Abstract
Background and aim
FKBP1A, a gene encoding the FK506-binding protein 1A, has emerged as a significant player in cancer progression and prognosis. This study aimed to comprehensively investigate the multifaceted role of FKBP1A in cancer, focusing on its differential expression patterns, prognostic implications, genetic alterations, and associations with the tumor microenvironment.
Methods and results
Using large-scale datasets, including GTEx, TCGA, HPA, and cBioPortal, we analyzed FKBP1A expression across normal tissues and various cancer types. Our findings revealed that FKBP1A exhibited aberrant upregulation in most human cancers, making it a potential biomarker for malignancy. Moreover, FKBP1A expression correlated with poor overall survival, disease-specific survival, disease-free interval, and progression-free interval in several cancers, indicating its prognostic significance. Genetic alteration analysis showed that FKBP1A gene amplification was prevalent, particularly in ovarian cancer. Furthermore, FKBP1A expression was associated with tumor mutational burden and microsatellite instability, highlighting its potential involvement in tumor-immune response. Notably, FKBP1A expression positively correlated with stromal and immune cell scores, suggesting its role in shaping the tumor microenvironment. Additionally, according to the functional enrichment analysis, experimental validation in lung adenocarcinoma confirmed the role of FKBP1A through the regulation of EGFR signaling by apoptosis, which is consistent with drug sensitivity analysis to some extent.
Conclusion
In conclusion, FKBP1A exhibits differential expression in cancer, serves as a prognostic indicator, undergoes genetic alterations, and influences the tumor-immune microenvironment. These findings shed light on the multifaceted role of FKBP1A in cancer development and progression, suggesting its potential as a therapeutic target and guidance of clinical drugs selection, and provide valuable insights into patient prognosis for interventions based on pharmaceuticals.
Graphical Abstract
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The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors.
References
Annett S, Moore G, Robson T (2020) FK506 binding proteins and inflammation related signalling pathways; basic biology, current status and future prospects for pharmacological intervention. Pharmacol Ther 215:107623. https://doi.org/10.1016/j.pharmthera.2020.107623
Bagchi S, Yuan R, Engleman EG (2021) Immune checkpoint inhibitors for the treatment of cancer: clinical impact and mechanisms of response and resistance. Annu Rev Pathol 16:223–249. https://doi.org/10.1146/annurev-pathol-042020-042741
Bonner JM, Boulianne GL (2017) Diverse structures, functions and uses of FK506 binding proteins. Cell Signal 38:97–105. https://doi.org/10.1016/j.cellsig.2017.06.013
Chen X, Song E (2019) Turning foes to friends: targeting cancer-associated fibroblasts. Nat Rev Drug Discov 18(2):99–115. https://doi.org/10.1038/s41573-018-0004-1
Chen Y, Mcandrews KM, Kalluri R (2021) Clinical and therapeutic relevance of cancer-associated fibroblasts. Nat Rev Clin Oncol 18(12):792–804. https://doi.org/10.1038/s41571-021-00546-5
Devarakonda S, Rotolo F, Tsao MS et al (2018) Tumor mutation burden as a biomarker in resected non-small-cell lung cancer. J Clin Oncol 36(30):2995–3006. https://doi.org/10.1200/jco.2018.78.1963
Haider T, Pandey V, Banjare N et al (2020) Drug resistance in cancer: mechanisms and tackling strategies. Pharmacol Rep: PR 72(5):1125–1151. https://doi.org/10.1007/s43440-020-00138-7
Jauliac S, López-Rodriguez C, Shaw LM et al (2002) The role of NFAT transcription factors in integrin-mediated carcinoma invasion. Nat Cell Biol 4(7):540–544. https://doi.org/10.1038/ncb816
Kulis M, Esteller M (2010) DNA methylation and cancer. Adv Genet 70:27–56. https://doi.org/10.1016/b978-0-12-380866-0.60002-2
Lee DW, Han SW, Bae JM et al (2019) Tumor mutation burden and prognosis in patients with colorectal cancer treated with adjuvant fluoropyrimidine and oxaliplatin. Clin Cancer Res 25(20):6141–6147. https://doi.org/10.1158/1078-0432.Ccr-19-1105
Leng W, Liu Q, Zhang S et al (2020) LncRNA AFAP1-AS1 modulates the sensitivity of paclitaxel-resistant prostate cancer cells to paclitaxel via miR-195-5p/FKBP1A axis. Cancer Biol Ther 21(11):1072–1080. https://doi.org/10.1080/15384047.2020.1829266
Li W, Li K, Wei H et al (2022) Syntaxin-6, a reliable biomarker for predicting the prognosis of patients with cancer and the effectiveness of immunotherapy. Cancers. https://doi.org/10.3390/cancers15010027
Liu F, Wang YQ, Meng L et al (2013) FK506-binding protein 12 ligands: a patent review. Expert Opin Ther Pat 23(11):1435–1449. https://doi.org/10.1517/13543776.2013.828695
Liu T, Xiong J, Yi S et al (2017) FKBP12 enhances sensitivity to chemotherapy-induced cancer cell apoptosis by inhibiting MDM2. Oncogene 36(12):1678–1686. https://doi.org/10.1038/onc.2016.331
Lopez-Ilasaca M, Schiene C, Küllertz G et al (1998) Effects of FK506-binding protein 12 and FK506 on autophosphorylation of epidermal growth factor receptor. J Biol Chem 273(16):9430–9434. https://doi.org/10.1074/jbc.273.16.9430
Luo Y, Lin J, Zhang Y et al (2020) LncRNA PCAT6 predicts poor prognosis in hepatocellular carcinoma and promotes proliferation through the regulation of cell cycle arrest and apoptosis. Cell Biochem Funct 38(7):895–904. https://doi.org/10.1002/cbf.3510
Mathea S, Li S, Schierhorn A et al (2011) Suppression of EGFR autophosphorylation by FKBP12. Biochemistry 50(50):10844–10850. https://doi.org/10.1021/bi2013855
Patel D, Dabhi AM, Dmello C et al (2022) FKBP1A upregulation correlates with poor prognosis and increased metastatic potential of HNSCC. Cell Biol Int 46(3):443–453. https://doi.org/10.1002/cbin.11741
Popova NV, Jücker M (2021) The role of mTOR signaling as a therapeutic target in cancer. Int J Mol Sci. https://doi.org/10.3390/ijms22041743
Romano S, Di Pace A, Sorrentino A et al (2010) FK506 binding proteins as targets in anticancer therapy. Anticancer Agents Med Chem 10(9):651–656. https://doi.org/10.2174/187152010794479816
Schmelzle T, Hall MN (2000) TOR, a central controller of cell growth. Cell 103(2):253–262. https://doi.org/10.1016/s0092-8674(00)00117-3
Shi J, Zhang W, You M et al (2016) Pioglitazone inhibits EGFR/MDM2 signaling-mediated PPARγ degradation. Eur J Pharmacol 791:316–321. https://doi.org/10.1016/j.ejphar.2016.09.010
Steuer CE, Ramalingam SS (2018) Tumor mutation burden: leading immunotherapy to the era of precision medicine? J Clin Oncol 36(7):631–632. https://doi.org/10.1200/jco.2017.76.8770
Thorsson V, Gibbs DL, Brown SD et al (2018) The immune landscape of cancer. Immunity 48(4):812-830.e814. https://doi.org/10.1016/j.immuni.2018.03.023
Tong M, Jiang Y (2015) FK506-binding proteins and their diverse functions. Curr Mol Pharmacol 9(1):48–65. https://doi.org/10.2174/1874467208666150519113541
Tyner JW, Haderk F, Kumaraswamy A et al (2022) Understanding drug sensitivity and tackling resistance in cancer. Can Res 82(8):1448–1460. https://doi.org/10.1158/0008-5472.can-21-3695
Vasaikar SV, Straub P, Wang J et al (2018) LinkedOmics: analyzing multi-omics data within and across 32 cancer types. Nucleic Acids Res 46(D1):D956-d963. https://doi.org/10.1093/nar/gkx1090
Vasan N, Baselga J, Hyman DM (2019) A view on drug resistance in cancer. Nature 575(7782):299–309. https://doi.org/10.1038/s41586-019-1730-1
Vilar E, Gruber SB (2010) Microsatellite instability in colorectal cancer-the stable evidence. Nat Rev Clin Oncol 7(3):153–162. https://doi.org/10.1038/nrclinonc.2009.237
Waickman AT, Powell JD (2012) Mammalian target of rapamycin integrates diverse inputs to guide the outcome of antigen recognition in T cells. J Immunol 188(10):4721–4729. https://doi.org/10.4049/jimmunol.1103143
Xing M, Wang J, Yang Q et al (2019) FKBP12 is a predictive biomarker for efficacy of anthracycline-based chemotherapy in breast cancer. Cancer Chemother Pharmacol 84(4):861–872. https://doi.org/10.1007/s00280-019-03923-1
Xu Y, Jin J, Zhang W et al (2016) EGFR/MDM2 signaling promotes NF-κB activation via PPARγ degradation. Carcinogenesis 37(2):215–222. https://doi.org/10.1093/carcin/bgv252
Ye W, Shi Z, Zhou Y et al (2022) Autophagy-related signatures as prognostic indicators for hepatocellular carcinoma. Front Oncol 12:654449. https://doi.org/10.3389/fonc.2022.654449
Yuan H, Yan M, Zhang G et al (2019) CancerSEA: a cancer single-cell state atlas. Nucleic Acids Res 47(D1):D900-d908. https://doi.org/10.1093/nar/gky939
Zeng D, Li M, Zhou R et al (2019) Tumor microenvironment characterization in gastric cancer identifies prognostic and immunotherapeutically relevant gene signatures. Cancer Immunol Res 7(5):737–750. https://doi.org/10.1158/2326-6066.Cir-18-0436
Zhang Y, Zhang D, Lv J et al (2019) LncRNA SNHG15 acts as an oncogene in prostate cancer by regulating miR-338-3p/FKBP1A axis. Gene 705:44–50. https://doi.org/10.1016/j.gene.2019.04.033
Acknowledgements
This research benefits from the help and support in many aspects, and here, we would like to express our deep gratitude to Dr. Yue-Yuan Zheng, Scientific Research Center, the Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China.
Funding
This research was supported by the National Natural Science Foundation of China (Grant No. 81971470, 32170913, and 32370982), the Shenzhen Science and Technology Innovation Committee Programs (JCY20190809143803732 and JCYJ20210324120602008).
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BH and YC supervised the study; YZ and HX collected the data and performed the analysis and experiments; YZ, HX, SP and HT wrote the paper. BH and YC revised the paper. All authors read and approved the final manuscript.
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Zhang, Y., Xu, H., Pi, S. et al. The prognostic and immunological role of FKBP1A in an integrated muti-omics cancers analysis, especially lung cancer. J Cancer Res Clin Oncol 149, 16589–16608 (2023). https://doi.org/10.1007/s00432-023-05362-1
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DOI: https://doi.org/10.1007/s00432-023-05362-1