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 Gao10, Jing Li11, Ming Yan12. 1. Department of Orthopaedics, Xijing Hospital, The Fourth Military Medical University, Xi'an, People's Republic of China. 2. School of Aerospace Medicine, Fourth Military Medical University, 169 Chang Le Xi Road, Xi'an, 710032, Shaanxi, China. 3. Department of Intensive Care Unit, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, Jiangsu, China. 4. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People's Republic of China. 5. Hou Zonglian Medical Experimental Class, Xi'an Jiaotong University, Xi'an, Shaanxi, China. 6. Department of Endocrinology, Shanghai National Research Center for Endocrine and Metabolic Disease, State Key Laboratory of Medical Genomics, Shanghai Institute for Endocrine and Metabolic Disease, Ruijin Hospital. Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China. 7. Department of Spine Surgery, Daxing Hospital, Xi'an, Shaanxi, China. 8. College of Clinical Medicine, Jilin University, Changchun, China. 9. Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. 10. School of Aerospace Medicine, Fourth Military Medical University, 169 Chang Le Xi Road, Xi'an, 710032, Shaanxi, China. gaoyuan1109@hotmail.com. 11. Department of Orthopaedics, Xijing Hospital, The Fourth Military Medical University, Xi'an, People's Republic of China. 13359265058@189.cn. 12. Department of Orthopaedics, Xijing Hospital, The Fourth Military Medical University, Xi'an, People's Republic of China. yanming_spine@163.com.
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 profiles from GSE12865, GSE14359, GSE33382, GSE36001 and GSE99671 were obtained respectively from GEO database. Differentially expressed genes were identified, 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 identified 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 affinity. Meanwhile, they were precited to be efficient and safe drugs with low-ames mutagenicity, none weight evidence of carcinogenicity, as well as non-toxic with liver. CONCLUSIONS: This study revealed the significance of 10-gene signature in the development of osteosarcoma. Besides, drug candidates identified in this study provided a solid basis on MMP9 inhibitors' development.
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 profiles from GSE12865, GSE14359, GSE33382, GSE36001 and GSE99671 were obtained respectively from GEO database. Differentially expressed genes were identified, 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 identified 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 affinity. Meanwhile, they were precited to be efficient and safe drugs with low-ames mutagenicity, none weight evidence of carcinogenicity, as well as non-toxic with liver. CONCLUSIONS: This study revealed the significance of 10-gene signature in the development of osteosarcoma. Besides, drug candidates identified in this study provided a solid basis on MMP9 inhibitors' development.
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