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Downloaded from Gene Expression Omnibus (GEO) Li et al. Cancer Cell Int (2021) 21:377 https://doi.org/10.1186/s12935-021-02041-4 Cancer Cell International PRIMARY RESEARCH Open Access Ten-gene signature reveals the signifcance of clinical prognosis and immuno-correlation of osteosarcoma and study on novel skeleton inhibitors regarding MMP9 Weihang Li1, Ziyi Ding1, Dong Wang1, Chengfei Li2, Yikai Pan2, Yingjing Zhao3, Hongzhe Zhao4, Tianxing Lu5, Rui Xu6, Shilei Zhang1, Bin Yuan7, Yunlong Zhao8, Yanjiang Yin9, Yuan Gao2*, Jing Li1* and Ming Yan1* Abstract Objectives: This study aimed to identify novel targets in the carcinogenesis, therapy and prognosis of osteosarcoma from genomic level, together with screening ideal lead compounds with potential inhibition regarding MMP-9. Methods: Gene expression profles from GSE12865, GSE14359, GSE33382, GSE36001 and GSE99671 were obtained respectively from GEO database. Diferentially expressed genes were identifed, and functional enrichment analysis, such as GO, KEGG, GSEA, PPI were performed to make a comprehensive understanding of the hub genes. Next, a series of high-precision computational techniques were conducted to screen potential lead compounds targeting MMP9, including virtual screening, ADME, toxicity prediction, and accurate docking analysis. Results: 10 genes, MMP9, CD74, SPP1, CXCL12, TYROBP, FCER1G, HCLS1, ARHGDIB, LAPTM5 and IGF1R were identi- fed as hub genes in the initiation of osteosarcoma. Machine learning, multivariate Cox analysis, ssGSEA and survival analysis demonstrated that these genes had values in prognosis, immune-correlation and targeted treatment. Tow novel compounds, ZINC000072131515 and ZINC000004228235, were screened as potential inhibitor regarding MMP9, and they could bind to MMP9 with favorable interaction energy and high binding afnity. Meanwhile, they were precited to be efcient and safe drugs with low-ames mutagenicity, none weight evidence of carcinogenicity, as well as non-toxic with liver. Conclusions: This study revealed the signifcance of 10-gene signature in the development of osteosarcoma. Besides, drug candidates identifed in this study provided a solid basis on MMP9 inhibitors’ development. Keywords: Biomarkers, Diferential gene expression analysis, Inhibitor, Matrix metalloproteinase-9, Virtual Screening Introduction Osteosarcoma (OS), one of the most common malig- nant neoplasm, accounts for 20–40% of all bone can- cers, which is characterized by the direct formation of *Correspondence: [email protected]; [email protected]; osteoid tissue, osteoid- and spindle-shaped matrix cell [email protected] 1 Department of Orthopaedics, Xijing Hospital, The Fourth Military in immature bones [1]. Te main clinical manifesta- Medical University, Xi’an, People’s Republic of China tion of OS patients frequently sufers from swelling and 2 School of Aerospace Medicine, Fourth Military Medical University, 169 bone pain, while systematic symptoms, such as weight Chang Le Xi Road, Xi’an 710032, Shaanxi, China Full list of author information is available at the end of the article loss, pallor, night sweats, fever and anorexia are seldomly © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Li et al. Cancer Cell Int (2021) 21:377 Page 2 of 22 seen [2]. Osteosarcoma appears mainly in childhood and on studying the hub genes among metastasis and non- adolescents, together with an overall incidence of 0.3– metastasis osteosarcoma, that is to say, current research 0.4/100000 individuals per year [3, 4]. samples were mostly osteosarcoma samples whereas Currently, the main clinical treatment for patients with normal bone tissues were not included in study, while OS included surgery, radiotherapy, and chemotherapy. another extremely vital research about hub genes among Since the 1970s, with the introduction and invention of osteosarcoma and normal bone tissue, had hardly been neoadjuvant chemotherapy and limb salvage surgery for reported. Consequently, the combination of bioinformat- OS, the overall survival rate had improved signifcantly. ics and structural biology study were performed in this Despite advances in surgical technique and targeted study to accelerate the understanding of hub genes and chemotherapy, optimal treatment outcomes in OS are discovery of inhibitors regarding OS. still negatively impacted by infection, tumor immunity, Te accurate diferential diagnosis is the key to con- complications [5–8]. Te overall prognosis of patients duct precise prognosis as well as target-therapy [20]. Tis with OS is only 20%, especially in patients with metas- study frstly aimed to identify hub genes using diferential tasis disease or tumor recurrence [9]. Overall expres- expression method in the occurrence of osteosarcoma. sion as well as imbalance of MMP9 are associated with a 5 mRNA microarray datasets (GSE12865, GSE14359, variety of diseases, regulating and inhibiting MMP9 is an GSE33382, GSE36001, GSE99671) involving osteosar- essential therapeutic approach to treat various diseases coma and correspondent normal bone samples were including cancer. Terefore, MMP9 inhibitors could be downloaded from Gene Expression Omnibus (GEO). regarded as anticancer drugs [10]. JNJ0966, GS-5745, two Next, the mutual diferentially expressed genes (DEGs) chemotherapy drugs, were selective inhibitors regarding were screened with Venn analysis. Gene Ontology (GO), matrix metalloproteinase-9 (MMP-9), had shown pro- Kyoto Encyclopedia of Genes and Genomes (KEGG) spective view in treatment of encephalomyelitis, ulcera- methods were performed to discover molecular function tive colitis and gastric cancer [11, 12]. However, only few changes and abnormal signaling pathways by displaying inhibitors had a relatively promising function in inhib- their molecular function, biological process and cellular iting MMP9. Meanwhile, researches based on MMP9 component. Protein–protein interaction (PPI) analysis inhibitors regarding osteosarcoma had hardly been was conducted further to fnd the most-linked genes with reported before, which could make signifcance in tar- OS. Subsequently, this study further performed machine geted chemotherapy regarding osteosarcoma. Terefore, learning and survival analysis in third party TCGA and based on the fact that poor prognosis and lack of efective GEPIA2 database to validate and confrm our results. targeted therapies as well as tumor-related biomarkers in Finally, this study conducted structural biology analysis OS, there is an urgent need to explore novel predictive including a series of structural and chemical methods and prognostic biomarkers as well as discover lead com- to screen ideal lead compounds based on identifed hub pound inhibitors regarding OS, in order to make a com- genes, which may have biological efects in the treatment prehensive understanding of oncogene and eventually of OS and provide new ideas for medication develop- improve the prognosis of patients. ment in pharmacologic market. Tis study provided a Recent decades, with the rapid development of high- set of method fow to understand the cause and molec- throughput technology, large-scale RNA sequence ular events of OS, then ofered a list of drug candidates transcriptome data as well as gene microarray chips, with pharmacological properties from ZINC15 database, bioinformatics analysis have displayed a promising view which made a solid basis theory for gene products inhibi- to identify prognostic genes, elucidate the oncogenic tors’ research. Te whole diagram and workfow of this mechanism for plenty of neoplasms and fnally improve study was shown in Fig. 1. the treatment of cancers [13, 14]. It helps us study the initiation, progression and metastasis of diferent neo- Materials and methods plasms under transcriptome level, which makes it pos- Datasets from GEO and TCGA database sible to explore the molecular mechanisms and discover Gene expression profles of GSE12865, GSE14359, disease-specifc biomarkers of OS in this study. Natural GSE33382, GSE36001 and GSE99671 were downloaded compounds and their derivatives play an essential role in from Gene Expression Omnibus (https:// www. ncbi. today’s pharmacologic market [15, 16]. Due to their mal- nlm. nih. gov/ geo/). Multiple sample sets were used in leable, convertibility and readily available property, they this study to avoid clinical and race bias among difer- have made a great contribution to medication design and ent studies. Te inclusion criteria were as follows: sam- improvement in treating cancers [17–19]. To the best ples which were
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