Skip to main content

Advertisement

Springer Nature Link
Log in

Muti-omics integration analysis revealed molecular network alterations in human nonfunctional pituitary neuroendocrine tumors in the framework of 3P medicine

  • Review
  • Published:
EPMA Journal Aims and scope Submit manuscript

Abstract

Nonfuctional pituitary neuroendocrine tumor (NF-PitNET) is highly heterogeneous and generally considered a common intracranial tumor. A series of molecules are involved in NF-PitNET pathogenesis that alter in multiple levels of genome, transcriptome, proteome, and metabolome, and those molecules mutually interact to form dynamically associated molecular-network systems. This article reviewed signaling pathway alterations in NF-PitNET based on the analyses of the genome, transcriptome, proteome, and metabolome, and emphasized signaling pathway network alterations based on the integrative omics, including calcium signaling pathway, cGMP-PKG signaling pathway, mTOR signaling pathway, PI3K/AKT signaling pathway, MAPK (mitogen-activated protein kinase) signaling pathway, oxidative stress response, mitochondrial dysfunction, and cell cycle dysregulation, and those signaling pathway networks are important for NF-PitNET formation and progression. Especially, this review article emphasized the altered signaling pathways and their key molecules related to NF-PitNET invasiveness and aggressiveness that are challenging clinical problems. Furthermore, the currently used medication and potential therapeutic agents that target these important signaling pathway networks are also summarized. These signaling pathway network changes offer important resources for insights into molecular mechanisms, discovery of effective biomarkers, and therapeutic targets for patient stratification, predictive diagnosis, prognostic assessment, and targeted therapy of NF-PitNET.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data Availability

All data and materials are available in the current manuscript.

Code availability

Not applicable.

References

  1. Ostrom QT, Gittleman H, Fulop J, Liu M, Blanda R, Kromer C, et al. CBTRUS Statistical Report: primary brain and central nervous system tumors diagnosed in the United States in 2008–2012. Neuro Oncol. 2015;17(Suppl 4):iv1–62. https://doi.org/10.1093/neuonc/nov189.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Molitch ME. Diagnosis and treatment of pituitary adenomas: a review. JAMA. 2017;317:516–24. https://doi.org/10.1001/jama.2016.19699.

    Article  PubMed  Google Scholar 

  3. Andela CD, Lobatto DJ, Pereira AM, van Furth WR, Biermasz NR. How non-functioning pituitary adenomas can affect health-related quality of life: a conceptual model and literature review. Pituitary. 2018;21:208–16. https://doi.org/10.1007/s11102-017-0860-4.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Greenman Y, Stern N. Non-functioning pituitary adenomas. Best Pract Res Clin Endocrinol Metab. 2009;23:625–38. https://doi.org/10.1016/j.beem.2009.05.005.

    Article  CAS  PubMed  Google Scholar 

  5. Tampourlou M, Fountas A, Ntali G, Karavitaki N. Mortality in patients with non-functioning pituitary adenoma. Pituitary. 2018;21(2):203–7. https://doi.org/10.1007/s11102-018-0863-9.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Mete O, Lopes MB. Overview of the 2017 WHO classification of pituitary tumors. Endocr Pathol. 2017;28:228–43. https://doi.org/10.1007/s12022-017-9498-z.

    Article  CAS  PubMed  Google Scholar 

  7. Drummond J, Roncaroli F, Grossman AB, Korbonits M. Clinical and pathological aspects of silent pituitary adenomas. J Clin Endocrinol Metab. 2019;104:2473–89. https://doi.org/10.1210/jc.2018-00688.

    Article  PubMed  Google Scholar 

  8. Scheithauer BW, Kovacs KT, Laws ER Jr, Randall RV. Pathology of invasive pituitary tumors with special reference to functional classification. J Neurosurg. 1986;65:733–44. https://doi.org/10.3171/jns.1986.65.6.0733.

    Article  CAS  PubMed  Google Scholar 

  9. Wang H, Chen K, Yang Z, Li W, Wang C, Zhang G, et al. Diagnosis of invasive nonfunctional pituitary adenomas by serum extracellular vesicles. Anal Chem. 2019;91:9580–9. https://doi.org/10.1021/acs.analchem.9b00914.

    Article  CAS  PubMed  Google Scholar 

  10. Long Y, Lu M, Cheng T, Zhan X, Zhan X. Multiomics-based signaling pathway network alterations in human non-functional pituitary adenomas. Front Endocrinol (Lausanne). 2019;10:835. https://doi.org/10.3389/fendo.2019.00835.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Wu B, Jiang S, Wang X, Zhong S, Bi Y, Yi D, Liu G, Hu D, Dou G, Chen Y, Wu Y, Dong J. Identification of driver genes and key pathways of non-functional pituitary adenomas predicts the therapeutic effect of STO-609. PLoS One. 2020;15:e0240230. https://doi.org/10.1371/journal.pone.0240230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Joshi H, Vastrad B, Vastrad C. Identification of important invasion-related genes in non-functional pituitary adenomas. J Mol Neurosci. 2019;68:565–89. https://doi.org/10.1007/s12031-019-01318-8.

    Article  CAS  PubMed  Google Scholar 

  13. Song W, Qian L, Jing G, Jie F, Xiaosong S, Chunhui L, et al. Aberrant expression of the sFRP and WIF1 genes in invasive non-functioning pituitary adenomas. Mol Cell Endocrinol. 2018;474:168–75. https://doi.org/10.1016/j.mce.2018.03.005.

    Article  CAS  PubMed  Google Scholar 

  14. Esapa CT, Harris PE. Mutation analysis of protein kinase A catalytic subunit in thyroid adenomas and pituitary tumours. Eur J Endocrinol. 1999;141:409–12. https://doi.org/10.1530/eje.0.1410409.

    Article  CAS  PubMed  Google Scholar 

  15. Farrell WE, Talbot JA, Bicknell EJ, Simpson D, Clayton RN. Genomic sequence analysis of a key residue (Arg183) in human G alpha q in invasive non-functional pituitary adenomas. Clin Endocrinol (Oxf). 1997;47:241–4. https://doi.org/10.1046/j.1365-2265.1997.2891088.x.

    Article  CAS  PubMed  Google Scholar 

  16. Faccenda E, Melmed S, Bevan JS, Eidne KA. Structure of the thyrotrophin-releasing hormone receptor in human pituitary adenomas. Clin Endocrinol (Oxf). 1996;44:341–7. https://doi.org/10.1046/j.1365-2265.1996.684506.x.

    Article  CAS  PubMed  Google Scholar 

  17. Zhu H, Guo J, Shen Y, Dong W, Gao H, Miao Y, et al. Functions and mechanisms of tumor necrosis factor-α and noncoding RNAs in bone-invasive pituitary adenomas. Clin Cancer Res. 2018;24:5757–66. https://doi.org/10.1158/1078-0432.ccr-18-0472.

    Article  CAS  PubMed  Google Scholar 

  18. Taniguchi-Ponciano K, Gomez-Apo E, Chavez-Macias L, Vargas G, Espinosa-Cardenas E, Ramirez-Renteria C, et al. Molecular alterations in non-functioning pituitary adenomas. Cancer Biomark. 2020;28:193–9. https://doi.org/10.3233/cbm-191121.

    Article  CAS  PubMed  Google Scholar 

  19. Kim YH, Kim JH. Transcriptome Analysis identifies an attenuated local immune response in invasive nonfunctioning pituitary adenomas. Endocrinol Metab (Seoul). 2019;34:314–22. https://doi.org/10.3803/EnM.2019.34.3.314.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wu S, Gu Y, Huang Y, Wong TC, Ding H, Liu T, et al. Novel biomarkers for non-functioning invasive pituitary adenomas were identified by using analysis of microRNAs expression profile. Biochem Genet. 2017;55:253–67. https://doi.org/10.1007/s10528-017-9794-9.

    Article  CAS  PubMed  Google Scholar 

  21. Xing W, Qi Z. Genome-wide identification of lncRNAs and mRNAs differentially expressed in non-functioning pituitary adenoma and construction of an lncRNA-mRNA co-expression network. Biol Open. 2019;8(1):bio037127. https://doi.org/10.1242/bio.037127.

    Article  CAS  PubMed  Google Scholar 

  22. Guo J, Fang Q, Liu Y, Xie W, Zhang Y, Li C. Identifying critical protein-coding genes and long non-coding RNAs in non-functioning pituitary adenoma recurrence. Oncol Lett. 2021;21:264. https://doi.org/10.3892/ol.2021.12525.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Li J, Li C, Wang J, Song G, Zhao Z, Wang H, et al. Genome-wide analysis of differentially expressed lncRNAs and mRNAs in primary gonadotrophin adenomas by RNA-seq. Oncotarget. 2017;8:4585–606. https://doi.org/10.18632/oncotarget.13948.

    Article  PubMed  Google Scholar 

  24. Lee M, Marinoni I, Irmler M, Psaras T, Honegger JB, Beschorner R, et al. Transcriptome analysis of MENX-associated rat pituitary adenomas identifies novel molecular mechanisms involved in the pathogenesis of human pituitary gonadotroph adenomas. Acta Neuropathol. 2013;126:137–50. https://doi.org/10.1007/s00401-013-1132-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Richardson TE, Shen ZJ, Kanchwala M, Xing C, Filatenkov A, Shang P, et al. Aggressive behavior in silent subtype III pituitary adenomas may depend on suppression of local immune response: a whole transcriptome analysis. J Neuropathol Exp Neurol. 2017;76:874–82. https://doi.org/10.1093/jnen/nlx072.

    Article  CAS  PubMed  Google Scholar 

  26. Zhan X, Desiderio DM. Signaling pathway networks mined from human pituitary adenoma proteomics data. BMC Med Genomics. 2010;3:13. https://doi.org/10.1186/1755-8794-3-13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Qian S, Zhan X, Lu M, Li N, Long Y, Li X, et al. Quantitative analysis of ubiquitinated proteins in human pituitary and pituitary adenoma tissues. Front Endocrinol (Lausanne). 2019;10:328. https://doi.org/10.3389/fendo.2019.00328.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Li J, Wen S, Li B, Li N, Zhan X. Phosphorylation-mediated molecular pathway changes in human pituitary neuroendocrine tumors identified by quantitative phosphoproteomics. Cells. 2021;10(9):2225. https://doi.org/10.3390/cells10092225.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhan X, Desiderio DM, Wang X, Zhan X, Guo T, Li M, et al. Identification of the proteomic variations of invasive relative to non-invasive non-functional pituitary adenomas. Electrophoresis. 2014;35:2184–94. https://doi.org/10.1002/elps.201300590.

    Article  CAS  PubMed  Google Scholar 

  30. Zhan X, Wang X, Long Y, Desiderio DM. Heterogeneity analysis of the proteomes in clinically nonfunctional pituitary adenomas. BMC Med Genomics. 2014;7:69. https://doi.org/10.1186/s12920-014-0069-6.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Wang X, Guo T, Peng F, Long Y, Mu Y, Yang H, et al. Proteomic and functional profiles of a follicle-stimulating hormone positive human nonfunctional pituitary adenoma. Electrophoresis. 2015;36:1289–304. https://doi.org/10.1002/elps.201500006.

    Article  CAS  PubMed  Google Scholar 

  32. Wang Y, Cheng T, Lu M, Mu Y, Li B, Li X, et al. TMT-based quantitative proteomics revealed follicle-stimulating hormone (FSH)-related molecular characterizations for potentially prognostic assessment and personalized treatment of FSH-positive non-functional pituitary adenomas. EPMA J. 2019;10:395–414. https://doi.org/10.1007/s13167-019-00187-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Simpson DJ, Frost SJ, Bicknell JE, Broome JC, McNicol AM, Clayton RN, et al. Aberrant expression of G(1)/S regulators is a frequent event in sporadic pituitary adenomas. Carcinogenesis. 2001;22:1149–54. https://doi.org/10.1093/carcin/22.8.1149.

    Article  CAS  PubMed  Google Scholar 

  34. Cheng S, Xie W, Miao Y, Guo J, Wang J, Li C, et al. Identification of key genes in invasive clinically non-functioning pituitary adenoma by integrating analysis of DNA methylation and mRNA expression profiles. J Transl Med. 2019;17(1):407. https://doi.org/10.1186/s12967-019-02148-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wei Z, Zhou C, Li M, Huang R, Deng H, Shen S, et al. Integrated multi-omics profiling of nonfunctioning pituitary adenomas. Pituitary. 2021;24:312–25. https://doi.org/10.1007/s11102-020-01109-0.

    Article  CAS  PubMed  Google Scholar 

  36. Yu SY, Hong LC, Feng J, Wu YT, Zhang YZ. Integrative proteomics and transcriptomics identify novel invasive-related biomarkers of non-functioning pituitary adenomas. Tumour Biol. 2016;37:8923–30. https://doi.org/10.1007/s13277-015-4767-2.

    Article  CAS  PubMed  Google Scholar 

  37. Feng J, Yu SY, Li CZ, Li ZY, Zhang YZ. Integrative proteomics and transcriptomics revealed that activation of the IL-6R/JAK2/STAT3/MMP9 signaling pathway is correlated with invasion of pituitary null cell adenomas. Mol Cell Endocrinol. 2016;436:195–203. https://doi.org/10.1016/j.mce.2016.07.025.

    Article  CAS  PubMed  Google Scholar 

  38. Cheng T, Wang Y, Lu M, Zhan X, Zhou T, Li B, et al. Quantitative analysis of proteome in non-functional pituitary adenomas: clinical relevance and potential benefits for the patients. Front Endocrinol (Lausanne). 2019;10:854. https://doi.org/10.3389/fendo.2019.00854.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Liu D, Li J, Li N, Lu M, Wen S, Zhan X. Integration of quantitative phosphoproteomics and transcriptomics revealed phosphorylation-mediated molecular events as useful tools for a potential patient stratification and personalized treatment of human nonfunctional pituitary adenomas. EPMA J. 2020;11:419–67. https://doi.org/10.1007/s13167-020-00215-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wen S, Li J, Yang J, Li B, Li N, Zhan X. Quantitative acetylomics revealed acetylation-mediated molecular pathway network changes in human nonfunctional pituitary neuroendocrine tumors. Front Endocrinol (Lausanne). 2021;12:753606. https://doi.org/10.3389/fendo.2021.753606.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Wang Z, Guo X, Wang W, Gao L, Bao X, Feng M, et al. UPLC-MS/MS-based lipidomic profiles revealed aberrant lipids associated with invasiveness of silent corticotroph adenoma. J Clin Endocrinol Metab. 2021;106:e273–87. https://doi.org/10.1210/clinem/dgaa708.

    Article  PubMed  Google Scholar 

  42. Feng J, Gao H, Zhang Q, Zhou Y, Li C, Zhao S, et al. Metabolic profiling reveals distinct metabolic alterations in different subtypes of pituitary adenomas and confers therapeutic targets. J Transl Med. 2019;17:291. https://doi.org/10.1186/s12967-019-2042-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Panda AC, Abdelmohsen K, Gorospe M. SASP regulation by noncoding RNA. Mech Ageing Dev. 2017;168:37–43. https://doi.org/10.1016/j.mad.2017.05.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yang Q, Wang Y, Zhang S, Tang J, Li F, Yin J, et al. Biomarker discovery for immunotherapy of pituitary adenomas: enhanced robustness and prediction ability by modern computational tools. Int J Mol Sci. 2019;20(1):151. https://doi.org/10.3390/ijms20010151.

    Article  CAS  PubMed Central  Google Scholar 

  45. Monti C, Zilocchi M, Colugnat I, Alberio T. Proteomics turns functional. J Proteomics. 2019;198:36–44. https://doi.org/10.1016/j.jprot.2018.12.012.

    Article  CAS  PubMed  Google Scholar 

  46. Karimi P, Shahrokni A, Ranjbar MR. Implementation of proteomics for cancer research: past, present, and future. Asian Pac J Cancer Prev. 2014;15:2433–8. https://doi.org/10.7314/apjcp.2014.15.6.2433.

    Article  PubMed  Google Scholar 

  47. Li N, Desiderio DM, Zhan X. The use of mass spectrometry in a proteome-centered multiomics study of human pituitary adenomas. Mass Spectrom Rev. 2021. https://doi.org/10.1002/mas.21710.

    Article  PubMed  Google Scholar 

  48. Walsh MT, Couldwell WT. Symptomatic cystic degeneration of a clinically silent corticotroph tumor of the pituitary gland. Skull Base. 2010;20:367–70. https://doi.org/10.1055/s-0030-1253579.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Zhou W, Song Y, Xu H, Zhou K, Zhang W, Chen J, et al. In nonfunctional pituitary adenomas, estrogen receptors and slug contribute to development of invasiveness. J Clin Endocrinol Metab. 2011;96:E1237-1245. https://doi.org/10.1210/jc.2010-3040.

    Article  CAS  PubMed  Google Scholar 

  50. Hu R, Wang X, Zhan X. Multi-parameter systematic strategies for predictive, preventive and personalised medicine in cancer. EPMA J. 2013;4:2. https://doi.org/10.1186/1878-5085-4-2.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Zhan X, Desiderio DM. Comparative proteomics analysis of human pituitary adenomas: current status and future perspectives. Mass Spectrom Rev. 2005;24:783–813. https://doi.org/10.1002/mas.20039.

    Article  CAS  PubMed  Google Scholar 

  52. Rinschen MM, Ivanisevic J. Identification of bioactive metabolites using activity metabolomics. Nat Rev Mol Cell Biol. 2019;20:353–67. https://doi.org/10.1038/s41580-019-0108-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Johnson CH, Ivanisevic J, Siuzdak G. Metabolomics: beyond biomarkers and towards mechanisms. Nat Rev Mol Cell Biol. 2016;17:451–9. https://doi.org/10.1038/nrm.2016.25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Hu C, Zhou Y, Feng J, Zhou S, Li C, Zhao S, et al. Untargeted lipidomics reveals specific lipid abnormalities in nonfunctioning human pituitary adenomas. J Proteome Res. 2020;19:455–63. https://doi.org/10.1021/acs.jproteome.9b00637.

    Article  CAS  PubMed  Google Scholar 

  55. Ijare OB, Baskin DS, Pichumani K. Ex Vivo (1)H NMR study of pituitary adenomas to differentiate various immunohistochemical subtypes. Sci Rep. 2019;9:3007. https://doi.org/10.1038/s41598-019-38542-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ijare OB, Holan C, Hebert J, Sharpe MA, Baskin DS, Pichumani K. Elevated levels of circulating betahydroxybutyrate in pituitary tumor patients may differentiate prolactinomas from other immunohistochemical subtypes. Sci Rep. 2020;10:1334. https://doi.org/10.1038/s41598-020-58244-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Hasin Y, Seldin M, Lusis A. Multi-omics approaches to disease. Genome Biol. 2017;18:83. https://doi.org/10.1186/s13059-017-1215-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Esteller M. Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet. 2007;8:286–98. https://doi.org/10.1038/nrg2005.

    Article  CAS  PubMed  Google Scholar 

  59. Kober P, Boresowicz J, Rusetska N, Maksymowicz M. The role of aberrant DNA methylation in misregulation of gene expression in gonadotroph nonfunctioning pituitary tumors. Cancers (Basel). 2019;11(11):1650. https://doi.org/10.3390/cancers11111650.

    Article  CAS  PubMed Central  Google Scholar 

  60. Cheng S, Li C, Xie W, Miao Y, Guo J, Wang J, et al. Integrated analysis of DNA methylation and mRNA expression profiles to identify key genes involved in the regrowth of clinically non-functioning pituitary adenoma. Aging (Albany NY). 2020;12:2408–27. https://doi.org/10.18632/aging.102751.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Duong CV, Emes RD, Wessely F, Yacqub-Usman K, Clayton RN, Farrell WE. Quantitative, genome-wide analysis of the DNA methylome in sporadic pituitary adenomas. Endocr Relat Cancer. 2012;19:805–16. https://doi.org/10.1530/erc-12-0251.

    Article  CAS  PubMed  Google Scholar 

  62. Ling C, Pease M, Shi L, Punj V, Shiroishi MS, Commins D, et al. A pilot genome-scale profiling of DNA methylation in sporadic pituitary macroadenomas: association with tumor invasion and histopathological subtype. PLoS One. 2014;9:e96178. https://doi.org/10.1371/journal.pone.0096178.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Salomon MP, Wang X, Marzese DM, Hsu SC, Nelson N. The epigenomic landscape of pituitary adenomas reveals specific alterations and differentiates among acromegaly, Cushing’s disease and endocrine-inactive subtypes. Clin Cancer Res. 2018;24:4126–36. https://doi.org/10.1158/1078-0432.ccr-17-2206.

    Article  CAS  PubMed  Google Scholar 

  64. Crick F. Central dogma of molecular biology. Nature. 1970;227:561–3. https://doi.org/10.1038/227561a0.

    Article  CAS  PubMed  Google Scholar 

  65. Lee H, Zhang Z, Krause HM. Long noncoding RNAs and repetitive elements: Junk or intimate evolutionary partners? Trends Genet. 2019;35:892–902. https://doi.org/10.1016/j.tig.2019.09.006.

    Article  CAS  PubMed  Google Scholar 

  66. Anastasiadou E, Jacob LS, Slack FJ. Non-coding RNA networks in cancer. Nat Rev Cancer. 2018;18:5–18. https://doi.org/10.1038/nrc.2017.99.

    Article  CAS  PubMed  Google Scholar 

  67. Li X, Gianoulis TA, Yip KY, Gerstein M, Snyder M. Extensive in vivo metabolite-protein interactions revealed by large-scale systematic analyses. Cell. 2010;143:639–50. https://doi.org/10.1016/j.cell.2010.09.048.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Cheng C, Geng F, Cheng X, Guo D. Lipid metabolism reprogramming and its potential targets in cancer. Cancer Commun (Lond). 2018;38:27. https://doi.org/10.1186/s40880-018-0301-4.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Ahuja M, Jha A, Maléth J, Park S, Muallem S. cAMP and Ca2+ signaling in secretory epithelia: crosstalk and synergism. Cell Calcium. 2014;55:385–93. https://doi.org/10.1016/j.ceca.2014.01.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Spada A, Lania A, Mantovani S. Cellular abnormalities in pituitary tumors. Metabolism. 1996;45:46–8. https://doi.org/10.1016/s0026-0495(96)90079-7.

    Article  CAS  PubMed  Google Scholar 

  71. Lania A, Gil-del-Alamo P, Saccomanno K, Persani L, Faglia G, Spada A. Mechanism of action of pituitary adenylate cyclase-activating polypeptide (PACAP) in human nonfunctioning pituitary tumors. J Neuroendocrinol. 1995;7:695–702. https://doi.org/10.1111/j.1365-2826.1995.tb00811.x.

    Article  CAS  PubMed  Google Scholar 

  72. Romoli R, Lania A, Mantovani G, Corbetta S, Persani L, Spada A. Expression of calcium-sensing receptor and characterization of intracellular signaling in human pituitary adenomas. J Clin Endocrinol Metab. 1999;84:2848–53. https://doi.org/10.1210/jcem.84.8.5922.

    Article  CAS  PubMed  Google Scholar 

  73. Berridge MJ, Bootman MD, Roderick HL. Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol. 2003;4:517–29. https://doi.org/10.1038/nrm1155.

    Article  CAS  PubMed  Google Scholar 

  74. Carafoli E, Santella L, Branca D, Brini M. Generation, control, and processing of cellular calcium signals. Crit Rev Biochem Mol Biol. 2001;36:107–260. https://doi.org/10.1080/20014091074183.

    Article  CAS  PubMed  Google Scholar 

  75. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet. 2006;7:606–19. https://doi.org/10.1038/nrg1879.

    Article  CAS  PubMed  Google Scholar 

  76. Alzahrani AS. PI3K/Akt/mTOR inhibitors in cancer: at the bench and bedside. Semin Cancer Biol. 2019;59:125–32. https://doi.org/10.1016/j.semcancer.2019.07.009.

    Article  CAS  PubMed  Google Scholar 

  77. Ediriweera MK, Tennekoon KH, Samarakoon SR. Role of the PI3K/AKT/mTOR signaling pathway in ovarian cancer: biological and therapeutic significance. Semin Cancer Biol. 2019;59:147–60. https://doi.org/10.1016/j.semcancer.2019.05.012.

    Article  CAS  PubMed  Google Scholar 

  78. Fattahi S, Amjadi-Moheb F, Tabaripour R, Ashrafi GH, Akhavan-Niaki H. PI3K/AKT/mTOR signaling in gastric cancer: epigenetics and beyond. Life Sci. 2020;262:118513. https://doi.org/10.1016/j.lfs.2020.118513.

    Article  CAS  PubMed  Google Scholar 

  79. Chamcheu JC, Roy T, Uddin MB, Banang-Mbeumi S, Chamcheu RN, Walker AL, et al. Role and therapeutic targeting of the PI3K/Akt/mTOR signaling pathway in skin cancer: a review of current status and future trends on natural and synthetic agents therapy. Cells. 2019;8:803. https://doi.org/10.3390/cells8080803.

    Article  CAS  PubMed Central  Google Scholar 

  80. Trovato M, Torre ML, Ragonese M, Simone A, Scarfì R, Barresi V, et al. HGF/c-met system targeting PI3K/AKT and STAT3/phosphorylated-STAT3 pathways in pituitary adenomas: an immunohistochemical characterization in view of targeted therapies. Endocrine. 2013;44:735–43. https://doi.org/10.1007/s12020-013-9950-x.

    Article  CAS  PubMed  Google Scholar 

  81. Murat CB, Braga PB, Fortes MA, Bronstein MD, Corrêa-Giannella ML, Giorgi RR. Mutation and genomic amplification of the PIK3CA proto-oncogene in pituitary adenomas. Braz J Med Biol Res. 2012;45:851–5. https://doi.org/10.1590/s0100-879x2012007500115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Wang RQ, Lan YL, Lou JC, Lyu YZ, Hao YC, Su QF, et al. Expression and methylation status of LAMA2 are associated with the invasiveness of nonfunctioning PitNET. Ther Adv Endocrinol Metab. 2019;10:2042018818821296. https://doi.org/10.1177/2042018818821296.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest. 2008;118:3065–74. https://doi.org/10.1172/jci34739.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Xiao Z, Yang X, Zhang K, Liu Z, Shao Z, Song C, et al. Estrogen receptor α/prolactin receptor bilateral crosstalk promotes bromocriptine resistance in prolactinomas. Int J Med Sci. 2020;17:3174–89. https://doi.org/10.7150/ijms.51176.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Pópulo H, Lopes JM, Soares P. The mTOR signalling pathway in human cancer. Int J Mol Sci. 2012;13:1886–918. https://doi.org/10.3390/ijms13021886.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Rubinfeld H, Shimon I. PI3K/Akt/mTOR and Raf/MEK/ERK signaling pathways perturbations in non-functioning pituitary adenomas. Endocrine. 2012;42:285–91. https://doi.org/10.1007/s12020-012-9682-3.

    Article  CAS  PubMed  Google Scholar 

  87. Jia W, Sanders AJ, Jia G, Liu X, Lu R, Jiang WG. Expression of the mTOR pathway regulators in human pituitary adenomas indicates the clinical course. Anticancer Res. 2013;33:3123–31.

    PubMed  Google Scholar 

  88. Tanoue T, Nishida E. Docking interactions in the mitogen-activated protein kinase cascades. Pharmacol Ther. 2002;93:193–202. https://doi.org/10.1016/s0163-7258(02)00188-2.

    Article  CAS  PubMed  Google Scholar 

  89. Fang JY, Richardson BC. The MAPK signalling pathways and colorectal cancer. Lancet Oncol. 2005;6:322–7. https://doi.org/10.1016/s1470-2045(05)70168-6.

    Article  CAS  PubMed  Google Scholar 

  90. Yong HY, Koh MS, Moon A. The p38 MAPK inhibitors for the treatment of inflammatory diseases and cancer. Expert Opin Investig Drugs. 2009;18:1893–905. https://doi.org/10.1517/13543780903321490.

    Article  CAS  PubMed  Google Scholar 

  91. Peng WX, Huang JG, Yang L, Gong AH, Mo YY. Linc-RoR promotes MAPK/ERK signaling and confers estrogen-independent growth of breast cancer. Mol Cancer. 2017;16:161. https://doi.org/10.1186/s12943-017-0727-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Ewing I, Pedder-Smith S, Franchi G, Ruscica M, Emery M, Vax V, et al. A mutation and expression analysis of the oncogene BRAF in pituitary adenomas. Clin Endocrinol (Oxf). 2007;66:348–52. https://doi.org/10.1111/j.1365-2265.2006.02735.x.

    Article  CAS  PubMed  Google Scholar 

  93. Roof AK, Gutierrez-Hartmann A. Consider the context: Ras/ERK and PI3K/AKT/mTOR signaling outcomes are pituitary cell type-specific. Mol Cell Endocrinol. 2018;463:87–96. https://doi.org/10.1016/j.mce.2017.04.019.

    Article  CAS  PubMed  Google Scholar 

  94. Pagotto U, Arzberger T, Theodoropoulou M, Grübler Y, Pantaloni C, Saeger W, et al. The expression of the antiproliferative gene ZAC is lost or highly reduced in nonfunctioning pituitary adenomas. Cancer Res. 2000;60:6794–9.

    CAS  PubMed  Google Scholar 

  95. Theodoropoulou M, Zhang J, Laupheimer S, Paez-Pereda M, Erneux C, Florio T, et al. Octreotide, a somatostatin analogue, mediates its antiproliferative action in pituitary tumor cells by altering phosphatidylinositol 3-kinase signaling and inducing Zac1 expression. Cancer Res. 2006;66:1576–82. https://doi.org/10.1158/0008-5472.can-05-1189.

    Article  CAS  PubMed  Google Scholar 

  96. Hayes JD, Dinkova-Kostova AT, Tew KD. Oxidative stress in cancer. Cancer Cell. 2020;38:167–97. https://doi.org/10.1016/j.ccell.2020.06.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Zhan X, Desiderio DM. Nitroproteins from a human pituitary adenoma tissue discovered with a nitrotyrosine affinity column and tandem mass spectrometry. Anal Biochem. 2006;354:279–89. https://doi.org/10.1016/j.ab.2006.05.024.

    Article  CAS  PubMed  Google Scholar 

  98. Sabatino ME, Grondona E, Sosa LDV, Mongi Bragato B, Carreño L, Juarez V, et al. Oxidative stress and mitochondrial adaptive shift during pituitary tumoral growth. Free Radic Biol Med. 2018;120:41–55. https://doi.org/10.1016/j.freeradbiomed.2018.03.019.

    Article  CAS  PubMed  Google Scholar 

  99. Zhan X, Li J, Zhou T. Targeting Nrf2-mediated oxidative stress response signaling pathways as new therapeutic strategy for pituitary adenomas. Front Pharmacol. 2021;12:565748. https://doi.org/10.3389/fphar.2021.565748.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Zhan X, Desiderio DM. The use of variations in proteomes to predict, prevent, and personalize treatment for clinically nonfunctional pituitary adenomas. EPMA J. 2010;1:439–59. https://doi.org/10.1007/s13167-010-0028-z.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Wallace DC. Mitochondria and cancer. Nat Rev Cancer. 2012;12:685–98. https://doi.org/10.1038/nrc3365.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Annesley SJ, Fisher PR. Mitochondria in health and disease. Cells. 2019;8(7):680. https://doi.org/10.3390/cells8070680.

    Article  CAS  PubMed Central  Google Scholar 

  103. Srinivasan S, Guha M, Kashina A, Avadhani NG. Mitochondrial dysfunction and mitochondrial dynamics-The cancer connection. Biochim Biophys Acta Bioenerg. 2017;1858:602–14. https://doi.org/10.1016/j.bbabio.2017.01.004.

    Article  CAS  Google Scholar 

  104. Horoupian DS. Large mitochondria in a pituitary adenoma with hyperprolactinemia. Cancer. 1980;46:537–42. https://doi.org/10.1002/1097-0142(19800801)46:3%3c537::aid-cncr2820460319%3e3.0.co;2-6.

    Article  CAS  PubMed  Google Scholar 

  105. Saeger W, Lüdecke DK, Buchfelder M, Fahlbusch R, Quabbe HJ, Petersenn S. Pathohistological classification of pituitary tumors: 10 years of experience with the German Pituitary Tumor Registry. Eur J Endocrinol. 2007;156:203–16. https://doi.org/10.1530/eje.1.02326.

    Article  CAS  PubMed  Google Scholar 

  106. An J, Zhang Y, He J, Zang Z, Zhou Z, Pei X, et al. Lactate dehydrogenase A promotes the invasion and proliferation of pituitary adenoma. Sci Rep. 2017;7:4734. https://doi.org/10.1038/s41598-017-04366-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Dénes J, Swords F, Rattenberry E, Stals K, Owens M, Cranston T, et al. Heterogeneous genetic background of the association of pheochromocytoma/paraganglioma and pituitary adenoma: results from a large patient cohort. J Clin Endocrinol Metab. 2015;100:E531-541. https://doi.org/10.1210/jc.2014-3399.

    Article  CAS  PubMed  Google Scholar 

  108. Wang D, Wong HK, Feng YB, Zhang ZJ. 18beta-glycyrrhetinic acid induces apoptosis in pituitary adenoma cells via ROS/MAPKs-mediated pathway. J Neurooncol. 2014;116:221–30. https://doi.org/10.1007/s11060-013-1292-2.

    Article  CAS  PubMed  Google Scholar 

  109. Xiong S, Mu T, Wang G, Jiang X. Mitochondria-mediated apoptosis in mammals. Protein. Cell. 2014;5:737–49. https://doi.org/10.1007/s13238-014-0089-1.

    Article  CAS  Google Scholar 

  110. Gao F, Pan S, Liu B, Zhang H. TFF3 knockout in human pituitary adenoma cell HP75 facilitates cell apoptosis via mitochondrial pathway. Int J Clin Exp Pathol. 2015;8:14568–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Tanase C, Albulescu R, Codrici E, Calenic B, Popescu ID, Mihai S, et al. Decreased expression of APAF-1 and increased expression of cathepsin B in invasive pituitary adenoma. Onco Targets Ther. 2015;8:81–90. https://doi.org/10.2147/ott.s70886.

    Article  PubMed  Google Scholar 

  112. Li N, Zhan X. Mitochondrial dysfunction pathway networks and mitochondrial dynamics in the pathogenesis of pituitary adenomas. Front Endocrinol (Lausanne). 2019;10:690. https://doi.org/10.3389/fendo.2019.00690.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Deyu H, Luqing C, Xianglian L, Pu G, Qirong L, Xu W, et al. Protective mechanisms involving enhanced mitochondrial functions and mitophagy against T-2 toxin-induced toxicities in GH3 cells. Toxicol Lett. 2018;295:41–53. https://doi.org/10.1016/j.toxlet.2018.05.041.

    Article  CAS  PubMed  Google Scholar 

  114. Kar S. Unraveling cell-cycle dynamics in cancer. Cell Syst. 2016;2:8–10. https://doi.org/10.1016/j.cels.2016.01.007.

    Article  CAS  PubMed  Google Scholar 

  115. Simpson DJ, Hibberts NA, McNicol AM, Clayton RN, Farrell WE. Loss of pRb expression in pituitary adenomas is associated with methylation of the RB1 CpG island. Cancer Res. 2000;60:1211–6.

    CAS  PubMed  Google Scholar 

  116. Yoshino A, Katayama Y, Ogino A, Watanabe T, Yachi K, Ohta T, et al. Promoter hypermethylation profile of cell cycle regulator genes in pituitary adenomas. J Neurooncol. 2007;83:153–62. https://doi.org/10.1007/s11060-006-9316-9.

    Article  CAS  PubMed  Google Scholar 

  117. García-Fernández RA, García-Palencia P, Sánchez M, Gil-Gómez G, Sánchez B, Rollán E, et al. Combined loss of p21(waf1/cip1) and p27(kip1) enhances tumorigenesis in mice. Lab Invest. 2011;91:1634–42. https://doi.org/10.1038/labinvest.2011.133.

    Article  CAS  PubMed  Google Scholar 

  118. Gruppetta M, Formosa R, Falzon S, Ariff Scicluna S, Falzon E, Degeatano J, et al. Expression of cell cycle regulators and biomarkers of proliferation and regrowth in human pituitary adenomas. Pituitary. 2017;20:358–71. https://doi.org/10.1007/s11102-017-0803-0.

    Article  CAS  PubMed  Google Scholar 

  119. Matoušek P, Buzrla P. Factors That predict the growth of residual nonfunctional pituitary adenomas: correlations between relapse and cell cycle Markers. Biomed Res Int. 2018;2018:1876290. https://doi.org/10.1155/2018/1876290.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Butz H, Németh K, Czenke D, Likó I, Czirják S, Zivkovic V, et al. Systematic investigation of expression of G2/M transition genes reveals CDC25 alteration in nonfunctioning pituitary adenomas. Pathol Oncol Res. 2017;23:633–41. https://doi.org/10.1007/s12253-016-0163-5.

    Article  CAS  PubMed  Google Scholar 

  121. Vázquez-Borrego MC, Fuentes-Fayos AC, Herrera-Martínez AD, F LL, Ibáñez-Costa A, Moreno-Moreno P, et al. Biguanides exert antitumoral actions in pituitary tumor cells through AMPK-dependent and -independent mechanisms. J Clin Endocrinol Metab. 2019; 104:3501–3513. https://doi.org/10.1210/jc.2019-00056.

  122. Vázquez-Borrego MC, Fuentes-Fayos AC, Herrera-Martínez AD, Venegas-Moreno E, F LL, Fanciulli A, et al. Statins directly regulate pituitary cell function and exert antitumor effects in pituitary tumors. Neuroendocrinology. 2020; 110:1028–1041. https://doi.org/10.1159/000505923.

  123. Zeng J, See AP, Aziz K, Thiyagarajan S, Salih T, Gajula RP, et al. Nelfinavir induces radiation sensitization in pituitary adenoma cells. Cancer Biol Ther. 2011;12:657–63. https://doi.org/10.4161/cbt.12.7.17172.

    Article  CAS  PubMed  Google Scholar 

  124. Hubina E, Nanzer AM, Hanson MR, Ciccarelli E, Losa M, Gaia D, et al. Somatostatin analogues stimulate p27 expression and inhibit the MAP kinase pathway in pituitary tumours. Eur J Endocrinol. 2006;155:371–9. https://doi.org/10.1530/eje.1.02213.

    Article  CAS  PubMed  Google Scholar 

  125. Guzzo MF, Carvalho LR, Bronstein MD. Ketoconazole treatment decreases the viability of immortalized pituitary cell lines associated with an increased expression of apoptosis-related genes and cell cycle inhibitors. J Neuroendocrinol. 2015;27:616–23. https://doi.org/10.1111/jne.12277.

    Article  CAS  PubMed  Google Scholar 

  126. Petiti JP, Sosa LDV, Picech F, Moyano Crespo GD, Arevalo Rojas JZ, Pérez PA, et al. Trastuzumab inhibits pituitary tumor cell growth modulating the TGFB/SMAD2/3 pathway. Endocr Relat Cancer. 2018;25:837–52. https://doi.org/10.1530/erc-18-0067.

    Article  CAS  PubMed  Google Scholar 

  127. Lu M, Wang Y, Zhan X. The MAPK pathway-based drug therapeutic targets in pituitary adenomas. Front Endocrinol (Lausanne). 2019;10:330. https://doi.org/10.3389/fendo.2019.00330.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Dworakowska D, Wlodek E, Leontiou CA, Igreja S, Cakir M, Teng M, et al. Activation of RAF/MEK/ERK and PI3K/AKT/mTOR pathways in pituitary adenomas and their effects on downstream effectors. Endocr Relat Cancer. 2009;16:1329–38. https://doi.org/10.1677/erc-09-0101.

    Article  CAS  PubMed  Google Scholar 

  129. Xu M, Shorts-Cary L, Knox AJ, Kleinsmidt-DeMasters B, Lillehei K, Wierman ME. Epidermal growth factor receptor pathway substrate 8 is overexpressed in human pituitary tumors: role in proliferation and survival. Endocrinology. 2009;150:2064–71. https://doi.org/10.1210/en.2008-1265.

    Article  CAS  PubMed  Google Scholar 

  130. Rubinfeld H, Kammer A, Cohen O, Gorshtein A, Cohen ZR, Hadani M, et al. IGF1 induces cell proliferation in human pituitary tumors - functional blockade of IGF1 receptor as a novel therapeutic approach in non-functioning tumors. Mol Cell Endocrinol. 2014;390:93–101. https://doi.org/10.1016/j.mce.2014.04.007.

    Article  CAS  PubMed  Google Scholar 

  131. Sirotnak FM, Zakowski MF, Miller VA, Scher HI, Kris MG. Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. Clin Cancer Res. 2000;6:4885–92.

    CAS  PubMed  Google Scholar 

  132. Fukuoka H, Cooper O, Mizutani J, Tong Y, Ren SG, Bannykh S, et al. HER2/ErbB2 receptor signaling in rat and human prolactinoma cells: strategy for targeted prolactinoma therapy. Mol Endocrinol. 2011;25:92–103. https://doi.org/10.1210/me.2010-0353.

    Article  CAS  PubMed  Google Scholar 

  133. Vlotides G, Siegel E, Donangelo I, Gutman S, Ren SG, Melmed S. Rat prolactinoma cell growth regulation by epidermal growth factor receptor ligands. Cancer Res. 2008;68:6377–86. https://doi.org/10.1158/0008-5472.can-08-0508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Zatelli MC, Minoia M, Filieri C, Tagliati F, Buratto M, Ambrosio MR, et al. Effect of everolimus on cell viability in nonfunctioning pituitary adenomas. J Clin Endocrinol Metab. 2010;95:968–76. https://doi.org/10.1210/jc.2009-1641.

    Article  CAS  PubMed  Google Scholar 

  135. Cerovac V, Monteserin-Garcia J, Rubinfeld H, Buchfelder M, Losa M, Florio T, et al. The somatostatin analogue octreotide confers sensitivity to rapamycin treatment on pituitary tumor cells. Cancer Res. 2010;70:666–74. https://doi.org/10.1158/0008-5472.can-09-2951.

    Article  CAS  PubMed  Google Scholar 

  136. Koklesova L, Samec M, Liskova A, Zhai K, Büsselberg D, Giordano FA, Kubatka P, Golunitschaja O. Mitochondrial impairments in aetiopathology of multifactorial diseases: common origin but individual outcomes in context of 3P medicine. EPMA J. 2021;12(1):1–14. https://doi.org/10.1007/s13167-021-00237-2.

    Article  Google Scholar 

Download references

Acknowledgements

The authors acknowledge the financial support from the Shandong First Medical University Talent Introduction Funds (to X.Z.), Shandong First Medical University High-level Scientific Research Achievement Cultivation Funding Program (to X.Z.), the Shandong Provincial Natural Science Foundation (ZR202103020356/ZR2021MH156 to X.Z.), and the Academic Promotion Program of Shandong First Medical University (2019ZL002).

Funding

This work was supported by the Shandong First Medical University Talent Introduction Funds (to X.Z.), Shandong First Medical University High-level Scientific Research Achievement Cultivation Funding Program (to X.Z.), the Shandong Provincial Natural Science Foundation (ZR202103020356/ ZR2021MH156 to X.Z.), and the Academic Promotion Program of Shandong First Medical University (2019ZL002).

Author information

Authors and Affiliations

  1. Shandong Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, 440 Jiyan Road, Jinan, Shandong, 250117, People’s Republic of China

    Siqi Wen & Xianquan Zhan

  2. Medical Science and Technology Innovation Center, Shandong First Medical University, Jinan, 6699 Qingdao Road, Jinan, Shandong, 250117, People’s Republic of China

    Siqi Wen & Xianquan Zhan

  3. Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, People’s Republic of China

    Siqi Wen

  4. Department of Anesthesiology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, People’s Republic of China

    Chunling Li

  5. Gastroenterology Research Institute and Clinical Center, Shandong First Medical University, 38 Wuying Shan Road, Jinan, Shandong, 250031, People’s Republic of China

    Xianquan Zhan

Authors
  1. Siqi Wen
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Chunling Li
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Xianquan Zhan
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

S.Q. collected and analyzed literature, and wrote the manuscript. C.L. participated in the collection and analysis of literature. X.Z. conceived the concept, designed the manuscript, coordinated, wrote, and critically revised the manuscript, and was responsible for its financial support and the corresponding works. All authors approved the final manuscript.

Corresponding author

Correspondence to Xianquan Zhan.

Ethics declarations

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wen, S., Li, C. & Zhan, X. Muti-omics integration analysis revealed molecular network alterations in human nonfunctional pituitary neuroendocrine tumors in the framework of 3P medicine. EPMA Journal 13, 9–37 (2022). https://doi.org/10.1007/s13167-022-00274-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13167-022-00274-5

Keywords