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Combinatorial Chemistry & High Throughput Screening

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ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

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Research Article

ADAM19 and TUBB1 Correlate with Tumor Infiltrating Immune Cells and Predicts Prognosis in Osteosarcoma

Author(s): Jun Wang, Mingzhi Gong, Zhenggang Xiong, Yangyang Zhao and Deguo Xing*

Volume 26, Issue 1, 2023

Published on: 17 May, 2022

Page: [135 - 148] Pages: 14

DOI: 10.2174/1386207325666220406112305

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Abstract

Background: Osteosarcoma is the most common type of primary malignant bone tumor.

Introduction: This study aimed to explore potential key prognostic genes and their roles in osteosarcoma.

Methods: Three microarray datasets for osteosarcoma were downloaded from the GEO database. Differentially expressed genes (DEGs) were screened by the Limma package. Functional enrichment analysis was performed based on DAVID, GeneMANIA, and Metascape databases. Prognostic value of DEGs was elevated by survival analysis. CIBERSORT was used to assess the infiltrating abundance of 22 immune cells, followed by the Pearson correlation analysis between immune cells and prognosis-related genes. Gene set enrichment analysis and drug-gene interactions prediction were performed for prognosis-related genes.

Results: A total of 8 common up-regulated DEGs and 13 common down-regulated DEGs were screened in the GSE36001 and GSE56001 datasets. Enrichment analysis showed these DEGs were implicated in platelet activation, SMAD protein phosphorylation, lymphocyte/leukocyte/T cells activation, and cell migration. Survival analysis indicated that elevated expression of ADAM19 and TUBB1 were associated with a favorable prognosis. CIBERSORT algorithm revealed the higher infiltrating level of CD8 T cells, macrophages M0, and M2 in osteosarcoma. ADAM19 expression positively correlated with naïve B cells and negatively correlated with activated dendritic cells infiltrating abundance. TUBB1 expression positively correlated with gamma delta T cells while negatively correlated with helper follicular T cells infiltrating abundance. A total of 56 drugs were found to target TUBB1.

Conclusion: ADAM19 and TUBB1 could be prognostic biomarkers in osteosarcoma. Both their expression correlates with tumor infiltrating immune cells. TUBB1 was a multi-drug target that might be a therapeutic target in osteosarcoma.

Keywords: Osteosarcoma, predicts prognosis, ADAM19, TUBB1, prognostic biomarkers, leukocyte.

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[1]
Sadykova, L.R.; Ntekim, A.I.; Muyangwa-Semenova, M.; Rutland, C.S.; Jeyapalan, J.N.; Blatt, N.; Rizvanov, A.A. Epi-demiology and risk factors of osteosarcoma. Cancer Invest., 2020, 38(5), 259-269.
[http://dx.doi.org/10.1080/07357907.2020.1768401] [PMID: 32400205]
[2]
Lindsey, B.A.; Markel, J.E.; Kleinerman, E.S. Osteosarcoma overview. Rheumatol. Ther., 2017, 4(1), 25-43.
[http://dx.doi.org/10.1007/s40744-016-0050-2] [PMID: 27933467]
[3]
Song, K.; Song, J.; Lin, K.; Chen, F.; Ma, X.; Jiang, J.; Li, F. Survival analysis of patients with metastatic osteosarcoma: A surveillance, epidemiology, and end results population-based study. Int. Orthop., 2019, 43(8), 1983-1991.
[http://dx.doi.org/10.1007/s00264-019-04348-4] [PMID: 31127366]
[4]
Harrison, D.J.; Geller, D.S.; Gill, J.D.; Lewis, V.O.; Gorlick, R. Current and future therapeutic approaches for osteosar-coma. Expert Rev. Anticancer Ther., 2018, 18(1), 39-50.
[http://dx.doi.org/10.1080/14737140.2018.1413939] [PMID: 29210294]
[5]
Anderson, M.E. Update on survival in osteosarcoma. Orthop. Clin. North Am., 2016, 47(1), 283-292.
[http://dx.doi.org/10.1016/j.ocl.2015.08.022] [PMID: 26614941]
[6]
Wu, H.; Zhang, J.; Dai, R.; Xu, J.; Feng, H. Transferrin recep-tor-1 and VEGF are prognostic factors for osteosarcoma. J. Orthop. Surg. Res., 2019, 14(1), 296.
[http://dx.doi.org/10.1186/s13018-019-1301-z] [PMID: 31484533]
[7]
Ma, C.; Nie, X.G.; Wang, Y.L.; Liu, X.H.; Liang, X.; Zhou, Q.L.; Wu, D.P. CBX3 predicts an unfavorable prognosis and promotes tumorigenesis in osteosarcoma. Mol. Med. Rep., 2019, 19(5), 4205-4212.
[http://dx.doi.org/10.3892/mmr.2019.10104] [PMID: 30942427]
[8]
Heymann, M.F.; Lézot, F.; Heymann, D. The contribution of immune infiltrates and the local microenvironment in the pathogenesis of osteosarcoma. Cell. Immunol., 2019, 343, 103711.
[http://dx.doi.org/10.1016/j.cellimm.2017.10.011] [PMID: 29117898]
[9]
Yang, X.; Zhang, W.; Xu, P. NK cell and macrophages confer prognosis and reflect immune status in osteosarcoma. J. Cell. Biochem., 2018.
[PMID: 30556159]
[10]
Chen, Y.; Zhao, B.; Wang, X. Tumor infiltrating immune cells (TIICs) as a biomarker for prognosis benefits in patients with osteosarcoma. BMC Cancer, 2020, 20(1), 1022.
[http://dx.doi.org/10.1186/s12885-020-07536-3] [PMID: 33087099]
[11]
Smyth, G.; Ritchie, M.; Thorne, N.; Wettenhall, J.; Shi, W. Linear models for microarray data user’s guide; , 2010.
[12]
Dennis, G., Jr; Sherman, B.T.; Hosack, D.A.; Yang, J.; Gao, W.; Lane, H.C.; Lempicki, R.A. DAVID: database for annota-tion, visualization, and integrated discovery. Genome Biol., 2003, 4(5), 3.
[http://dx.doi.org/10.1186/gb-2003-4-5-p3] [PMID: 12734009]
[13]
Mostafavi, S.; Ray, D.; Warde-Farley, D.; Grouios, C.; Mor-ris, Q. GeneMANIA: A real-time multiple association network integration algorithm for predicting gene function. Genome Biol, 2008, 9 Suppl 1(Suppl 1), S4.
[http://dx.doi.org/10.1186/gb-2008-9-s1-s4]
[14]
Zhou, Y.; Zhou, B.; Pache, L.; Chang, M.; Khodabakhshi, A.H.; Tanaseichuk, O.; Benner, C.; Chanda, S.K. Metascape provides a biologist-oriented resource for the analysis of sys-tems-level datasets. Nat. Commun., 2019, 10(1), 1523.
[http://dx.doi.org/10.1038/s41467-019-09234-6] [PMID: 30944313]
[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]
Cotto, K.C.; Wagner, A.H.; Feng, Y.Y.; Kiwala, S.; Coffman, A.C.; Spies, G.; Wollam, A.; Spies, N.C.; Griffith, O.L.; Grif-fith, M. DGIdb 3.0: A redesign and expansion of the drug-gene interaction database. Nucleic Acids Res., 2018, 46(D1), D1068-D1073.
[http://dx.doi.org/10.1093/nar/gkx1143] [PMID: 29156001]
[17]
Fujita, N.; Takagi, S. The impact of Aggrus/podoplanin on platelet aggregation and tumour metastasis. J. Biochem., 2012, 152(5), 407-413.
[http://dx.doi.org/10.1093/jb/mvs108] [PMID: 22992842]
[18]
Takagi, S.; Takemoto, A.; Takami, M.; Oh-Hara, T.; Fujita, N. Platelets promote osteosarcoma cell growth through activation of the platelet-derived growth factor receptor-Akt signaling axis. Cancer Sci., 2014, 105(8), 983-988.
[http://dx.doi.org/10.1111/cas.12464] [PMID: 24974736]
[19]
Dong, F.; Liu, T.; Jin, H.; Wang, W. Chimaphilin inhibits human osteosarcoma cell invasion and metastasis through suppressing the TGF-β1-induced epithelial-to-mesenchymal transition markers via PI-3K/Akt, ERK1/2, and Smad signal-ing pathways. Can. J. Physiol. Pharmacol., 2018, 96(1), 1-7.
[http://dx.doi.org/10.1139/cjpp-2016-0522] [PMID: 28177668]
[20]
Jiang, X.; Zhang, Z.; Song, C.; Deng, H.; Yang, R.; Zhou, L.; Sun, Y.; Zhang, Q. Glaucocalyxin a reverses EMT and TGF-β1-induced EMT by inhibiting TGF-β1/Smad2/3 signaling pathway in osteosarcoma. Chem. Biol. Interact., 2019, 307, 158-166.
[http://dx.doi.org/10.1016/j.cbi.2019.05.005] [PMID: 31059706]
[21]
Trepat, X.; Chen, Z.; Jacobson, K. Cell migration. Compr. Physiol., 2012, 2(4), 2369-2392.
[http://dx.doi.org/10.1002/cphy.c110012] [PMID: 23720251]
[22]
Vilalta, M.; Rafat, M.; Graves, E.E. Effects of radiation on metastasis and tumor cell migration. Cell. Mol. Life Sci., 2016, 73(16), 2999-3007.
[http://dx.doi.org/10.1007/s00018-016-2210-5] [PMID: 27022944]
[23]
Edwards, D.R.; Handsley, M.M.; Pennington, C.J. The ADAM metalloproteinases. Mol. Aspects Med., 2008, 29(5), 258-289.
[http://dx.doi.org/10.1016/j.mam.2008.08.001] [PMID: 18762209]
[24]
Kong, R.; Gao, J.; Zhang, J.; Ji, L.; Yu, Y.; Zhang, L. Synovial mesenchymal stem cell-derived exosomal miR-320c enhanc-es chondrogenesis by targeting ADAM19. Future Med. Chem., 2022, 14(2), 81-96.
[http://dx.doi.org/10.4155/fmc-2021-0177]
[25]
Saha, N.; Robev, D.; Himanen, J.P.; Nikolov, D.B. ADAM proteases: Emerging role and targeting of the non-catalytic domains. Cancer Lett., 2019, 467, 50-57.
[http://dx.doi.org/10.1016/j.canlet.2019.10.003] [PMID: 31593799]
[26]
Garcia-Monclús, S.; López-Alemany, R.; Almacellas-Rabaiget, O.; Herrero-Martín, D.; Huertas-Martinez, J.; Lagares-Tena, L.; Alba-Pavón, P.; Hontecillas-Prieto, L.; Mo-ra, J.; de Álava, E.; Rello-Varona, S.; Giangrande, P.H.; Tirado, O.M. EphA2 receptor is a key player in the metastatic onset of ewing sarcoma. Int. J. Cancer, 2018, 143(5), 1188-1201.
[http://dx.doi.org/10.1002/ijc.31405] [PMID: 29582409]
[27]
Hoyne, G.; Rudnicka, C.; Sang, Q.X.; Roycik, M.; Howarth, S.; Leedman, P.; Schlaich, M.; Candy, P.; Matthews, V. Ge-netic and cellular studies highlight that a disintegrin and met-alloproteinase 19 is a protective biomarker in human prostate cancer. BMC Cancer, 2016, 16(1), 151.
[http://dx.doi.org/10.1186/s12885-016-2178-4] [PMID: 26912236]
[28]
Burley, K.; Westbury, S.K.; Mumford, A.D. TUBB1 variants and human platelet traits. Platelets, 2018, 29(2), 209-211.
[http://dx.doi.org/10.1080/09537104.2017.1411587] [PMID: 29333906]
[29]
Palma-Barqueros, V.; Bury, L. Expanding the genetic spec-trum of TUBB1-related thrombocytopenia. Blood Adv., 2021, 5(24), 5453-5467.
[http://dx.doi.org/10.1182/bloodadvances.2020004057]
[30]
Stoupa, A.; Adam, F.; Kariyawasam, D.; Strassel, C.; Gawade, S.; Szinnai, G.; Kauskot, A.; Lasne, D.; Janke, C.; Natarajan, K.; Schmitt, A.; Bole-Feysot, C.; Nitschke, P.; Léger, J.; Jabot-Hanin, F.; Tores, F.; Michel, A.; Munnich, A.; Besmond, C.; Scharfmann, R.; Lanza, F.; Borgel, D.; Polak, M.; Carré, A. TUBB1 mutations cause thyroid dysgenesis associated with abnormal platelet physiology. EMBO Mol. Med., 2018, 10(12), e9569.
[http://dx.doi.org/10.15252/emmm.201809569] [PMID: 30446499]
[31]
Han, Y.; Guo, W.; Ren, T.; Huang, Y.; Wang, S.; Liu, K.; Zheng, B.; Yang, K.; Zhang, H.; Liang, X. Tumor-associated macrophages promote lung metastasis and induce epithelial-mesenchymal transition in osteosarcoma by activating the COX-2/STAT3 axis. Cancer Lett., 2019, 440-441, 116-125.
[http://dx.doi.org/10.1016/j.canlet.2018.10.011] [PMID: 30343113]
[32]
Cersosimo, F.; Lonardi, S.; Bernardini, G.; Telfer, B.; Man-delli, G.E.; Santucci, A.; Vermi, W.; Giurisato, E. Tumor-Associated macrophages in osteosarcoma: from mechanisms to therapy. Int. J. Mol. Sci., 2020, 21(15), E5207.
[http://dx.doi.org/10.3390/ijms21155207] [PMID: 32717819]
[33]
Koehne de González, A.; Mansukhani, M.M.; Fernandes, H.; Hsiao, S.J. Pan-tumor screening for NTRK gene fusions using pan-TRK immunohistochemistry and RNA NGS fusion panel testing. Cancer Genet., 2022, 262-263, 47-52.
[http://dx.doi.org/10.1016/j.cancergen.2021.12.010] [PMID: 35007853]
[34]
Gitlin, A.D.; Nussenzweig, M.C. Immunology: Fifty years of B lymphocytes. Nature, 2015, 517(7533), 139-141.
[http://dx.doi.org/10.1038/517139a] [PMID: 25567266]
[35]
Zhang, Z.; Ma, L.; Goswami, S.; Ma, J.; Zheng, B.; Duan, M.; Liu, L.; Zhang, L.; Shi, J.; Dong, L.; Sun, Y.; Tian, L.; Gao, Q.; Zhang, X. Landscape of infiltrating B cells and their clini-cal significance in human hepatocellular carcinoma. OncoImmunology, 2019, 8(4), e1571388.
[http://dx.doi.org/10.1080/2162402X.2019.1571388] [PMID: 30906667]
[36]
Kawano, M.; Nishida, H.; Nakamoto, Y.; Tsumura, H.; Tsuchiya, H. Cryoimmunologic antitumor effects enhanced by dendritic cells in osteosarcoma. Clin. Orthop. Relat. Res., 2010, 468(5), 1373-1383.
[http://dx.doi.org/10.1007/s11999-010-1302-z] [PMID: 20232181]
[37]
Kawano, M.; Tanaka, K.; Itonaga, I.; Iwasaki, T.; Miyazaki, M.; Ikeda, S.; Tsumura, H. Dendritic cells combined with doxorubicin induces immunogenic cell death and exhibits an-titumor effects for osteosarcoma. Oncol. Lett., 2016, 11(3), 2169-2175.
[http://dx.doi.org/10.3892/ol.2016.4175] [PMID: 26998143]
[38]
Gao, W.; Zhou, J.; Ji, B. Evidence of interleukin 21 reduction in osteosarcoma patients due to PD-1/PD-L1-Mediated sup-pression of follicular helper T Cell functionality. DNA Cell Biol., 2017, 36(9), 794-800.
[http://dx.doi.org/10.1089/dna.2017.3669] [PMID: 28650673]

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