TCGA and Bioinformatics Reveal the Molecular Network and Prognostic Implication of Laminin Beta 1 in Cholangiocarcinoma
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Abstract
This study investigates the expression, prognostic relevance, and molecular network of laminin subunit beta 1 (LAMB1) in cholangiocarcinoma (CCA) using TCGA data and bioinformatics tools. LAMB1 mRNA expression in CCA tissues was analyzed using the TCGA-CHOL dataset via GEPIA2, and protein expression data was obtained from The Human Protein Atlas (HPA). Survival analysis was performed using Kaplan–Meier plots and the log-rank test. Correlated genes were identified via UALCAN and analyzed for protein–protein interactions using STRING, followed by Gene Ontology (GO) and KEGG pathway enrichment. TCGA data showed significant upregulation of LAMB1 mRNA in CCA, and HPA images revealed stronger protein staining in CCA than in normal tissues. Although LAMB1 expression showed no significant association with overall survival (OS) or disease-free survival (DFS) in TCGA-CHOL alone, analysis of the combined CHOL and liver hepatocellular carcinoma (LIHC) datasets revealed that patients with high LAMB1 expression had significantly shorter OS and DFS. Among 250 LAMB1-correlated genes, STRING analysis identified 51 interacting partners, with GO and KEGG analyses highlighting enrichment in cell proliferation, DNA repair, and extracellular matrix (ECM)-related pathways. Notably, agrin (AGRN), collagen type IV alpha 5 chain (COL4A5), integrin alpha-2 (ITGA2), and nidogen 1 (NID1) emerged as network neighbors of LAMB1, with high AGRN and ITGA2 expression correlating with poor prognosis. These genes participate in ECM–integrin crosstalk and mechanotransduction signaling, processes that facilitate tumor progression and resistance to therapy. Together with our previous findings that LAMB1 promotes drug resistance and malignant phenotypes in CCA cells, these results reinforce LAMB1 as a central component of ECM-associated signaling networks and support its potential as a prognostic biomarker and therapeutic target.
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References
Aumailley, M. (2013). The laminin family. Cell Adhesion and Migration, 7(1), 48-55. https://doi.org/10.4161/cam.22826
Aumailley, M., Bruckner-Tuderman, L., Carter, W. G., Deutzmann, R., Edgar, D., Ekblom, P., Engel, J., Engvall, E., Hohenester, E., Jones, J. C. R., Kleinman, H. K., Marinkovich, M. P., Martin, G. R., Mayer, U., Meneguzzi, G., Miner, J. H., Miyazaki, K., Patarroyo, M., Paulsson, M., Quaranta, V., Sanes, J. R., . . . Yurchenco, P. D. (2005). A simplified laminin nomenclature. Matrix Biology, 24(5), 326-332. https://doi.org/10.1016/j.matbio.2005.05.006
Banales, J. M., Cardinale, V., Carpino, G., Marzioni, M., Andersen, J. B., Invernizzi, P., Lind, G. E., Folseraas, T., Forbes, S. J., Fouassier, L., Geier, A., Calvisi, D. F., Mertens, J. C., Trauner, M., Benedetti, A., Maroni, L., Vaquero, J., Macias, R. I., Raggi, C., Perugorria, M. J., Gaudo, E., . . . Alvaro, D. (2016). Expert consensus document: cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the study of cholangiocarcinoma (ENS-CCA). Nature Reviews Gastroenterology and Hepatology, 13(5), 261-280. https://doi.org/10.1038/nrgastro.2016.51
Banales, J. M., Marin, J. J. G., Lamarca, A., Rodrigues, P. M., Khan, S. A., Roberts, L. R., Cardinale, V., Carpino, G., Andersen, J. B., Braconi, C., Calvisi, D. F., Perugorria, M. J., Fabris, L., Boulter, L., Macias, R. I. R., Gaudio, E., Alvaro, D., Gradilone, S. A., Strazzabosco, M., Marzioni, M., Coulouarn, C., . . . Gores, G. J. (2020). Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nature Reviews Gastroenterology and Hepatology, 17(9), 557-588. https://doi.org/10.1038/s41575-020-0310-z
Bertuccio, P., Malvezzi, M., Carioli, G., Hashim, D., Boffetta, P., El-Serag, H. B., La Vecchia, C., & Negri, E. (2019). Global trends in mortality from intrahepatic and extrahepatic cholangiocarcinoma. Journal of Hepatology, 71(1), 104-114. https://www.ncbi.nlm.nih.gov/pubmed/30910538
Chakraborty, S., & Hong, W. (2018). Linking extracellular matrix agrin to the hippo pathway in liver cancer and beyond. Cancers, 10(2), Article 45. https://doi.org/10.3390/cancers10020045
Chakraborty, S., Njah, K., Pobbati, A. V., Lim, Y. B., Raju, A., Lakshmanan, M., Tergaonkar, V., Lim, C. T., & Hong, W. (2017). Agrin as a mechanotransduction signal regulating YAP through the hippo pathway. Cell Reports, 18(10), 2464-2479. https://doi.org/10.1016/j.celrep.2017.02.041
Chandrashekar, D. S., Karthikeyan, S. K., Korla, P. K., Patel, H., Shovon, A. R., Athar, M., Netto, G. J., Qin, Z. S., Kumar, S., Manne, U., Creighton, C. J., & Varambally, S. (2022). UALCAN: An update to the integrated cancer data analysis platform. Neoplasia, 25, 18-27. https://doi.org/10.1016/j.neo.2022.01.001
Domogatskaya, A., Rodin, S., & Tryggvason, K. (2012). Functional diversity of laminins. Annual Review of Cell and Developmental Biology, 28, 523-553. https://doi.org/10.1146/annurev-cellbio-101011-155750
Feng, E., Yang, X., Yang, J., Qu, Q., & Li, X. (2025). LAMB1 promotes proliferation and metastasis in nasopharyngeal carcinoma and shapes the immune-suppressive tumor microenvironment. Brazilian Journal of Otorhinolaryngology, 91(2), Article 101551. https://doi.org/10.1016/j.bjorl.2024.101551
Forner, A., Vidili, G., Rengo, M., Bujanda, L., Ponz-Sarvisé, M., & Lamarca, A. (2019). Clinical presentation, diagnosis and staging of cholangiocarcinoma. Liver International, 39 (Suppl 1), 98-107. https://doi.org/10.1111/liv.14086
Givant-Horwitz, V., Davidson, B., & Reich, R. (2004). Laminin-induced signaling in tumor cells: the role of the M(r) 67,000 laminin receptor. Cancer research, 64(10), 3572-3579. https://doi.org/10.1158/0008-5472.Can-03-3424
Hohenester, E., & Yurchenco, P. D. (2013). Laminins in basement membrane assembly. Cell Adhesion and Migration, 7(1), 56-63. https://doi.org/10.4161/cam.21831
Huang, Y.-L., Liang, C.-Y., Ritz, D., Coelho, R., Septiadi, D., Estermann, M., Cumin, C., Rimmer, N., Schötzau, A., Núñez López, M., Fedier, A., Konantz, M., Vlajnic, T., Calabrese, D., Lengerke, C., David, L., Rothen-Rutishauser, B., Jacob, F., & Heinzelmann-Schwarz, V. (2020). Collagen-rich omentum is a premetastatic niche for integrin α2-mediated peritoneal metastasis. Elife, 9, Article e59442. https://doi.org/10.7554/eLife.59442
Hynes, R. O., Ruoslahti, E., & Springer, T. A. (2022). Reflections on integrins-past, present, and future: the albert lasker basic medical research award. Journal of the American Medical Association, 328(13), 1291-1292. https://doi.org/10.1001/jama.2022.17005
Islam, K., Thummarati, P., Kaewkong, P., Sripa, B., & Suthiphongchai, T. (2021). Role of laminin and cognate receptors in cholangiocarcinoma cell migration. Cell Adhesion and Migration, 15(1), 152-165. https://doi.org/10.1080/19336918.2021.1924422
Jayadev, R., Morais, M. R. P. T., Ellingford, J. M., Srinivasan, S., Naylor, R. W., Lawless, C., Li, A. S., Ingham, J. F., Hastie, E., Chi, Q., Fresquet, M., Koudis, N.-M., Thomas, H. B., O'Keefe, R. T., Williams, E., Adamson, A., Stuart, H. M., Banka, S., Smedley, D., Genomics England Research Consortium, Sherwood, D. R., & Lennon, R. (2022). A basement membrane discovery pipeline uncovers network complexity, regulators, and human disease associations. Science Advances, 8(20), Article eabn2265. https://doi.org/10.1126/sciadv.abn2265
Jayadev, R., & Sherwood, D. R. (2017). Basement membranes. Current Biology, 27(6), R207-R211. https://doi.org/10.1016/j.cub.2017.02.006
Kerdkumthong, K., Roytrakul, S., Songsurin, K., Pratummanee, K., Runsaeng, P., & Obchoei, S. (2024). Proteomics and bioinformatics identify drug-resistant-related genes with prognostic potential in cholangiocarcinoma. Biomolecules, 14(8), Article 969. https://doi.org/10.3390/biom14080969
Lee, H., Kim, W.-J., Kang, H.-G., Jang, J.-H., Choi, I. J., Chun, K.-H., & Kim, S.-J. (2021). Upregulation of LAMB1 via ERK/c-Jun axis promotes gastric cancer growth and motility. International Journal of Molecular Sciences, 22(2), Article 626. https://doi.org/10.3390/ijms22020626
Liu, T., Gan, H., He, S., Deng, J., Hu, X., Li, L., Cai, L., He, J., Long, H., Cai, J., Li, H., Zhang, Q., Wang, L., Chen, F., Chen, Y., Zhang, H., Li, J., Yang, L., Liu, Y., Yang, J.-H., Kuang, D.-M., ... Shan, H. (2022). RNA helicase DDX24 stabilizes LAMB1 to promote hepatocellular carcinoma progression. Cancer Research, 82(17), 3074-3087. https://doi.org/10.1158/0008-5472.Can-21-3748
Liu, T., Liu, J., Chen, Q., Wu, L., Zhang, L., Qiao, D., Huang, Z., Lu, T., Hu, A., & Wang, J. (2024). The prognostic value of bioinformatics analysis of ECM receptor signaling pathways and LAMB1 identification as a promising prognostic biomarker of lung adenocarcinoma. Medicine, 103(38), Article e39854. https://doi.org/10.1097/md.0000000000039854
Ma, X., Lu, T., Yang, Y., Qin, D., Tang, Z., Cui, Y., & Wang, R. (2024). DEAD-box helicase family proteins: emerging targets in digestive system cancers and advances in targeted drug development. Journal of Translational Medicine, 22(1), Article 1120. https://doi.org/10.1186/s12967-024-05930-0
Mokhtari, R. B., Sampath, D., Eversole, P., Lin, M. O. Y., Bosykh, D. A., Boopathy, G. T. K., Sivakumar, A., Wang, C.-C., Kumar, R., Sheng, J. Y. P., Karasik, E., Foster, B. A., Yu, H., Ling, X., Wu, W., Li, F., Ohler, Z. W., Brainson, C. F., Goodrich, D. W., Hong, W., & Chakraborty, S. (2025). An agrin-YAP/TAZ rigidity sensing module drives EGFR-addicted lung tumorigenesis. Advanced Science, 12(20), Article e2413443. https://doi.org/10.1002/advs.202413443
Oh, B. Y., Kim, K. H., Chung, S. S., Hong, K. S., & Lee, R. A. (2014). Role of β1-integrin in colorectal cancer: case-control study. Annals of Coloproctology, 30(2), 61-70. https://doi.org/10.3393/ac.2014.30.2.61
Patarroyo, M., Tryggvason, K., & Virtanen, I. (2002). Laminin isoforms in tumor invasion, angiogenesis and metastasis. Seminars in Cancer Biology, 12(3), 197-207. https://doi.org/10.1016/s1044-579x(02)00023-8
Pickup, M. W., Mouw, J. K., & Weaver, V. M. (2014). The extracellular matrix modulates the hallmarks of cancer. EMBO Reports, 15(12), 1243-1253. https://doi.org/10.15252/embr.201439246
Pontén, F., Jirström, K., & Uhlen, M. (2008). The human protein atlas--a tool for pathology. The Journal of Pathology, 216(4), 387-393. https://doi.org/10.1002/path.2440
Ran, T., Chen, Z., Zhao, L., Ran, W., Fan, J., Hong, S., & Yang, Z. (2021). LAMB1 is related to the T stage and indicates poor prognosis in gastric cancer. Technology in Cancer Research and Treatment, 20, Article 15330338211004944. https://doi.org/10.1177/15330338211004944
Rattanasinchai, C., Navasumrit, P., & Ruchirawat, M. (2022). Elevated ITGA2 expression promotes collagen type I-induced clonogenic growth of intrahepatic cholangiocarcinoma. Scientific Reports, 12(1), Article 22429. https://doi.org/10.1038/s41598-022-26747-1
Rokavec, M., Jaeckel, S., & Hermeking, H. (2023). Nidogen-1/NID1 function and regulation during progression and metastasis of colorectal cancer. Cancers, 15(22), Article 5316. https://doi.org/10.3390/cancers15225316
Sasaki, T., Fässler, R., & Hohenester, E. (2004). Laminin: the crux of basement membrane assembly. Journal of Cell Biology, 164(7), 959-963. https://doi.org/10.1083/jcb.200401058
Sun, H., Wang, Y., Wang, S., Xie, Y., Sun, K., Li, S., Cui, W., & Wang, K. (2023). The involvement of collagen family genes in tumor enlargement of gastric cancer. Scientific Reports, 13(1), Article 100. https://doi.org/10.1038/s41598-022-25061-0
Tang, Z., Kang, B., Li, C., Chen, T., & Zhang, Z. (2019). GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Research, 47(W1), W556-W560. https://doi.org/10.1093/nar/gkz430
Valle, J. W., Borbath, I., Khan, S. A., Huguet, F., Gruenberger, T., & Arnold, D. (2016). Biliary cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology, 27(suppl 5), v28-v37. https://doi.org/10.1093/annonc/mdw324
Xu, R.-C., Wang, F., Sun, J.-L., Abuduwaili, W., Zhang, G.-C., Liu, Z.-Y., Liu, T.-T., Dong, L., Shen, X.-Z., & Zhu, J.-M. (2022). A novel murine model of combined hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Journal of Translational Medicine, 20(1), Article 579. https://doi.org/10.1186/s12967-022-03791-z
Xue, T., Yeung, C. L. S., Mao, X., Tey, S. K., Lo, K. W., Tang, A. H. N., Yun, J. P., & Yam, J. W. P. (2025). Development of a broadly potent neutralizing antibody targeting Nidogen 1 effectively inhibits cancer growth and metastasis in preclinical tumor models. Journal of Translational Internal Medicine, 13(1), 78-92. https://doi.org/10.1515/jtim-2025-0008
Zeng, X., Wang, H. Y., Wang, Y. P., Bai, S. Y., Pu, K., Zheng, Y., Guo, Q. H., Guan, Q. L., Ji, R., & Zhou, Y. N. (2020). COL4A family: potential prognostic biomarkers and therapeutic targets for gastric cancer. Translational Cancer Research, 9(9), 5218-5232. https://doi.org/10.21037/tcr-20-517
Zhang, J., Ji, F., Tan, Y., Zhao, L., Zhao, Y., Liu, J., Shao, L., Shi, J., Ye, M., He, X., Jin, J., Zhao, B., Huang, J., Roessler, S., Zheng, X., & Ji, J. (2024). Oncogenic roles of laminin subunit gamma-2 in Iitrahepatic cholangiocarcinoma via promoting EGFR translation. Advanced Science, 11(21), Article e2309010. https://doi.org/10.1002/advs.202309010
Zhao, Z., Liu, H., Liu, Y., Wen, J., & Yuan, J. (2025). LAMB1 downregulation suppresses glioma progression by inhibiting aerobic glycolysis through regulation of the NF-κB/HK2 axis. Discover Oncology, 16(1), Article 131. https://doi.org/10.1007/s12672-025-01818-7
Zhong, W., Dai, L., Liu, J., & Zhou, S. (2018). Cholangiocarcinoma‑associated genes identified by integrative analysis of gene expression data. Molecular Medicine Reports, 17(4), 5744-5753. https://doi.org/10.3892/mmr.2018.8594
