Construction of the prognostic enhancer RNA regulatory network in osteosarcoma

Penghui Yan; Zhenyu Li; Shuyuan Xian; Siqiao Wang; Qing Fu; Jiwen Zhu; Xi Yue; Xinkun Zhang; Shaofeng Chen; Wei Zhang; Jianyu Lu; Huabin Yin; Runzhi Huang; Zongqiang Huang

doi:10.1016/j.tranon.2022.101499

Construction of the prognostic enhancer RNA regulatory network in osteosarcoma

Transl Oncol. 2022 Nov:25:101499. doi: 10.1016/j.tranon.2022.101499. Epub 2022 Aug 21.

Authors

Penghui Yan¹, Zhenyu Li², Shuyuan Xian², Siqiao Wang³, Qing Fu², Jiwen Zhu¹, Xi Yue¹, Xinkun Zhang⁴, Shaofeng Chen⁵, Wei Zhang⁶, Jianyu Lu⁶, Huabin Yin⁷, Runzhi Huang⁸, Zongqiang Huang⁹

Affiliations

¹ Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
² Tongji University School of Medicine, Shanghai 200092, China.
³ Tongji University School of Medicine, Shanghai 200092, China; Division of Spine, Department of Orthopedics, Tongji Hospital Affiliated to Tongji University School of Medicine, Shanghai 200065, China.
⁴ Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Department of Orthopedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
⁵ Department of Orthopedics, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China.
⁶ Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China.
⁷ Department of Orthopedics, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200065, China. Electronic address: yinhuabin@aliyun.com.
⁸ Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Tongji University School of Medicine, Shanghai 200092, China; Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China. Electronic address: 1810938@tongji.edu.cn.
⁹ Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China. Electronic address: gzhuangzq@163.com.

Abstract

Background: Osteosarcoma (OS) is a common malignant tumor in osteoarticular system, the 5-year overall survival of which is poor. Enhancer RNAs (eRNAs) have been implicated in the tumorigenesis of various cancer types, whereas their roles in OS tumorigenesis remains largely unclear.

Methods: Differentially expressed eRNAs (DEEs), transcription factors (DETFs), target genes (DETGs) were identified using limma (Linear Models for Microarray Analysis) package. Prognosis-related DEEs were accessed by univariate Cox regression analysis. A multivariate model was constructed to evaluate the prognosis of OS samples. Prognosis-related DEEs, DETFs, DETGs, immune cells, and hallmark gene sets were co-analyzed to construct an regulatory network. Specific inhibitors were also filtered by connectivity Map analysis. External validation and scRNA-seq analysis were performed to verify our key findings.

Results: 3,981 DETGs, 468 DEEs, 51 DETFs, and 27 differentially expressed hallmark gene sets were identified. A total of Multivariate risk predicting model based on 18 prognosis-related DEEs showed a high accuracy (area under curve (AUC) = 0.896). GW-8510 was the candidate inhibitor targeting prognosis-related DEEs (mean = 0.670, p < 0.001). Based on the OS tumorigenesis-related regulation network, we identified that CCAAT enhancer binding protein alpha (CEBPA, DETF) may regulate CD8A molecule (CD8A, DEE), thereby promoting the transcription of CD3E molecule (CD3E, DETG), which may affect allograft rejection based on CD8+ T cells.

Conclusion: We constructed an eRNA-based prognostic model for predicting the OS patients' prognosis and explored the potential regulation network for OS tumorigenesis by an integrated bioinformatics analysis, providing promising therapeutic targets for OS patients.

Keywords: CD3E; CD8A; CEBPA; Network; Osteosarcoma; eRNA.