Login Register Cart 0
Generic placeholder image

Current Genomics

Editor-in-Chief

ISSN (Print): 1389-2029
ISSN (Online): 1875-5488

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Prospective Analysis of Proteins Carried in Extracellular Vesicles with Clinical Outcome in Hepatocellular Carcinoma

Author(s): Wenbiao Chen, Feng Zhang, Huixuan Xu, Xianliang Hou and Donge Tang*

Volume 23, Issue 2, 2022

Published on: 24 March, 2022

Page: [109 - 117] Pages: 9

DOI: 10.2174/1389202923666220304125458

Price: $65

Abstract

Background: Extracellular vehicles (EVs) contain different proteins that relay information between tumor cells, thus promoting tumorigenesis. Therefore, EVs can serve as an ideal marker for tumor pathogenesis and clinical application.

Objective: Here, we characterised EV-specific proteins in hepatocellular carcinoma (HCC) samples and established their potential protein-protein interaction (PPI) networks.

Materials and Methods: We used multi-dimensional bioinformatics methods to mine a network module to use as a prognostic signature and validated the model’s prediction using additional datasets. The relationship between the prognostic model and tumor immune cells or the tumor microenvironment status was also examined.

Results: 1134 proteins from 316 HCC samples were mapped to the exoRBase database. HCC-specific EVs specifically expressed a total of 437 proteins. The PPI network revealed 321 proteins and 938 interaction pathways, which were mined to identify a three network module (3NM) with significant prognostic prediction ability. Validation of the 3NM in two more datasets demonstrated that the model outperformed the other signatures in prognostic prediction ability. Functional analysis revealed that the network proteins were involved in various tumor-related pathways. Additionally, these findings demonstrated a favorable association between the 3NM signature and macrophages, dendritic, and mast cells. Besides, the 3NM revealed the tumor microenvironment status, including hypoxia and inflammation.

Conclusion: These findings demonstrate that the 3NM signature reliably predicts HCC pathogenesis. Therefore, the model may be used as an effective prognostic biomarker in managing patients with HCC.

Keywords: Proteins, exosome, hepatocellular carcinoma, prognostic signature, gene, PPI networks.

Next »
Graphical Abstract

[1]
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[2]
Yang, J.D.; Hainaut, P.; Gores, G.J.; Amadou, A.; Plymoth, A.; Roberts, L.R. A global view of hepatocellular carcinoma: Trends, risk, prevention and management. Nat. Rev. Gastroenterol. Hepatol., 2019, 16(10), 589-604.
[http://dx.doi.org/10.1038/s41575-019-0186-y] [PMID: 31439937]
[3]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2015. CA Cancer J. Clin., 2015, 65(1), 5-29.
[http://dx.doi.org/10.3322/caac.21254] [PMID: 25559415]
[4]
Kalluri, R.; LeBleu, V.S. The biology, function, and biomedical applications of exosomes. Science, 2020, 367(6478), eaau6977.
[http://dx.doi.org/10.1126/science.aau6977] [PMID: 32029601]
[5]
Hessvik, N.P.; Llorente, A. Current knowledge on exosome biogenesis and release. Cell. Mol. Life Sci., 2018, 75(2), 193-208.
[http://dx.doi.org/10.1007/s00018-017-2595-9] [PMID: 28733901]
[6]
Whiteside, T.L. Tumor-derived exosomes and their role in cancer progression. Adv. Clin. Chem., 2016, 74, 103-141.
[http://dx.doi.org/10.1016/bs.acc.2015.12.005] [PMID: 27117662]
[7]
Kalluri, R. The biology and function of exosomes in cancer. J. Clin. Invest., 2016, 126(4), 1208-1215.
[http://dx.doi.org/10.1172/JCI81135] [PMID: 27035812]
[8]
McAndrews, K.M.; Kalluri, R. Mechanisms associated with biogenesis of exosomes in cancer. Mol. Cancer, 2019, 18(1), 52.
[http://dx.doi.org/10.1186/s12943-019-0963-9] [PMID: 30925917]
[9]
Tang, Z.; Li, D.; Hou, S.; Zhu, X. The cancer exosomes: Clinical implications, applications and challenges. Int. J. Cancer, 2020, 146(11), 2946-2959.
[PMID: 31671207]
[10]
Wu, A.Y.; Ueda, K.; Lai, C.P. Proteomic analysis of extracellular vesicles for cancer diagnostics. Proteomics, 2019, 19(1-2), e1800162.
[http://dx.doi.org/10.1002/pmic.201800162] [PMID: 30334355]
[11]
Wee, I.; Syn, N.; Sethi, G.; Goh, B.C.; Wang, L. Role of tumor-derived exosomes in cancer metastasis. Biochim. Biophys. Acta Rev. Cancer, 2019, 1871(1), 12-19.
[http://dx.doi.org/10.1016/j.bbcan.2018.10.004] [PMID: 30419312]
[12]
Zhang, H.; Deng, T.; Liu, R.; Bai, M.; Zhou, L.; Wang, X.; Li, S.; Wang, X.; Yang, H.; Li, J.; Ning, T.; Huang, D.; Li, H.; Zhang, L.; Ying, G.; Ba, Y. Exosome-delivered EGFR regulates liver microenvironment to promote gastric cancer liver metastasis. Nat. Commun., 2017, 8, 15016.
[http://dx.doi.org/10.1038/ncomms15016] [PMID: 28393839]
[13]
Xie, J.Y.; Wei, J.X.; Lv, L.H.; Han, Q.F.; Yang, W.B.; Li, G.L.; Wang, P.X.; Wu, S.B.; Duan, J.X.; Zhuo, W.F.; Liu, P.Q.; Min, J. Angiopoietin-2 induces angiogenesis via exosomes in human hepatocellular carcinoma. Cell Commun. Signal., 2020, 18(1), 46.
[http://dx.doi.org/10.1186/s12964-020-00535-8] [PMID: 32183816]
[14]
Chuang, H.Y.; Lee, E.; Liu, Y.T.; Lee, D.; Ideker, T. Network-based classification of breast cancer metastasis. Mol. Syst. Biol., 2007, 3, 140.
[http://dx.doi.org/10.1038/msb4100180] [PMID: 17940530]
[15]
Newman, A.M.; Liu, C.L.; Green, M.R.; Gentles, A.J.; Feng, W.; Xu, Y.; Hoang, C.D.; Diehn, M.; Alizadeh, A.A. Robust enumeration of cell subsets from tissue expression profiles. Nat. Methods, 2015, 12(5), 453-457.
[http://dx.doi.org/10.1038/nmeth.3337] [PMID: 25822800]
[16]
Buffa, F.M.; Harris, A.L.; West, C.M.; Miller, C.J. Large meta-analysis of multiple cancers reveals a common, compact and highly prognostic hypoxia metagene. Br. J. Cancer, 2010, 102(2), 428-435.
[http://dx.doi.org/10.1038/sj.bjc.6605450] [PMID: 20087356]
[17]
Masiero, M.; Simões, F.C.; Han, H.D.; Snell, C.; Peterkin, T.; Bridges, E.; Mangala, L.S.; Wu, S.Y.; Pradeep, S.; Li, D.; Han, C.; Dalton, H.; Lopez-Berestein, G.; Tuynman, J.B.; Mortensen, N.; Li, J.L.; Patient, R.; Sood, A.K.; Banham, A.H.; Harris, A.L.; Buffa, F.M. A core human primary tumor angiogenesis signature identifies the endothelial orphan receptor ELTD1 as a key regulator of angiogenesis. Cancer Cell, 2013, 24(2), 229-241.
[http://dx.doi.org/10.1016/j.ccr.2013.06.004] [PMID: 23871637]
[18]
Saloura, V.; Zuo, Z.; Koeppen, H.; Keck, M.K.; Khattri, A.; Boe, M.; Hegde, P.S.; Xiao, Y.; Nakamura, Y.; Vokes, E.E. Correlation of T-cell inflamed phenotype with mesenchymal subtype, expression of PD-L1, and other immune checkpoints in head and neck cancer. J. Clin. Oncol., 2014, 32(Suppl. 15), 6009.
[http://dx.doi.org/10.1200/jco.2014.32.15_suppl.6009]
[19]
Wilson, G.K.; Tennant, D.A.; McKeating, J.A. Hypoxia inducible factors in liver disease and hepatocellular carcinoma: Current understanding and future directions. J. Hepatol., 2014, 61(6), 1397-1406.
[http://dx.doi.org/10.1016/j.jhep.2014.08.025] [PMID: 25157983]
[20]
Wang, Z.; Chen, J.Q.; Liu, J.L.; Tian, L. Exosomes in tumor microenvironment: Novel transporters and biomarkers. J. Transl. Med., 2016, 14(1), 297.
[http://dx.doi.org/10.1186/s12967-016-1056-9] [PMID: 27756426]
[21]
Yang, X.X.; Sun, C.; Wang, L.; Guo, X.L. New insight into isolation, identification techniques and medical applications of exosomes. J. Control. Release, 2019, 308, 119-129.
[http://dx.doi.org/10.1016/j.jconrel.2019.07.021] [PMID: 31325471]
[22]
Li, S.; Li, Y.; Chen, B.; Zhao, J.; Yu, S.; Tang, Y.; Zheng, Q.; Li, Y.; Wang, P.; He, X.; Huang, S. exoRBase: A database of circRNA, lncRNA and mRNA in human blood exosomes. Nucleic Acids Res., 2018, 46(D1), D106-D112.
[http://dx.doi.org/10.1093/nar/gkx891] [PMID: 30053265]
[23]
Jalalian, S.H.; Ramezani, M.; Jalalian, S.A.; Abnous, K.; Taghdisi, S.M. Exosomes, new biomarkers in early cancer detection. Anal. Biochem., 2019, 571, 1-13.
[http://dx.doi.org/10.1016/j.ab.2019.02.013] [PMID: 30776327]
[24]
Li, T.; Wernersson, R.; Hansen, R.B.; Horn, H.; Mercer, J.; Slodkowicz, G.; Workman, C.T.; Rigina, O.; Rapacki, K.; Stærfeldt, H.H.; Brunak, S.; Jensen, T.S.; Lage, K. A scored human protein-protein interaction network to catalyze genomic interpretation. Nat. Methods, 2017, 14(1), 61-64.
[http://dx.doi.org/10.1038/nmeth.4083] [PMID: 27892958]
[25]
Degirolamo, C.; Sabbà, C.; Moschetta, A. Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23. Nat. Rev. Drug Discov., 2016, 15(1), 51-69.
[http://dx.doi.org/10.1038/nrd.2015.9] [PMID: 26567701]
[26]
Yan, T.; Ooi, W.F.; Qamra, A.; Cheung, A.; Ma, D.; Sundaram, G.M.; Xu, C.; Xing, M.; Poon, L.; Wang, J.; Loh, Y.P.; Ho, J.H.J.; Ng, J.J.Q.; Ramlee, M.K.; Aswad, L.; Rozen, S.G.; Ghosh, S.; Bard, F.A.; Sampath, P.; Tergaonkar, V.; Davies, J.O.J.; Hughes, J.R.; Goh, E.; Bi, X.; Fullwood, M.J.; Tan, P.; Li, S. HoxC5 and miR-615-3p target newly evolved genomic regions to repress hTERT and inhibit tumorigenesis. Nat. Commun., 2018, 9(1), 100.
[http://dx.doi.org/10.1038/s41467-017-02601-1] [PMID: 29311615]
[27]
Koufaris, C. Human and primate-specific microRNAs in cancer: Evolution, and significance in comparison with more distantly-related research models: The great potential of evolutionary young microRNA in cancer research. BioEssays, 2016, 38(3), 286-294.
[http://dx.doi.org/10.1002/bies.201500135] [PMID: 26800466]
[28]
Qi, L.; Chen, L.; Li, Y.; Qin, Y.; Pan, R.; Zhao, W.; Gu, Y.; Wang, H.; Wang, R.; Chen, X.; Guo, Z. Critical limitations of prognostic signatures based on risk scores summarized from gene expression levels: A case study for resected stage I non-small-cell lung cancer. Brief. Bioinform., 2016, 17(2), 233-242.
[http://dx.doi.org/10.1093/bib/bbv064] [PMID: 26254430]
[29]
Milane, L.; Singh, A.; Mattheolabakis, G.; Suresh, M.; Amiji, M.M. Exosome mediated communication within the tumor microenvironment. J. Control. Release, 2015, 219, 278-294.
[http://dx.doi.org/10.1016/j.jconrel.2015.06.029] [PMID: 26143224]
[30]
Meng, W.; Hao, Y.; He, C.; Li, L.; Zhu, G. Exosome-orchestrated hypoxic tumor microenvironment. Mol. Cancer, 2019, 18(1), 57.
[http://dx.doi.org/10.1186/s12943-019-0982-6] [PMID: 30925935]
[31]
Hu, C.; Chen, M.; Jiang, R.; Guo, Y.; Wu, M.; Zhang, X. Exosome-related tumor microenvironment. J. Cancer, 2018, 9(17), 3084-3092.
[http://dx.doi.org/10.7150/jca.26422] [PMID: 30210631]
[32]
Filipazzi, P.; Bürdek, M.; Villa, A.; Rivoltini, L.; Huber, V. Recent advances on the role of tumor exosomes in immunosuppression and disease progression. Semin. Cancer Biol., 2012, 22(4), 342-349.
[http://dx.doi.org/10.1016/j.semcancer.2012.02.005] [PMID: 22369922]
[33]
Dlamini, Z.; Francies, F.Z.; Hull, R.; Marima, R. Artificial Intelligence (AI) and big data in cancer and precision oncology. Comput. Struct. Biotechnol. J., 2020, 18, 2300-2311.
[http://dx.doi.org/10.1016/j.csbj.2020.08.019] [PMID: 32994889]
[34]
Zheng, H.; Zhang, G.; Zhang, L.; Wang, Q.; Li, H.; Han, Y.; Xie, L.; Yan, Z.; Li, Y.; An, Y.; Dong, H.; Zhu, W.; Guo, X. Comprehensive review of web servers and bioinformatics tools for cancer prognosis analysis. Front. Oncol., 2020, 10, 68.
[http://dx.doi.org/10.3389/fonc.2020.00068] [PMID: 32117725]
[35]
Zhang, X.; Ma, L.; Zhai, L.; Chen, D.; Li, Y.; Shang, Z.; Zhang, Z.; Gao, Y.; Yang, W.; Li, Y.; Pan, Y. Construction and validation of a three-microRNA signature as prognostic biomarker in patients with hepatocellular carcinoma. Int. J. Med. Sci., 2021, 18(4), 984-999.
[http://dx.doi.org/10.7150/ijms.49126] [PMID: 33456356]
[36]
Du, X.; Zhang, Y. Integrated analysis of immunity- and ferroptosis-related biomarker signatures to improve the prognosis prediction of hepatocellular carcinoma. Front. Genet., 2020, 11, 614888.
[http://dx.doi.org/10.3389/fgene.2020.614888] [PMID: 33391356]
[37]
Craig, A.J.; von Felden, J.; Garcia-Lezana, T.; Sarcognato, S.; Villanueva, A. Tumour evolution in hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol., 2020, 17(3), 139-152.
[http://dx.doi.org/10.1038/s41575-019-0229-4] [PMID: 31792430]
[38]
Zhang, S.; Zhou, Y.; Wang, Y.; Wang, Z.; Xiao, Q.; Zhang, Y.; Lou, Y.; Qiu, Y.; Zhu, F. The mechanistic, diagnostic and therapeutic novel nucleic acids for hepatocellular carcinoma emerging in past score years. Brief. Bioinform., 2021, 22(2), 1860-1883.
[http://dx.doi.org/10.1093/bib/bbaa023] [PMID: 32249290]

Rights & Permissions Print Cite
Article Metrics
37
1
© 2024 Bentham Science Publishers | Privacy Policy