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Construction of Bone Metastasis-Specific Regulation Network Based on Prognostic Stemness-Related Signatures in Breast Invasive Carcinoma

转移 骨转移 生物 乳腺癌 比例危险模型 计算生物学 转录因子 小桶 染色质免疫沉淀 肿瘤科 生物信息学 癌症研究 癌症 基因 基因表达 医学 转录组 内科学 遗传学 发起人
作者
Runzhi Huang,Zhenyu Li,Jiayao Zhang,Zhiwei Zeng,Jiaqi Zhang,Mingxiao Li,Siqao Wang,Shuyuan Xian,Yuna Xue,Xi Chen,Jie Li,Wing Yan Elizabeth Cheng,Bin Wang,Penghui Yan,Daoke Yang,Zongqiang Huang
出处
期刊:Frontiers in Oncology [Frontiers Media SA]
卷期号:10 被引量:4
标识
DOI:10.3389/fonc.2020.613333
摘要

Background Bone is the most common metastatic site of Breast invasive carcinoma (BRCA). In this study, the bone metastasis-specific regulation network of BRCA was constructed based on prognostic stemness-related signatures (PSRSs), their upstream transcription factors (TFs) and downstream pathways. Methods Clinical information and RNA-seq data of 1,080 primary BRCA samples (1,048 samples without bone metastasis and 32 samples with bone metastasis) were downloaded from The Cancer Genome Atlas (TCGA). The edgeR method was performed to identify differential expressed genes (DEGs). Next, mRNA stemness index (mRNAsi) was calculated by one-class logistic regression (OCLR). To analyze DEGs by classification, similar genes were integrated into the same module by weighted gene co-expression network analysis (WGCNA). Then, univariate and multivariate Cox proportional hazard regression were applied to find the PSRSs. Furthermore, PSRSs, 318 TFs obtained from Cistrome database and 50 hallmark pathways quantified by GSVA were integrated into co-expression analysis. Significant co-expression patterns were used to construct the bone metastasis-specific regulation network. Finally, spatial single-cell RNA-seq and chromatin immunoprecipitation sequence (ChIP-seq) data and multi-omics databases were applied to validate the key scientific hypothesis in the regulation network. Additionally, Connectivity Map (CMap) was utilized to select the potential inhibitors of bone metastasis-specific regulation network in BRCA. Results Based on edgeR and WGCNA method, 43 PSRSs were identified. In the bone metastasis-specific regulation network, MAF positively regulated CD248 (R = 0.435, P < 0.001), and hallmark apical junction was the potential pathway of CD248 (R = 0.353, P < 0.001). This regulatory pattern was supported by spatial single-cell RNA sequence, ChIP-seq data and multi-omics online databases. Additionally, alexidine was identified as the possible inhibitor for bone metastasis of BRCA by CMap analysis. Conclusion PSRSs played important roles in bone metastasis of BRCA, and the prognostic model based on PSRSs showed good performance. Especially, we proposed that CD248 was the most significant PSRS, which was positively regulated by MAF, influenced bone metastasis via apical junction pathway. And this axis might be inhibited by alexidine, which providing a potential treatment strategy for bone metastasis of BRCA.
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