5.0000016.
- Yu-jing T, Wen-jing T, Biao T. Integrated Analysis of Hub Genes and Pathways In Esophageal Carcinoma Based on NCBI’s Gene Expression Omnibus (GEO) Database: A Bioinformatics Analysis. Med. Sci. Monit. 2020; 26. https://doi.org/10.12659/MSM.923934.
- Kumar SU, Kumar DT, Siva R, Doss CGP, Zayed H. Integrative Bioinformatics Approaches to Map Potential Novel Genes and Pathways Involved in Ovarian Cancer. Front. Bioeng. Biotechnol. 2019; 7. https://doi.org/10.3389/fbioe.2019.00391.
- Yang Y, Qi S, Shi C, Han X, Yu J, Zhang L, Qin S, Gao Y. Identification of Metastasis and Prognosis-Associated Genes for Serous Ovarian Cancer. Biosci. Rep. 2020; 40. https://doi.org/10.1042/BSR20194324.
- Barrett T, Edgar R. Mining microarray data at NCBI's Gene Expression Omnibus (GEO). Methods Mol Biol. 2006; 338: 175–190. https://doi.org/10.1385/1-59745-097-9:175.
- Clough E, Barrett T. The Gene Expression Omnibus Database. Methods Mol Biol. 2016; 1418: 93–110. https://doi.org/10.1007/978-1-4939-3578-9_5.
- Vella D, Marini S, Vitali F, Di Silvestre D, Mauri G, Bellazzi R. MTGO: PPI Network Analysis Via Topological and Functional Module Identification. Sci. Rep. 2018; 8: 5499, https://doi.org/10.1038/s41598-018-23672-0.
- Murakami Y, Tripathi LP, Prathipati P, Mizuguchi K. Network Analysis and in Silico Prediction of Protein–Protein Interactions with Applications in Drug Discovery. Curr. Opin. Struct. Biol. 2017; 44: 134–142. https://doi.org/10.1016/j.sbi.2017.02.005.
- Tomkins JE, Manzoni C. Advances in Protein-Protein Interaction Network Analysis for Parkinson’s Disease. Neurobiol. Dis. 2021; 155: 105395. https://doi.org/10.1016/j.nbd.2021.105395.
- Li T, Gao X, Han L, Yu J, Li H. Identification of Hub Genes with Prognostic Values in Gastric Cancer by Bioinformatics Analysis. World J. Surg. Oncol. 2018; 16: 114. https://doi.org/10.1186/s12957-018-1409-3.
- Lv J, Li L. Hub Genes and Key Pathway Identification in Colorectal Cancer Based on Bioinformatic Analysis. Biomed Res. Int. 2019; 2019: 1–13. https://doi.org/10.1155/2019/1545680.
- Guo C, Liu Z, Yu Y, Chen Y, Liu H, Guo Y, Peng Z, Cai G, Hua Z, Han X, Li Z. TP53 /KRAS Co-Mutations Create Divergent Prognosis Signatures in Intrahepatic Cholangiocarcinoma. Front. Genet. 2022; 13. https://doi.org/10.3389/fgene.2022.844800.
- Deng L, Bao W, Zhang B, Zhang S, Chen Z, Zhu X, He B, Wu L, Chen X, Deng T, Chen B, Yu Z, Wang Y, Chen G. AZGP1 Activation by Lenvatinib Suppresses Intrahepatic Cholangiocarcinoma Epithelial-Mesenchymal Transition through the TGF-Β1/Smad3 Pathway. Cell Death Dis. 2023; 14: 590. https://doi.org/10.1038/s41419-023-06092-5.
- Zou W, Zhang Q, Sun R, Li X, He S. Study on TFF1 and PALB2 Gene Variants Associated with Gastric Carcinoma Risk in the Chinese Han Population. Cancer Epidemiol. 2023; 83: 102333. https://doi.org/10.1016/j.canep.2023.102333.
- Ghojazadeh M, Somi MH, Naseri A, Salehi-Pourmehr H, Hassannezhad S, Hajikamanaj Olia A, Kafshdouz L, Nikniaz Z. Systematic Review and Meta-Analysis of TP53, HER2/ERBB2, KRAS, APC, and PIK3CA Genes Expression Pattern in Gastric Cancer. Middle East J. Dig. Dis. 2022; 14: 335–345, https://doi.org/10.34172/mejdd.2022.292.
- Wu Y, Zhao H. Circ_0074027 Binds to EIF4A3 and Promotes Gastric Cancer Progression. Oncol. Lett. 2021; 22: 704, https://doi.org/10.3892/ol.2021.12965.
- Liang X, Chen W, Shi H, Gu X, Li Y, Qi Y, Xu K, Zhao A, Liu J. PTBP3 Contributes to the Metastasis of Gastric Cancer by Mediating CAV1 Alternative Splicing. Cell Death Dis. 2018; 9: 569, https://doi.org/10.1038/s41419-018-0608-8.
- Peng J, Liang S, Li L. SFRP1 Exerts Effects on Gastric Cancer Cells through GSK3β/Rac1‑mediated Restraint of TGFβ/Smad3 Signaling. Oncol. Rep. 2018. https://doi.org/10.3892/or.2018.6838.
- Fenoglio-Preiser CM, Wang J, Stemmermann GN, Noffsinger A. TP53 and Gastric Carcinoma: A Review. Hum. Mutat. 2003; 21: 258–270, https://doi.org/10.1002/humu.10180.
- Zhou Q, Zheng X, Chen L, Xu B, Yang X, Jiang J, Wu C. Smad2/3/4 Pathway Contributes to TGF-β-Induced MiRNA-181b Expression to Promote Gastric Cancer Metastasis by Targeting Timp3. Cell. Physiol. Biochem. 2016; 39: 453–466, https://doi.org/10.1159/000445638.
- Liu L, Zhou C, Zhou L, Peng L, Li D, Zhang X, Zhou M, Kuang P, Yuan Q, Song X, Yang M. Functional FEN1 Genetic Variants Contribute to Risk of Hepatocellular Carcinoma, Esophageal Cancer, Gastric Cancer and Colorectal Cancer. Carcinogenesis. 2012; 33: 119–123, https://doi.org/10.1093/carcin/bgr250.
- Zhu Z, Peng R, Cai H. The Value of Nucleoporin 188 in Diagnosis, Prognosis and Immunoregulation: From Pan-Cancer Analysis to Gastric Cancer Verification. Front. Immunol. 2025; 16. https://doi.org/10.3389/fimmu.2025.1586784.
- Muste Sadurni, M, Saponaro, M. Deregulations of RNA Pol II Subunits in Cancer. Appl. Biosci. 2023; 2: 459–476, https://doi.org/10.3390/applbiosci2030029.
- He K, Feng Y, An S, Liu F, Xiang G. Integrative Epigenomic Profiling Reveal AP-1 Is a Key Regulator in Intrahepatic Cholangiocarcinoma. Genomics. 2022; 114: 241–252, https://doi.org/10.1016/j.ygeno.2021.12.008.
- Subramanian V, Fields PA, Boyer LA. H2A.Z: A Molecular Rheostat for Transcriptional Control. F1000Prime Rep. 2015; 7. https://doi.org/10.12703/P7-01.
- Vardabasso C, Hasson D, Ratnakumar K, Chung C-Y, Duarte LF, Bernstein E. Histone Variants: Emerging Players in Cancer Biology. Cell. Mol. Life Sci. 2014; 71: 379–404, https://doi.org/10.1007/s00018-013-1343-z.
- Jafri Z, Li Y, Zhang J, O’Meara CH, Khachigian LM. Jun, an Oncological Foe or Friend? Int. J. Mol. Sci. 2025; 26: 555, https://doi.org/10.3390/ijms26020555.
- Bradner JE, Hnisz D, Young RA. Transcriptional Addiction in Cancer. Cell. 2017; 168: 629–643, https://doi.org/10.1016/j.cell.2016.12.013.
- Goetz JG, Lajoie P, Wiseman SM, Nabi IR. Caveolin-1 in Tumor Progression: The Good, the Bad and the Ugly. Cancer Metastasis Rev. 2008; 27: 715–735, https://doi.org/10.1007/s10555-008-9160-9.
- Xu J, Lamouille S, Derynck R. TGF-β-Induced Epithelial to Mesenchymal Transition. Cell Res. 2009; 19: 156–172, https://doi.org/10.1038/cr.2009.5.