Deep Analysis of Neuroblastoma Core Regulatory Circuitries Using Online Databases and Integrated Bioinformatics Shows Their Pan-cancer Roles As Prognostic Predictors

Overview

Journal Discov Oncol

Publisher Springer

Specialty Oncology

Date 2022 Feb 24

PMID 35201514

Authors

Leila Jahangiri

Perla Pucci

Tala Ishola

Joao Pereira

Megan L Cavanagh

Suzanne D Turner

Affiliations

Soon will be listed here.

Abstract

Aim: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Citing Articles

Cell types or cell states? An investigation of adrenergic and mesenchymal cell phenotypes in neuroblastoma.

Bukkuri A, Andersson S, Mazariegos M, Brown J, Hammarlund E, Mohlin S iScience. 2024; 27(12):111433.

PMID: 39687008 PMC: 11648246. DOI: 10.1016/j.isci.2024.111433.

Bioinformatics Prediction for Network-Based Integrative Multi-Omics Expression Data Analysis in Hirschsprung Disease.

Lucena-Padros H, Bravo-Gil N, Tous C, Rojano E, Seoane-Zonjic P, Fernandez R Biomolecules. 2024; 14(2).

PMID: 38397401 PMC: 10886964. DOI: 10.3390/biom14020164.

Neuroblastoma Interaction with the Tumour Microenvironment and Its Implications for Treatment and Disease Progression.

Jahangiri L Curr Oncol. 2023; 30(10):9116-9140.

PMID: 37887559 PMC: 10605583. DOI: 10.3390/curroncol30100659.

Gene expression in organoids: an expanding horizon.

Smirnov A, Melino G, Candi E Biol Direct. 2023; 18(1):11.

PMID: 36964575 PMC: 10038780. DOI: 10.1186/s13062-023-00360-2.

References

Lin S, Zhao M, Lv Y, Mao G, Ding S, Peng F . The lncRNA GATA3-AS1/miR-495-3p/CENPU axis predicts poor prognosis of breast cancer via the PLK1 signaling pathway. Aging (Albany NY). 2021; 13(10):13663-13679. PMC: 8202843. DOI: 10.18632/aging.202909. View

Hammerle B, Yanez Y, Palanca S, Canete A, Burks D, Castel V . Targeting neuroblastoma stem cells with retinoic acid and proteasome inhibitor. PLoS One. 2013; 8(10):e76761. PMC: 3792090. DOI: 10.1371/journal.pone.0076761. View

Zhou G, Xia J . OmicsNet: a web-based tool for creation and visual analysis of biological networks in 3D space. Nucleic Acids Res. 2018; 46(W1):W514-W522. PMC: 6030925. DOI: 10.1093/nar/gky510. View

Chen Z, Chen Y, Li Y, Lian W, Zheng K, Zhang Y . Prrx1 promotes stemness and angiogenesis via activating TGF-β/smad pathway and upregulating proangiogenic factors in glioma. Cell Death Dis. 2021; 12(6):615. PMC: 8206106. DOI: 10.1038/s41419-021-03882-7. View

Ohira M, Oba S, Nakamura Y, Isogai E, Kaneko S, Nakagawa A . Expression profiling using a tumor-specific cDNA microarray predicts the prognosis of intermediate risk neuroblastomas. Cancer Cell. 2005; 7(4):337-50. DOI: 10.1016/j.ccr.2005.03.019. View

Durinck K, Speleman F . Epigenetic regulation of neuroblastoma development. Cell Tissue Res. 2018; 372(2):309-324. DOI: 10.1007/s00441-017-2773-y. View

Jahangiri L, Tsaprouni L, Trigg R, Williams J, Gkoutos G, Turner S . Core regulatory circuitries in defining cancer cell identity across the malignant spectrum. Open Biol. 2020; 10(7):200121. PMC: 7574545. DOI: 10.1098/rsob.200121. View

Thomas P, Campbell M, Kejariwal A, Mi H, Karlak B, Daverman R . PANTHER: a library of protein families and subfamilies indexed by function. Genome Res. 2003; 13(9):2129-41. PMC: 403709. DOI: 10.1101/gr.772403. View

McLennan R, Teddy J, Kasemeier-Kulesa J, Romine M, Kulesa P . Vascular endothelial growth factor (VEGF) regulates cranial neural crest migration in vivo. Dev Biol. 2009; 339(1):114-25. PMC: 3498053. DOI: 10.1016/j.ydbio.2009.12.022. View

10.

Liu Z, Wang J, Lv R . Downregulation of long non-coding RNA DBH-AS1 inhibits osteosarcoma progression by PI3K-AKT signaling pathways and indicates good prognosis. Eur Rev Med Pharmacol Sci. 2019; 23(4):1418-1427. DOI: 10.26355/eurrev_201902_17098. View

11.

Wiles A, Karrs J, Pitt S, Almenara J, Powers C, Smith S . GATA3 is a reliable marker for neuroblastoma in limited samples, including FNA Cell Blocks, core biopsies, and touch imprints. Cancer Cytopathol. 2017; 125(12):940-946. DOI: 10.1002/cncy.21927. View

12.

Bao R, Spranger S, Hernandez K, Zha Y, Pytel P, Luke J . Immunogenomic determinants of tumor microenvironment correlate with superior survival in high-risk neuroblastoma. J Immunother Cancer. 2021; 9(7). PMC: 8287618. DOI: 10.1136/jitc-2021-002417. View

13.

Gryder B, Pomella S, Sayers C, Wu X, Song Y, Chiarella A . Histone hyperacetylation disrupts core gene regulatory architecture in rhabdomyosarcoma. Nat Genet. 2019; 51(12):1714-1722. PMC: 6886578. DOI: 10.1038/s41588-019-0534-4. View

14.

Boeva V, Louis-Brennetot C, Peltier A, Durand S, Pierre-Eugene C, Raynal V . Heterogeneity of neuroblastoma cell identity defined by transcriptional circuitries. Nat Genet. 2017; 49(9):1408-1413. DOI: 10.1038/ng.3921. View

15.

Pratt D, Chen J, Pillich R, Rynkov V, Gary A, Demchak B . NDEx 2.0: A Clearinghouse for Research on Cancer Pathways. Cancer Res. 2017; 77(21):e58-e61. PMC: 5679399. DOI: 10.1158/0008-5472.CAN-17-0606. View

16.

Bao J, Chen X, Hou Y, Kang G, Li Q, Xu Y . LncRNA DBH-AS1 facilitates the tumorigenesis of hepatocellular carcinoma by targeting miR-138 via FAK/Src/ERK pathway. Biomed Pharmacother. 2018; 107:824-833. DOI: 10.1016/j.biopha.2018.08.079. View

17.

Huang M, Chen Y, Yang M, Guo A, Xu Y, Xu L . dbCoRC: a database of core transcriptional regulatory circuitries modeled by H3K27ac ChIP-seq signals. Nucleic Acids Res. 2017; 46(D1):D71-D77. PMC: 5753200. DOI: 10.1093/nar/gkx796. View

18.

Li T, Fan J, Wang B, Traugh N, Chen Q, Liu J . TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells. Cancer Res. 2017; 77(21):e108-e110. PMC: 6042652. DOI: 10.1158/0008-5472.CAN-17-0307. View

19.

Orqueda A, Gatti C, Ogara M, Falzone T . SOX-11 regulates LINE-1 retrotransposon activity during neuronal differentiation. FEBS Lett. 2018; 592(22):3708-3719. DOI: 10.1002/1873-3468.13260. View

20.

Spill F, Reynolds D, Kamm R, Zaman M . Impact of the physical microenvironment on tumor progression and metastasis. Curr Opin Biotechnol. 2016; 40:41-48. PMC: 4975620. DOI: 10.1016/j.copbio.2016.02.007. View