Jahangiri Leila, Pucci Perla, Ishola Tala, Pereira Joao, Cavanagh Megan L, Turner Suzanne D
Department of Life Sciences, Birmingham City University, Birmingham, UK.
School of Science & Technology, Nottingham Trent University, Clifton Lane, Nottingham, NG11 8NS, UK.
Discov Oncol. 2021 Nov 29;12(1):56. doi: 10.1007/s12672-021-00452-3.
Neuroblastoma is a heterogeneous childhood cancer derived from the neural crest. The dual cell identities of neuroblastoma include Mesenchymal (MES) and Adrenergic (ADRN). These identities are conferred by a small set of tightly-regulated transcription factors (TFs) binding super enhancers, collectively forming core regulatory circuitries (CRCs). The purpose of this study was to gain a deep understanding of the role of MES and ADRN TFs in neuroblastoma and other cancers as potential indicators of disease prognosis, progression, and relapse.
To that end, we first investigated the expression and mutational profile of MES and ADRN TFs in neuroblastoma. Moreover, we established their correlation with neuroblastoma risk groups and overall survival while establishing their extended networks with long non-coding RNAs (lncRNAs). Furthermore, we analysed the pan-cancer expression and mutational profile of these TFs and their correlation with patient survival and finally their network connectivity, using a panel of bioinformatic tools including GEPIA2, human pathology atlas, TIMER2, Omicsnet, and Cytoscape.
We show the association of multiple MES and ADRN TFs with neuroblastoma risk groups and overall survival and find significantly higher expression of various MES and ADRN TFs compared to normal tissues and their association with overall survival and disease-free survival in multiple cancers. Moreover, we report the strong correlation of the expression of these TFs with the infiltration of stromal and immune cells in the tumour microenvironment and with stemness and metastasis-related genes. Furthermore, we reveal extended pan-cancer networks comprising these TFs that influence the tumour microenvironment and metastasis and may be useful indicators of cancer prognosis and patient survival.
Our meta-analysis shows the significance of MES and ADRN TFs as indicators of patient prognosis and the putative utility of these TFs as potential novel biomarkers.
神经母细胞瘤是一种源自神经嵴的异质性儿童癌症。神经母细胞瘤的双重细胞身份包括间充质（MES）和肾上腺素能（ADRN）。这些身份由一小组紧密调控的转录因子（TFs）赋予，这些转录因子与超级增强子结合，共同形成核心调控回路（CRCs）。本研究的目的是深入了解MES和ADRN转录因子在神经母细胞瘤和其他癌症中的作用，作为疾病预后、进展和复发的潜在指标。
为此，我们首先研究了神经母细胞瘤中MES和ADRN转录因子的表达和突变谱。此外，我们建立了它们与神经母细胞瘤风险组和总生存期的相关性，同时建立了它们与长链非编码RNA（lncRNAs）的扩展网络。此外，我们使用包括GEPIA2、人类病理图谱、TIMER2、Omicsnet和Cytoscape在内的一系列生物信息学工具，分析了这些转录因子的泛癌表达和突变谱，以及它们与患者生存期的相关性，最后分析了它们的网络连通性。
我们展示了多个MES和ADRN转录因子与神经母细胞瘤风险组和总生存期的关联，发现与正常组织相比，各种MES和ADRN转录因子的表达显著更高，并且它们与多种癌症的总生存期和无病生存期相关。此外，我们报告了这些转录因子的表达与肿瘤微环境中基质和免疫细胞的浸润以及与干性和转移相关基因的强烈相关性。此外，我们揭示了包含这些转录因子的扩展泛癌网络，这些网络影响肿瘤微环境和转移，可能是癌症预后和患者生存期的有用指标。
我们的荟萃分析表明MES和ADRN转录因子作为患者预后指标的重要性，以及这些转录因子作为潜在新型生物标志物的推定效用。
