1.Graduate School, Guangxi University of Chinese Medicine, Guangxi Zhuang Autonomous Region, Nanning 530022, China;
2.Department of Orthopedics, the First Affiliated Hospital of Guangxi University of Chinese Medicine, Guangxi Zhuang Autonomous Region, Nanning 530023, China;
3.Intensive Care Unit, Joint Logistics Support Force 910th Hospital, Fujian Province, Quanzhou 362000, China
Abstract:Objective To screen the differentially expressed genes (DEGs) methylated in osteosarcoma (OS) patients related to prognosis based on bioinformatics methods, and to provide a direction for the treatment and research of OS. Methods The OS gene chip (GSE36001) and OS methylation gene chip (GSE36002) were downloaded from the gene expression omnibus database, and the differences were analyzed and pooled to obtain the DEGs. Enrichment analysis of DEGs was performed, and the protein- protein interaction (PPI) network of DEGs was constructed by the STRING database. Cytoscape 3.6 software was used to screen the core genes of PPI network, and survival analysis was performed. Results A total of 532 up- regulated and 281 down-regulated DEGs were identified in differential analysis of GSE36001, and 3 433 hypermethylated DEGs and 2 212 hypomethylated DEGs were identified in differential methylation analysis of GSE36002, after intersection, 128 down-regulated OS hypermethylated DEGs and 44 up-regulated OS hypomethylated DEGs were obtained. OS hypermethylated DEGs were mainly involved in epidermal development and skin cell differentiation, and hypomethylated DEGs were mainly involved in cell differentiation and other biological processes. OS hypermethylated DEGs involved cytokine- cytokine receptor interactions and hypomethylated DEGs involved Ca2+ and other pathways. Eight core genes were identified by PPI analysis. Survival analysis results showed that the survival rate of OS patients with high expression of ALOX5AP, HCK, LAPTM5, RAC2, LCP2, AIF1, TYROBP, and PLEK were higher than those of patients with low expression (P<0.05). Conclusion Eight core methylated DEGs, including ALOX5AP, HCK, and LAPTM5, etc. may affect the prognosis of patients with OS.
[1] Zhang W,Wei L,Weng J,et al. Advances in the Research of Osteosarcoma Stem Cells and its Related Genes [J]. Cell Biol Int,2021,46(3):336-343.
[2] Eaton BR,Schwarz R,Vatner R,et al. Osteosarcoma [J]. Pediatr Blood Cancer,2021,68(S2):e28352.
[3] Casali PG,Bielack S,Abecassis N,et al. Bone sarcomas:ESMO-PaedCan-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up [J]. Ann Oncol,2018, 29(S4):v79-v95.
[4] Sonaglio V,de Carvalho AC,Toledo SR,et al. Aberrant DNA methylation of ESR1 and p14ARF genes could be useful as prognostic indicators in osteosarcoma [J]. Onco Targets Ther, 2013,6:713-723.
[5] Wang F,Qin G,Liu J,et al. Integrated Genome-Wide Met- hylation and Expression Analyses Reveal Key Regulators in Osteosarcoma [J]. Comput Math Methods Med,2020,2020:7067649.
[6] Tian W,Li Y,Zhang J,et al. Combined analysis of DNA methylation and gene expression profiles of osteosarcoma identified several prognosis signatures [J]. Gene,2018,650:7-14.
[7] Pagiatakis C,Musolino E,Gornati R,et al. Epigenetics of aging and disease:a brief overview[J]. Aging Clin Exp Res,2021,33(4):737-745.
[8] 刘晓林,丁小燕,刘藜,等.血管性认知障碍肾阳虚证的调查研究及DNA甲基化本质[J].中国实验方剂学杂志,2023,29(6):111-119.
[9] 朱然,张瑞丰,程馨,等.哺乳动物卵母细胞的DNA甲基化和组蛋白修饰[J].生物医学转化,2022,3(4):2-14.
[10] 刘用,肖狄,康静璠,等.冠状动脉慢血流的发病机制及其DNA甲基化研究进展[J].中国医药,2023,18(6):931-934.
[11] Jones PA. Functions of DNA methylation:islands,start sites,gene bodies and beyond [J]. Nat Rev Genet,2012,13(7):484-492.
[12] Ehrlich M. DNA hypermethylation in disease:mechanisms and clinical relevance [J]. Epigenetics,2019,14(12):1141- 1163.
[13] Kresse SH,Rydbeck H,Sk?覽rn M,et al. Integrative analysis reveals relationships of genetic and epigenetic alterations in osteosarcoma [J]. PLoS One,2012,7(11):e48262.
[14] Jing Y,Liang H,Zhang Y,et al. Up-regulation of Toll-like Receptor 9 in Osteosarcoma [J]. Anticancer Res,2015,35(11):5839-5843.
[15] Das S,Shapiro B,Vucic EA,et al. Tumor Cell-Derived IL1β Promotes Desmoplasia and Immune Suppression in Pancreatic Cancer [J]. Cancer Res,2020,80(5):1088-1101.
[16] Mori T,Sato Y,Miyamoto K,et al. TNFα promotes osteosarcoma progression by maintaining tumor cells in an undifferentiated state [J]. Oncogene,2014,33(33):4236-4241.
[17] Jing Y,Liang H,Zhang Y,et al. Up-regulation of Toll-like Receptor 9 in Osteosarcoma [J]. Anticancer Res,2015,35(11):5839-5843.
[18] Dhaini HR,Thomas DG,Giordano TJ,et al. Cytochrome P450 CYP3A4/5 expression as a biomarker of outcome in osteosarcoma [J]. J Clin Oncol,2003,21(13):2481-2485.
[19] Lu Y,Cederbaum AI. Cytochrome P450s and Alcoholic Liver Disease [J]. Curr Pharm Des,2018,24(14):1502-1517.
[20] Trujillo-Paolillo A,Tesser-Gamba F,Petrilli AS,et al. CYP genes in osteosarcoma:Their role in tumorigenesis,pulmonary metastatic microenvironment and treatment response [J]. Oncotarget,2017,8(24):38530-38540.
[21] Lv H,Zhen C,Liu J,et al. β-Phenethyl Isothiocyanate Induces Cell Death in Human Osteosarcoma through Altering Iron Metabolism,Disturbing the Redox Balance,and Activating the MAPK Signaling Pathway [J]. Oxid Med Cell Longev,2020,2020:5021983.
[22] Cassinelli G,Lanzi C. Heparanase:A Potential Therapeutic Target in Sarcomas [J]. Adv Exp Med Biol,2020,1221:405- 431.
[23] Fan MK,Zhang GC,Chen W,et al. Siglec-15 Promotes Tumor Progression in Osteosarcoma via DUSP1/MAPK Pathway [J]. Front Oncol,2021,11:710689.
[24] Liu W,Li T,Hu W,et al. Hematopoietic cell kinase enhances osteosarcoma development via the MEK/ERK pathway [J]. J Cell Mol Med,2021,25(18):8789-8795.
[25] Gu Y,Byrne MC,Paranavitana NC,et al. Rac2,a hematopo- iesis-specific Rho GTPase,specifically regulates mast cell protease gene expression in bone marrow-derived mast cells [J]. Mol Cell Biol,2002,22(21):7645-7657.
[26] Gomez JC,Soltys J,Okano K,et al. The role of Rac2 in regulating neutrophil production in the bone marrow and circulating neutrophil counts [J]. Am J Pathol,2008,173(2): 507-517.
[27] Shao X,Miao M,Qi X,et al. Ras-proximate-1 GTPase- activating protein and Rac2 may play pivotal roles in the initial development of myelodysplastic syndrome [J]. Oncol Lett,2012,4(2):289-298.
[28] Motto DG,Ross SE,Wu J,et al. Implication of the GRB2- associated phosphoprotein SLP-76 in T cell receptor-mediated interleukin 2 production [J]. J Exp Med,1996,183(4):1937-1943.
[29] Blomberg OS,Spagnuolo L,de Visser KE. Immune regulation of metastasis:mechanistic insights and therapeutic opportunities [J]. Dis Model Mech,2018,11(10):dmm036236.
[30] Chu S,Wang H,Yu M. A putative molecular network associated with colon cancer metastasis constructed from microarray data [J]. World J Surg Oncol,2017,15(1):115.
[31] Jiang H,Dong L,Gong F,et al. Inflammatory genes are novel prognostic biomarkers for colorectal cancer [J]. Int J Mol Med,2018,42(1):368-380.
[32] Li Y,Min W,Li M,et al. Identification of hub genes and regulatory factors of glioblastoma multiforme subgroups by RNA-seq data analysis [J]. Int J Mol Med,2016,38(4):1170-1178.
[33] Li T,Feng Z,Jia S,et al. Daintain/AIF-1 promotes breast cancer cell migration by up-regulated TNF-α via activate p38 MAPK signaling pathway [J]. Breast Cancer Res Treat,2012,131(3):891-898.
[34] Lanier LL,Corliss B,Wu J,et al. Association of DAP12 with activating CD94/NKG2C NK cell receptors [J]. Immunity,1998,8(6):693-701.
[35] Zheng L,Ren L,Kouhi A,et al. A Humanized Lym-1 CAR with Novel DAP10/DAP12 Signaling Domains Demonstrates Reduced Tonic Signaling and Increased Antitumor Activity in B-Cell Lymphoma Models [J]. Clin Cancer Res,2020,26(14):3694-3706.
[36] Jay TR,von Saucken VE,Landreth GE. TREM2 in Neurodegenerative Diseases [J]. Mol Neurodegener,2017,12(1):56.
[37] Krisenko MO,Geahlen RL. Calling in SYK:SYK’s dual role as a tumor promoter and tumor suppressor in cancer [J]. Biochim Biophys Acta,2015,1853(1):254-263.
[38] Liang T,Chen J,Xu G,et al. TYROBP,TLR4 and ITGAM regulated macrophages polarization and immune checkpoints expression in osteosarcoma [J]. Sci Rep,2021,11(1):19315.