Multi-genomic analysis of 260 adrenocortical cancer patient tumors identifies novel network BIRC5-hsa-miR-335-5p-PAX8-AS1 strongly associated with poor survival

  • Chitra Subramanian
    Department of Surgery, Michigan Medicine, Ann Arbor, MI
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  • Reid McCallister
    Department of Surgery, Michigan Medicine, Ann Arbor, MI
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  • Mark S. Cohen
    Reprint requests: Mark S. Cohen MD, FSSO, FACS, Professor of Surgery, Pharmacology, and Biomedical Engineering, Vice Chair in Surgery for Clinical Operations, Director, Medical School Pathway of Excellence in Innovation and Entrepreneurship, Director Center for Surgical Innovation, Department of Surgery, University of Michigan Hospital and Health Systems, 2920K Taubman Center, SPC 5331, 1500 East Medical Center Drive, Ann Arbor, MI 48109-5331.
    Department of Surgery, Michigan Medicine, Ann Arbor, MI

    Department of Pharmacology, University of Michigan, Ann Arbor, MI

    Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI
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Published:October 03, 2022DOI:



      Adrenocortical carcinoma is a rare endocrine cancer with poor overall survival. Linking survival outcomes to a common target across multiple genomic datasets incorporating microRNA-long non-coding RNA dysregulation have not been well described. We hypothesized that a multi-database analysis of microRNA-long noncoding RNA-messenger RNA regulatory networks associated with survival will identify novel biomarkers.


      Significantly dysregulated genes or microRNA in adrenocortical carcinoma compared to normal adrenal was identified from sequencing data for 260 human adrenocortical carcinomas using GEO2R. The miRnet identified hub microRNA and genes and long noncoding RNA and microRNA associated with survival genes. The R2 generated Kaplan-Meier curves. The database miRTarBase linked genes associated with poor survival and dysregulated microRNA.


      Analysis of genes and microRNAs differentially regulated in >50% of datasets revealed 75 genes and 12 microRNAs were upregulated, and 167 genes and 12 microRNAs were downregulated (bonf. P < .05). Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed cell cycle, P53 signaling, arachidonic acid and innate immune response, and PI3/Akt are altered in adrenocortical carcinoma. A microRNA-target interaction network of differentially regulated microRNAs identified upregulated miRNA107, 103a-3p and 27a-3p, 16-5p, and downregulated 335-5p to have the highest degree of interaction with upregulated (ie, TPX2, CDK1, BIRC5, PRC1, CCNB1, GINS1) and downregulated (ie, RSPO3, NR2F1, TLR4, HOXA5, USP53, SLC16A9) hub genes as well as hub long noncoding RNAs XIST, NEAT1, KCNQ1OT1, and PAX8-AS1. Survival analysis revealed that the hub genes are associated with poor overall survival (P < .05) of adrenocortical carcinoma in the Cancer Genome Atlas data.


      A messenger RNA–microRNA–long noncoding RNA network analysis identified the BIRC5-miR335-5p-PAX8-AS1 network as one that was associated with poor overall survival in adrenocortical carcinoma, warranting further validation as a potential therapeutic target.
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        • Else T.
        • Kim A.C.
        • Sabolch A.
        • et al.
        Adrenocortical carcinoma.
        Endocr Rev. 2014; 35: 282-326
        • Allolio B.
        • Fassnacht M.
        Clinical review: adrenocortical carcinoma: clinical update.
        J Clin Endocrinol Metab. 2006; 91: 2027-2037
        • Pommier R.F.
        • Brennan M.F.
        An eleven-year experience with adrenocortical carcinoma.
        Surgery. 1992; 112 (discussion 70–1): 963-970
        • Glenn J.A.
        • Else T.
        • Hughes D.T.
        • et al.
        Longitudinal patterns of recurrence in patients with adrenocortical carcinoma.
        Surgery. 2019; 165: 186-195
        • Ayala-Ramirez M.
        • Jasim S.
        • Feng L.
        • et al.
        Adrenocortical carcinoma: clinical outcomes and prognosis of 330 patients at a tertiary care center.
        Eur J Endocrinol. 2013; 169: 891-899
        • Fassnacht M.
        • Dekkers O.M.
        • Else T.
        • et al.
        European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors.
        Eur J Endocrinol. 2018; 179: G1-G46
        • Lagana M.
        • Grisanti S.
        • Cosentini D.
        • et al.
        Efficacy of the EDP-M scheme plus adjunctive surgery in the management of patients with advanced adrenocortical carcinoma: the Brescia experience.
        Cancers (Basel). 2020; 12: 941
        • De Filpo G.
        • Mannelli M.
        • Canu L.
        Adrenocortical carcinoma: current treatment options.
        Curr Opin Oncol. 2021; 33: 16-22
        • Gebert L.F.R.
        • MacRae I.J.
        Regulation of microRNA function in animals.
        Nat Rev Mol Cell Biol. 2019; 20: 21-37
        • Lin S.
        • Gregory R.I.
        MicroRNA biogenesis pathways in cancer.
        Nat Rev Cancer. 2015; 15: 321-333
        • Rupaimoole R.
        • Slack F.J.
        MicroRNA therapeutics: towards a new era for the management of cancer and other diseases.
        Nat Rev Drug Discov. 2017; 16: 203-222
        • Hassan N.
        • Zhao J.T.
        • Sidhu S.B.
        The role of microRNAs in the pathophysiology of adrenal tumors.
        Mol Cell Endocrinol. 2017; 456: 36-43
        • Crona J.
        • Beuschlein F.
        Adrenocortical carcinoma - towards genomics guided clinical care.
        Nat Rev Endocrinol. 2019; 15: 548-560
        • Huang da W.
        • Sherman B.T.
        • Lempicki R.A.
        Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources.
        Nat Protoc. 2009; 4: 44-57
        • Huang da W.
        • Sherman B.T.
        • Lempicki R.A.
        Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists.
        Nucleic Acids Res. 2009; 37: 1-13
      1. Amsterdam University Medical Centers. R2: genomics analysis and visualization platform. Accessed 5 June 2022.

        • Li F.
        • Aljahdali I.
        • Ling X.
        Cancer therapeutics using survivin BIRC5 as a target: what can we do after over two decades of study?.
        J Exp Clin Cancer Res. 2019; 38: 368
        • Kanczkowski W.
        • Tymoszuk P.
        • Ehrhart-Bornstein M.
        • Wirth M.P.
        • Zacharowski K.
        • Bornstein S.R.
        Abrogation of TLR4 and CD14 expression and signaling in human adrenocortical tumors.
        J Clin Endocrinol Metab. 2010; 95: E421-E429
        • Khalil B.D.
        • Sanchez R.
        • Rahman T.
        • et al.
        An NR2F1-specific agonist suppresses metastasis by inducing cancer cell dormancy.
        J Exp Med. 2022; 219e20210836
        • Fernandez-Ranvier G.G.
        • Weng J.
        • et al.
        Identification of biomarkers of adrenocortical carcinoma using genomewide gene expression profiling.
        Arch Surg. 2008; 143 (discussion 846): 841-846
        • Chen D.
        • Shen Z.
        • Cheng X.
        • et al.
        Homeobox A5 activates p53 pathway to inhibit proliferation and promote apoptosis of adrenocortical carcinoma cells by inducing Aldo-Keto reductase family 1 member B10 expression.
        Bioengineered. 2021; 12: 1964-1975
        • Cheng W.
        • Tang Y.
        • Tong X.
        • et al.
        USP53 activated by H3K27 acetylation regulates cell viability, apoptosis, and metabolism in esophageal carcinoma via the AMPK signaling pathway.
        Carcinogenesis. 2022; 43: 349-359
        • Zhao X.
        • Wu X.
        • Wang H.
        • Yu H.
        • Wang J.
        USP53 promotes apoptosis and inhibits glycolysis in lung adenocarcinoma through FKBP51-AKT1 signaling.
        Mol Carcinog. 2020; 59: 1000-1011
        • Ye L.
        • Wang F.
        • Wu H.
        • et al.
        Functions and targets of miR-335 in cancer.
        Onco Targets Ther. 2021; 14: 3335-3349
        • Zhou P.
        • Xu T.
        • Hu H.
        • Hua F.
        Overexpression of PAX8-AS1 inhibits malignant phenotypes of papillary thyroid carcinoma cells via miR-96-5p/PKN2 axis.
        Int J Endocrinol. 2021; 20215499963