Volume 8, Issue 4, December 2020, Page: 82-93
FKBPL Is a Potential Prognostic Biomarker and Correlated with Immune Infiltrates and T Cells Exhaustion in Hepatocellular Carcinoma
Feng Tian, Department of General surgery, Lishui People's Hospital, the Six Affiliated Hospital of Wenzhou Medical University, Lishui, China
Lifu Wang, Department of General surgery, Lishui People's Hospital, the Six Affiliated Hospital of Wenzhou Medical University, Lishui, China
Baiqiang Ma, Department of General surgery, Lishui People's Hospital, the Six Affiliated Hospital of Wenzhou Medical University, Lishui, China
Bingzhen Li, Department of General surgery, Lishui People's Hospital, the Six Affiliated Hospital of Wenzhou Medical University, Lishui, China
Daxia Cai, Institute of Hematology, Jinan University, Guangzhou, P. R. China
Received: Nov. 11, 2020;       Accepted: Nov. 20, 2020;       Published: Nov. 27, 2020
DOI: 10.11648/j.crj.20200804.14       View        Downloads  
Abstract
Hepatocellular carcinoma (HCC) is a malignant tumor with high mortality and poor prognosis. And FKBPL plays a crucial role on the development of cancers. This study aims to explore the prognostic potential of FKBPL and comprehensively analyze the correlations between FKBPL, immune infiltration, and T cells function in HCC. GEO database, Oncomine databases, TIMER2.0 and GEPIA2 were used to analyze FKBPL expression, relationship between FKBPL expression and survival of HCC patients as well as immune infiltration, related gene marker sets and T cells exhaustion in HCC. We used STRING database to analysis PPI (protein-protein interaction) for FKBPL and visualization by Cytoscape. Metascape was used for enrichment analysis. FKBPL upregulates in most of the cancer types including HCC. Survival analysis demonstrated that FKBPL shows significant impact on survival of HCC patients with overall survival and disease-free survival. And survival rate of HCC patients with high FKBPL expression was significantly correlated with race, gender and tumor purity of HCC patients. Moreover, FKBPL expression positively correlates with high immune infiltration levels in most of the immune cells and functional T cells including exhausted T cells, Th1, Th2 and Tfh. Specifically, multiple key genes of exhausted T cells comprising PD-1, CTLA4, LAG3, TIM-3, and GZMB have remarkable interaction with FKBPL. At last, we found10 genes including PRRT1, ANKRD49, RBCK1, CSNK1D, HSP90AA1, HSP90AB1, GTSE1, CDKN1A, AVPR2, and EGFL8 were interacted with FKBPL. Enrichment analysis showed that apoptotic signaling pathway, regulation of myeloid cell differentiation, cell death in response to oxidative stress, PIP3 activates AKT signaling may involve in HCC tumor progression about FKBPL. In conclusion, FKBPL is a potential prognostic biomarker and correlated with immune infiltrates and T cells exhaustion in HCC.
Keywords
Hepatocellular Carcinoma (HCC), FKBPL, Prognosis, Immunotherapy, Immune Infiltration, T Cells Exhaustion
To cite this article
Feng Tian, Lifu Wang, Baiqiang Ma, Bingzhen Li, Daxia Cai, FKBPL Is a Potential Prognostic Biomarker and Correlated with Immune Infiltrates and T Cells Exhaustion in Hepatocellular Carcinoma, Cancer Research Journal. Vol. 8, No. 4, 2020, pp. 82-93. doi: 10.11648/j.crj.20200804.14
Copyright
Copyright © 2020 Authors retain the copyright of this article.
This article is an open access article distributed under the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Reference
[1]
Forner, A., Reig, M. & Bruix, J. Hepatocellular carcinoma. The Lancet 391, 1301-1314, doi: 10.1016/s0140-6736(18)30010-2 (2018).
[2]
De Toni, E. N. et al. Age independent survival benefit for patients with hepatocellular carcinoma (HCC) without metastases at diagnosis: a population-based study. Gut 69, 168-176, doi: 10.1136/gutjnl-2018-318193 (2020).
[3]
Jiang, Y., Han, Q. J. & Zhang, J. Hepatocellular carcinoma: Mechanisms of progression and immunotherapy. World J Gastroenterol 25, 3151-3167, doi: 10.3748/wjg.v25.i25.3151 (2019).
[4]
Zhang, H. et al. Tumor-infiltrating Neutrophils is Prognostic and Predictive for Postoperative Adjuvant Chemotherapy Benefit in Patients With Gastric Cancer. Ann Surg 267, 311-318, doi: 10.1097/SLA.0000000000002058 (2018).
[5]
Li, C. et al. Prophylactic In Vivo Hematopoietic Stem Cell Gene Therapy with an Immune Checkpoint Inhibitor Reverses Tumor Growth in Syngeneic Mouse Tumor Models. Cancer Res 80, 549-560, doi: 10.1158/0008-5472.CAN-19-1044 (2020).
[6]
Merli, P. et al. Role of interferon-gamma in immune-mediated graft failure after allogeneic hematopoietic stem cell transplantation. Haematologica 104, 2314-2323, doi: 10.3324/haematol.2019.216101 (2019).
[7]
Tian, X., Shen, H., Li, Z., Wang, T. & Wang, S. Tumor-derived exosomes, myeloid-derived suppressor cells, and tumor microenvironment. J Hematol Oncol 12, 84, doi: 10.1186/s13045-019-0772-z (2019).
[8]
Zhou, J. et al. Hepatoma-intrinsic CCRK inhibition diminishes myeloid-derived suppressor cell immunosuppression and enhances immune-checkpoint blockade efficacy. Gut 67, 931-944, doi: 10.1136/gutjnl-2017-314032 (2018).
[9]
Jia, Y. et al. Impaired function of CD4+ T follicular helper (Tfh) cells associated with hepatocellular carcinoma progression. PLoS One 10, e0117458, doi: 10.1371/journal.pone.0117458 (2015).
[10]
Ehling, J. & Tacke, F. Role of chemokine pathways in hepatobiliary cancer. Cancer Lett 379, 173-183, doi: 10.1016/j.canlet.2015.06.017 (2016).
[11]
Rohr-Udilova, N. et al. Deviations of the immune cell landscape between healthy liver and hepatocellular carcinoma. Sci Rep 8, 6220, doi: 10.1038/s41598-018-24437-5 (2018).
[12]
Khemlina, G., Ikeda, S. & Kurzrock, R. The biology of Hepatocellular carcinoma: implications for genomic and immune therapies. Mol Cancer 16, 149, doi: 10.1186/s12943-017-0712-x (2017).
[13]
Rao, N., Lee, Y. F. & Ge, R. Novel endogenous angiogenesis inhibitors and their therapeutic potential. Acta Pharmacol Sin 36, 1177-1190, doi: 10.1038/aps.2015.73 (2015).
[14]
McKeen, H. D. et al. The emerging role of FK506-binding proteins as cancer biomarkers: a focus on FKBPL. Biochem Soc Trans 39, 663-668, doi: 10.1042/BST0390663 (2011).
[15]
Todd, N. et al. Role of a novel angiogenesis FKBPL-CD44 pathway in preeclampsia risk stratification and mesenchymal stem cell treatment. J Clin Endocrinol Metab, doi: 10.1210/clinem/dgaa403 (2020).
[16]
Tang, Z., Kang, B., Li, C., Chen, T. & Zhang, Z. GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res 47, W556-W560, doi: 10.1093/nar/gkz430 (2019).
[17]
Tung, E. K. et al. Clinicopathological and prognostic significance of serum and tissue Dickkopf-1 levels in human hepatocellular carcinoma. Liver Int 31, 1494-1504, doi: 10.1111/j.1478-3231.2011.02597.x (2011).
[18]
Melis, M. et al. Viral expression and molecular profiling in liver tissue versus microdissected hepatocytes in hepatitis B virus - associated hepatocellular carcinoma. Journal of Translational Medicine 12, doi: 10.1186/s12967-014-0230-1 (2014).
[19]
Funk, K. et al. BAX Redistribution Induces Apoptosis Resistance and Selective Stress Sensitivity in Human HCC. Cancers (Basel) 12, doi: 10.3390/cancers12061437 (2020).
[20]
Woo, H. G. et al. Integrative analysis of genomic and epigenomic regulation of the transcriptome in liver cancer. Nature Communications 8, doi: 10.1038/s41467-017-00991-w (2017).
[21]
Wang, H.-W. et al. Forfeited hepatogenesis program and increased embryonic stem cell traits in young hepatocellular carcinoma (HCC) comparing to elderly HCC. BMC Genomics 14, doi: 10.1186/1471-2164-14-736. (2013).
[22]
Chaisaingmongkol, J. et al. Common Molecular Subtypes Among Asian Hepatocellular Carcinoma and Cholangiocarcinoma. Cancer Cell 32, 57-70 e53, doi: 10.1016/j.ccell.2017.05.009 (2017).
[23]
Wang, Y.-H. et al. Plasmalemmal Vesicle Associated Protein (PLVAP) as a therapeutic target for treatment of hepatocellular carcinoma. BMC Cancer 14, doi: 10.1186/1471-2407-14-815 (2014).
[24]
Wang, S. M., Ooi, L. L. & Hui, K. M. Identification and validation of a novel gene signature associated with the recurrence of human hepatocellular carcinoma. Clin Cancer Res 13, 6275-6283, doi: 10.1158/1078-0432. CCR-06-2236 (2007).
[25]
Chen, Y. L., Wang, T. H., Hsu, H. C., Yuan, R. H. & Jeng, Y. M. Overexpression of CTHRC1 in hepatocellular carcinoma promotes tumor invasion and predicts poor prognosis. PLoS One 8, e70324, doi: 10.1371/journal.pone.0070324 (2013).
[26]
Li, T. et al. TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res 48, W509-W514, doi: 10.1093/nar/gkaa407 (2020).
[27]
Szklarczyk, D. et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res 47, D607-D613, doi: 10.1093/nar/gky1131 (2019).
[28]
Zhou, Y. et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun 10, 1523, doi: 10.1038/s41467-019-09234-6 (2019).
[29]
Azimi, F. et al. Tumor-infiltrating lymphocyte grade is an independent predictor of sentinel lymph node status and survival in patients with cutaneous melanoma. J Clin Oncol 30, 2678-2683, doi: 10.1200/JCO.2011.37.8539 (2012).
[30]
Guo, S. & Deng, C. X. Effect of Stromal Cells in Tumor Microenvironment on Metastasis Initiation. Int J Biol Sci 14, 2083-2093, doi: 10.7150/ijbs.25720 (2018).
[31]
Hinshaw, D. C. & Shevde, L. A. The Tumor Microenvironment Innately Modulates Cancer Progression. Cancer Res 79, 4557-4566, doi: 10.1158/0008-5472. CAN-18-3962 (2019).
[32]
Wu, T. & Dai, Y. Tumor microenvironment and therapeutic response. Cancer Lett 387, 61-68, doi: 10.1016/j.canlet.2016.01.043 (2017).
[33]
Sawant, A. et al. Depletion of plasmacytoid dendritic cells inhibits tumor growth and prevents bone metastasis of breast cancer cells. J Immunol 189, 4258-4265, doi: 10.4049/jimmunol.1101855 (2012).
[34]
Zgajnar, N. R. et al. Biological Actions of the Hsp90-binding Immunophilins FKBP51 and FKBP52. Biomolecules 9, doi: 10.3390/biom9020052 (2019).
[35]
Annett, S., Moore, G. & Robson, T. FK506 binding proteins and inflammation related signalling pathways; basic biology, current status and future prospects for pharmacological intervention. Pharmacol Ther 215, 107623, doi: 10.1016/j.pharmthera.2020.107623 (2020).
[36]
Alsaab, H. O. et al. PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome. Front Pharmacol 8, 561, doi: 10.3389/fphar.2017.00561 (2017).
[37]
Yakkundi, A. et al. FKBPL is a critical antiangiogenic regulator of developmental and pathological angiogenesis. Arterioscler Thromb Vasc Biol 35, 845-854, doi: 10.1161/ATVBAHA.114.304539 (2015).
[38]
Liu, Y. et al. Proteomic mining in the dysplastic liver of WHV/c-myc mice--insights and indicators for early hepatocarcinogenesis. FEBS J 277, 4039-4053, doi: 10.1111/j.1742-4658.2010.07795.x (2010).
[39]
Lin, I.-Y. et al. Identification of FKBP11 as a biomarker for hepatocellular carcinoma. Anticancer Research 33, 2763-2769 (2013).
[40]
Higgins, J. P. T. et al. Expression of FKBP12 in Benign and Malignant Vascular Endothelium: an Immunohistochemical Study on Conventional Sections and Tissue Microarrays. The American Journal of Surgical Pathology 27, 58–64, doi: 10.1097/00000478-200301000-00007. (2003).
[41]
Khatua, S. et al. Overexpression of the EGFR/FKBP12/HIF-2α Pathway Identified in Childhood Astrocytomas by Angiogenesis Gene Profiling. Cancer Research 63, 1865-1870 (2003).
[42]
Erdmann, F., Jarczowski, F., Weiwad, M., Fischer, G. & Edlich, F. Hsp90-mediated inhibition of FKBP38 regulates apoptosis in neuroblastoma cells. FEBS Lett 581, 5709-5714, doi: 10.1016/j.febslet.2007.11.037 (2007).
[43]
Desmetz, C. et al. Identification of a new panel of serum autoantibodies associated with the presence of in situ carcinoma of the breast in younger women. Clin Cancer Res 15, 4733-4741, doi: 10.1158/1078-0432. CCR-08-3307 (2009).
[44]
Lin, J. F. et al. Identification of candidate prostate cancer biomarkers in prostate needle biopsy specimens using proteomic analysis. Int J Cancer 121, 2596-2605, doi: 10.1002/ijc.23016 (2007).
[45]
Jiang, W. et al. FK506 binding protein mediates glioma cell growth and sensitivity to rapamycin treatment by regulating NF-kappaB signaling pathway. Neoplasia 10, 235-243, doi: 10.1593/neo.07929 (2008).
[46]
Periyasamy, S., Hinds, T., Jr., Shemshedini, L., Shou, W. & Sanchez, E. R. FKBP51 and Cyp40 are positive regulators of androgen-dependent prostate cancer cell growth and the targets of FK506 and cyclosporin A. Oncogene 29, 1691-1701, doi: 10.1038/onc.2009.458 (2010).
[47]
Baughman, G., Wiederrecht, G. J., Campbell, N. F. & Bourgeois, S. FKBP51, a Novel T-Cell-Specific Immunophilin Capable of Calcineurin Inhibition. Molecular and Cellular Biology 15, 4395-4402, doi: 10.1128/mcb.15.8.4395 (1995).
[48]
Pei, H. et al. FKBP51 affects cancer cell response to chemotherapy by negatively regulating Akt. Cancer Cell 16, 259-266, doi: 10.1016/j.ccr.2009.07.016 (2009).
[49]
Olesen, S. H. et al. Human FK506 binding protein 65 is associated with colorectal cancer. Mol Cell Proteomics 4, 534-544, doi: 10.1074/mcp. M400217-MCP200 (2005).
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