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  • Review Article
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Circulating non-coding RNA biomarkers of endocrine tumours

Abstract

Circulating non-coding RNA (ncRNA) molecules are being investigated as biomarkers of malignancy, prognosis and follow-up in several neoplasms, including endocrine tumours of the pituitary, parathyroid, pancreas and adrenal glands. Most of these tumours are classified as neuroendocrine neoplasms (comprised of neuroendocrine tumours and neuroendocrine carcinomas) and include tumours of variable aggressivity. We consider them together here in this Review owing to similarities in their clinical presentation, pathomechanism and genetic background. No preoperative biomarkers of malignancy are available for several forms of these endocrine tumours. Moreover, biomarkers are also needed for the follow-up of tumour progression (especially in hormonally inactive tumours), prognosis and treatment efficacy monitoring. Circulating blood-borne ncRNAs show promising utility as biomarkers. These ncRNAs, including microRNAs, long non-coding RNAs and circular RNAs, are involved in several aspects of gene expression regulation, and their stability and tissue-specific expression could make them ideal biomarkers. However, no circulating ncRNA biomarkers have yet been introduced into routine clinical practice, which is mostly owing to methodological and standardization problems. In this Review, following a brief synopsis of these endocrine tumours and the biology of ncRNAs, the major research findings, pathomechanisms and methodological questions are discussed along with an outlook for future studies.

Key points

  • Endocrine tumours, including pituitary, pancreatic and parathyroid neuroendocrine tumours, adrenocortical cancer and phaeochromocytoma–paraganglioma, share common features in their pathogenesis, genetic background and associated clinical challenges.

  • Non-coding RNAs (ncRNAs) can be exploited as tissue-specific biomarkers of malignancy, prognosis and follow-up, and their circulating counterparts can be measured in blood samples as a form of liquid biopsy.

  • Circulating microRNAs show promising utility as biomarkers of malignancy and prognosis in adrenocortical tumours, and several other differentially expressed ncRNAs were reported in other endocrine tumours.

  • Apart from circulating miR-483-5p and miR-143-3p, few overlaps are observed in the circulating ncRNA molecules expressed from different types of endocrine tumour.

  • None of these biomarkers has yet been introduced into clinical practice, which is mainly owing to difficulties in standardization and methodology.

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Fig. 1: The common genetic background and pathomechanisms of ACC, PPGL, pitNETs, panNETs and parathyroid NETs.
Fig. 2: Biogenesis and secretion of extracellular non-coding RNAs.
Fig. 3: The origin of tumour-associated circulating non-coding RNA.

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References

  1. Herrera-Martínez, A. D. et al. Neuroendocrine neoplasms: current and potential diagnostic, predictive and prognostic markers. Endocr. Relat. Cancer 26, R157–R179 (2019).

    Article  PubMed  Google Scholar 

  2. Smolkova, B. et al. Liquid biopsy and preclinical tools for advancing diagnosis and treatment of patients with pancreatic neuroendocrine neoplasms. Crit. Rev. Oncol. Hematol. 180, 103865 (2022).

    Article  PubMed  Google Scholar 

  3. Fassnacht, M. et al. Adrenocortical carcinomas and malignant phaeochromocytomas: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 31, 1476–1490 (2020).

    Article  CAS  PubMed  Google Scholar 

  4. Russano, M. et al. Liquid biopsy and tumor heterogeneity in metastatic solid tumors: the potentiality of blood samples. J. Exp. Clin. Cancer Res. 39, 95 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Asa, S. L. & Mete, O. Endocrine pathology: past, present and future. Pathology 50, 111–118 (2018).

    Article  PubMed  Google Scholar 

  6. Rindi, G. et al. Overview of the 2022 WHO classification of neuroendocrine neoplasms. Endocr. Pathol. 33, 115–154 (2022). A comprehensive review on the current classification of NETs.

    Article  CAS  PubMed  Google Scholar 

  7. Asa, S. L., Mete, O., Perry, A. & Osamura, R. Y. Overview of the 2022 WHO classification of pituitary tumors. Endocr. Pathol. 33, 6–26 (2022). A recent review on the current classification of pituitary tumours.

    Article  CAS  PubMed  Google Scholar 

  8. Yeh, M. W. et al. Incidence and prevalence of primary hyperparathyroidism in a racially mixed population. J. Clin. Endocrinol. Metab. 98, 1122–1129 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Minisola, S. et al. Epidemiology, pathophysiology, and genetics of primary hyperparathyroidism. J. Bone Miner. Res. 37, 2315–2329 (2022).

    Article  PubMed  Google Scholar 

  10. Daly, A. F. & Beckers, A. The epidemiology of pituitary adenomas. Endocrinol. Metab. Clin. North Am. 49, 347–355 (2020).

    Article  PubMed  Google Scholar 

  11. Dasari, A. et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 3, 1335–1342 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Heaphy C. M. & Singhi A. D. The diagnostic and prognostic utility of incorporating DAXX, ATRX, and alternative lengthening of telomeres (ALT) to the evaluation of pancreatic neuroendocrine tumors (PanNETs). Hum. Pathol. 129, 11–20 (2022).

    Article  CAS  PubMed  Google Scholar 

  13. Berends, A. M. A. et al. Incidence of pheochromocytoma and sympathetic paraganglioma in the Netherlands: a nationwide study and systematic review. Eur. J. Int. Med. 51, 68–73 (2018).

    Article  Google Scholar 

  14. Lenders, J. W. M. et al. Genetics, diagnosis, management and future directions of research of phaeochromocytoma and paraganglioma: a position statement and consensus of the Working Group on Endocrine Hypertension of the European Society of Hypertension. J. Hypertens. 38, 1443–1456 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bancos, I. & Prete, A. Approach to the patient with adrenal incidentaloma. J. Clin. Endocrinol. Metab. 106, 3331–3353 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Angelousi, A. et al. Molecular targeted therapies in adrenal, pituitary and parathyroid malignancies. Endocr. Relat. Cancer 24, R239–R259 (2017).

    Article  PubMed  Google Scholar 

  17. Fishbein, L. et al. Comprehensive molecular characterization of pheochromocytoma and paraganglioma. Cancer Cell 31, 181–193 (2017). A ground-breaking study on the molecular features of PPGL.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Marini, F. et al. Genetics and epigenetics of parathyroid carcinoma. Front. Endocrinol. 13, 834362 (2022).

    Article  Google Scholar 

  19. Gaujoux, S. et al. Wnt/beta-catenin and 3′,5′-cyclic adenosine 5′-monophosphate/protein kinase A signaling pathways alterations and somatic beta-catenin gene mutations in the progression of adrenocortical tumors. J. Clin. Endocrinol. Metab. 93, 4135–4140 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. Nosé, V., Gill, A., Teijeiro, J. M. C., Perren, A. & Erickson, L. Overview of the 2022 WHO classification of familial endocrine tumor syndromes. Endocr. Pathol. 33, 197–227 (2022).

    Article  PubMed  Google Scholar 

  21. Brandi, M. L. et al. Multiple endocrine neoplasia type 1: latest insights. Endocr. Rev. 42, 133–170 (2021).

    Article  PubMed  Google Scholar 

  22. Ruggeri, R. M. et al. Multiple endocrine neoplasia type 4 (MEN4): a thorough update on the latest and least known MEN syndrome. Endocrine 82, 480–490 (2023).

    Article  CAS  PubMed  Google Scholar 

  23. Minnetti, M. & Grossman, A. Somatic and germline mutations in NETs: implications for their diagnosis and management. Best Pract. Res. Clin. Endocrinol. Metab. 30, 115–127 (2016).

    Article  CAS  PubMed  Google Scholar 

  24. MacFarlane, J. et al. A review of the tumour spectrum of germline succinate dehydrogenase gene mutations: beyond phaeochromocytoma and paraganglioma. Clin. Endocrinol. 93, 528–538 (2020).

    Article  CAS  Google Scholar 

  25. Huang, J. et al. The same pocket in menin binds both MLL and JUND but has opposite effects on transcription. Nature 482, 542–546 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Matkar, S., Thiel, A. & Hua, X. Menin: a scaffold protein that controls gene expression and cell signaling. Trends Biochem. Sci. 38, 394–402 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kaji, H., Canaff, L., Lebrun, J. J., Goltzman, D. & Hendy, G. N. Inactivation of menin, a Smad3-interacting protein, blocks transforming growth factor type beta signaling. Proc. Natl Acad. Sci. USA 98, 3837–3842 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wong, C. et al. Two well-differentiated pancreatic neuroendocrine tumor mouse models. Cell Death Diff. 27, 269–283 (2020).

    Article  CAS  Google Scholar 

  29. Luo, J., Manning, B. D. & Cantley, L. C. Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell. 4, 257–262 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Segouffin-Cariou, C. & Billaud, M. Transforming ability of MEN2A-RET requires activation of the phosphatidylinositol 3-kinase/AKT signaling pathway. J. Biol. Chem. 275, 3568–3576 (2000).

    Article  CAS  PubMed  Google Scholar 

  31. Anastasaki, C., Orozco, P. & Gutmann, D. H. RAS and beyond: the many faces of the neurofibromatosis type 1 protein. Dis. Mod. Mech. 15, dmm049362 (2022).

    Article  CAS  Google Scholar 

  32. Adhikary, S. & Eilers, M. Transcriptional regulation and transformation by Myc proteins. Nat. Rev. Mol. Cell Biol. 6, 635–645 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Augert, A. et al. MAX functions as a tumor suppressor and rewires metabolism in small cell lung cancer. Cancer Cell 38, 97–114.e117 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Cetani, F. et al. Approach to the patient with parathyroid carcinoma. J. Clin. Endocrinol. Metab. 109, 256–268 (2023).

    Article  PubMed  Google Scholar 

  35. Raverot, G. et al. European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas. Eur. J. Endocrinol. 178, G1–G24 (2018).

    Article  CAS  PubMed  Google Scholar 

  36. Bevere, M. et al. An overview of circulating biomarkers in neuroendocrine neoplasms: a clinical guide. Diagnostics 13, 2820 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin. Pharmacol. Ther. 69, 89–95 (2001).

    Article  Google Scholar 

  38. FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) Resource. https://www.ncbi.nlm.nih.gov/books/NBK326791/ (FDA–NIH, 2016).

  39. Paik, S. et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J. Clin. Oncol. 24, 3726–3734 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Anfossi, S., Babayan, A., Pantel, K. & Calin, G. A. Clinical utility of circulating non-coding RNAs — an update. Nat. Rev. Clin. Oncol. 15, 541–563 (2018). A comprehensive review on the clinical applicability of circulating ncRNA.

    Article  PubMed  Google Scholar 

  41. Lewis, B. P., Burge, C. B. & Bartel, D. P. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120, 15–20 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Mattick, J. S. et al. Long non-coding RNAs: definitions, functions, challenges and recommendations. Nat. Rev. Mol. Cell. Biol. 24, 430–447 (2023). A recent review on lncRNA.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhao, X., Cai, Y. & Xu, J. Circular RNAs: biogenesis, mechanism, and function in human cancers. Int. J. Mol. Sci. 20, 3926 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Li, X., Yang, L. & Chen, L. L. The biogenesis, functions, and challenges of circular RNAs. Mol. Cell. 71, 428–442 (2018).

    Article  CAS  PubMed  Google Scholar 

  45. Cortez, M. A. et al. MicroRNAs in body fluids — the mix of hormones and biomarkers. Nat. Rev. Clin. Oncol. 8, 467–477 (2011). An important review that raises the relevance of circulating miRNAs as hormones.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Théry, C. et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J. Extracell. Ves. 7, 1535750 (2018).

    Article  Google Scholar 

  47. Minciacchi, V. R., Freeman, M. R. & Di Vizio, D. Extracellular vesicles in cancer: exosomes, microvesicles and the emerging role of large oncosomes. Semin. Cell Dev. Biol. 40, 41–51 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Arroyo, J. D. et al. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc. Natl Acad. Sci. USA 108, 5003–5008 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Turchinovich, A., Weiz, L., Langheinz, A. & Burwinkel, B. Characterization of extracellular circulating microRNA. Nucleic Acids Res. 39, 7223–7233 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Michell, D. L. & Vickers, K. C. Lipoprotein carriers of microRNAs. Biochim. Biophys. Acta 1861, 2069–2074 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Tay, Y., Rinn, J. & Pandolfi, P. P. The multilayered complexity of ceRNA crosstalk and competition. Nature 505, 344–352 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Wu, Q., Li, L., Jia, Y., Xu, T. & Zhou, X. Advances in studies of circulating microRNAs: origination, transportation, and distal target regulation. J. Cell Comm. Signal. 17, 445–455 (2023).

    Article  CAS  Google Scholar 

  53. Mitchell, P. S. et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc. Natl Acad. Sci. USA 105, 10513–10518 (2008). A paper that describes the potential relevance of circulating miRNAs in cancer diagnostics.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Orso, F. et al. Stroma-derived miR-214 coordinates tumor dissemination. J. Exp. Clin. Cancer Res. 42, 20 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Liang, X., Zhang, L., Wang, S., Han, Q. & Zhao, R. C. Exosomes secreted by mesenchymal stem cells promote endothelial cell angiogenesis by transferring miR-125a. J. Cell Sci. 129, 2182–2189 (2016).

    Article  CAS  PubMed  Google Scholar 

  56. Pritchard, C. C. et al. Blood cell origin of circulating microRNAs: a cautionary note for cancer biomarker studies. Cancer Prev. Res. 5, 492–497 (2012). A very important study that raises the blood cell origin of circulating miRNAs detected in patients with cancer.

    Article  CAS  Google Scholar 

  57. Leonard, S., Karabegović, I., Ikram, M. A., Ahmad, S. & Ghanbari, M. Plasma circulating microRNAs associated with blood-based immune markers: a population-based study. Clin. Exp. Immunol. 215, 251–260 (2023).

    Article  PubMed Central  Google Scholar 

  58. Catellani, C. et al. Specific miRNAs change after 3 months of GH treatment and contribute to explain the growth response after 12 months. Front. Endocrinol. 13, 896640 (2022).

    Article  Google Scholar 

  59. Igaz, I. et al. Analysis of circulating microRNAs in vivo following administration of dexamethasone and adrenocorticotropin. Int. J. Endocrinol. 2015, 589230 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Piña-Sánchez, P., Valdez-Salazar, H. A. & Ruiz-Tachiquín, M. E. Circulating microRNAs and their role in the immune response in triple-negative breast cancer. Oncol. Lett. 20, 224 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Németh, K. et al. Comprehensive analysis of circulating miRNAs in the plasma of patients with pituitary adenomas. J. Clin. Endocrinol. Metab. 104, 4151–4168 (2019). The most comprehensive analysis to date of circulating miRNAs in patients with pituitary tumours.

    Article  PubMed  Google Scholar 

  62. Kövesdi, A. et al. Circulating miRNA increases the diagnostic accuracy of chromogranin a in metastatic pancreatic neuroendocrine tumors. Cancers 12, 2488 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Lu, J. et al. MicroRNA expression profiles classify human cancers. Nature 435, 834–838 (2005).

    Article  CAS  PubMed  Google Scholar 

  64. Gahlawat, A. W., Fahed, L., Witte, T. & Schott, S. Total circulating microRNA level as an independent prognostic marker for risk stratification in breast cancer. Br. J. Cancer 127, 156–162 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Salido-Guadarrama, I., Romero-Cordoba, S., Peralta-Zaragoza, O., Hidalgo-Miranda, A. & Rodríguez-Dorantes, M. MicroRNAs transported by exosomes in body fluids as mediators of intercellular communication in cancer. OncoTargets Ther. 7, 1327–1338 (2014).

    Google Scholar 

  66. Xiong, Y. et al. Exosomal hsa-miR-21-5p derived from growth hormone-secreting pituitary adenoma promotes abnormal bone formation in acromegaly. Transl. Res. 215, 1–16 (2020).

    Article  CAS  PubMed  Google Scholar 

  67. Pardini, B. & Calin, G. A. MicroRNAs and long non-coding RNAs and their hormone-like activities in cancer. Cancers 11, 378 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Nagy, Z. et al. Evaluation of 9-cis retinoic acid and mitotane as antitumoral agents in an adrenocortical xenograft model. Am. J. Cancer Res. 5, 3645–3658 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Xiong, J. et al. An exploration of non-coding RNAs in extracellular vesicles delivered by swine anterior pituitary. Front. Genet. 12, 772753 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Koh, W. et al. Noninvasive in vivo monitoring of tissue-specific global gene expression in humans. Proc. Natl Acad. Sci. USA 111, 7361–7366 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Decmann, A., Perge, P., Turai, P. I., Patócs, A. & Igaz, P. Non-coding RNAs in adrenocortical cancer: from pathogenesis to diagnosis. Cancers 12, 461 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Veronese, A. et al. Oncogenic role of miR-483-3p at the IGF2/483 locus. Cancer Res. 70, 3140–3149 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Veronese, A. et al. Mutated beta-catenin evades a microRNA-dependent regulatory loop. Proc. Natl Acad. Sci. USA 108, 4840–4845 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Patel, D. et al. MiR-34a and miR-483-5p are candidate serum biomarkers for adrenocortical tumors. Surgery 154, 1224–1228 (2013).

    Article  PubMed  Google Scholar 

  75. Chabre, O. et al. Serum miR-483-5p and miR-195 are predictive of recurrence risk in adrenocortical cancer patients. Endocr. Relat. Cancer 20, 579–594 (2013).

    Article  CAS  PubMed  Google Scholar 

  76. Szabo, D. R. et al. Analysis of circulating microRNAs in adrenocortical tumors. Lab. Invest. 94, 331–339 (2014).

    Article  CAS  PubMed  Google Scholar 

  77. Perge, P. et al. Evaluation and diagnostic potential of circulating extracellular vesicle-associated microRNAs in adrenocortical tumors. Sci. Rep. 7, 5474 (2017). A paper reporting high diagnostic accuracy of exosomal circulating miR-483-5p for the differentiation of ACA and ACC.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Decmann, A. et al. MicroRNA expression profiling in adrenal myelolipoma. J. Clin. Endocrinol. Metab. 103, 3522–3530 (2018).

    Article  PubMed  Google Scholar 

  79. Decmann, A. et al. Comparison of plasma and urinary microRNA-483-5p for the diagnosis of adrenocortical malignancy. J. Biotechnol. 297, 49–53 (2019).

    Article  CAS  PubMed  Google Scholar 

  80. Qiao, Y. et al. MiR-483-5p controls angiogenesis in vitro and targets serum response factor. FEBS Lett. 585, 3095–3100 (2011).

    Article  CAS  PubMed  Google Scholar 

  81. Song, Q. et al. miR-483-5p promotes invasion and metastasis of lung adenocarcinoma by targeting RhoGDI1 and ALCAM. Cancer Res. 74, 3031–3042 (2014).

    Article  CAS  PubMed  Google Scholar 

  82. Agosta, C. et al. MiR-483-5p and miR-139-5p promote aggressiveness by targeting N-myc downstream-regulated gene family members in adrenocortical cancer. Int. J. Cancer 143, 944–957 (2018).

    Article  CAS  PubMed  Google Scholar 

  83. Patterson, E. et al. The microRNA expression changes associated with malignancy and SDHB mutation in pheochromocytoma. Endocr. Relat. Cancer 19, 157–166 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Castro-Vega, L. J. et al. Overexpression of miR-483-5p is confined to metastases and linked to high circulating levels in patients with metastatic pheochromocytoma/paraganglioma. Clin. Transl. Med. 10, e260 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Devlin, C., Greco, S., Martelli, F. & Ivan, M. miR-210: more than a silent player in hypoxia. IUBMB Life 63, 94–100 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Ruff, S. M. et al. MicroRNA-210 may be a preoperative biomarker of malignant pheochromocytomas and paragangliomas. J. Surg. Res. 243, 1–7 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Calsina, B. et al. Integrative multi-omics analysis identifies a prognostic miRNA signature and a targetable miR-21-3p/TSC2/mTOR axis in metastatic pheochromocytoma/paraganglioma. Theranostics 9, 4946–4958 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Wang, K. et al. Personalized drug testing in human pheochromocytoma/paraganglioma primary cultures. Endocr. Relat. Cancer 29, 285–306 (2022).

    Article  CAS  PubMed  Google Scholar 

  89. Bautista-Sánchez, D. et al. The promising role of miR-21 as a cancer biomarker and its importance in RNA-based therapeutics. Mol. Ther. Nucl. Acids 20, 409–420 (2020).

    Article  Google Scholar 

  90. Perge, P. et al. Analysis of circulating extracellular vesicle-associated microRNAs in cortisol-producing adrenocortical tumors. Endocrine 59, 280–287 (2018).

    Article  CAS  PubMed  Google Scholar 

  91. Salvianti, F. et al. New insights in the clinical and translational relevance of miR483-5p in adrenocortical cancer. Oncotarget 8, 65525–65533 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Oreglia, M. et al. Early postoperative circulating miR-483-5p is a prognosis marker for adrenocortical cancer. Cancers 12, 724 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Jung, S. et al. Preclinical progress and first translational steps for a liposomal chemotherapy protocol against adrenocortical carcinoma. Endocr. Relat. Cancer 23, 825–837 (2016).

    Article  CAS  PubMed  Google Scholar 

  94. Reel, P. S. et al. Machine learning for classification of hypertension subtypes using multi-omics: a multi-centre, retrospective, data-driven study. EBioMedicine 84, 104276 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Vetrivel, S. et al. Circulating microRNA expression in Cushing’s syndrome. Front. Endocrinol. 12, 620012 (2021).

    Article  Google Scholar 

  96. Hara, K. et al. Heterogeneous circulating miRNA profiles of PBMAH. Front. Endocrinol. 13, 1073328 (2022).

    Article  Google Scholar 

  97. Decmann, A. et al. Circulating miRNA expression profiling in primary aldosteronism. Front. Endocrinol. 10, 739 (2019).

    Article  Google Scholar 

  98. Wang, J. et al. Expression profile of serum-related exosomal miRNAs from parathyroid tumor. Endocrine 72, 239–248 (2021).

    Article  CAS  PubMed  Google Scholar 

  99. Krupinova, J. et al. Serum circulating miRNA-342-3p as a potential diagnostic biomarker in parathyroid carcinomas: a pilot study. Endocrinol. Diabetes Metab. 4, e00284 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Yavropoulou, M. P. et al. Circulating and tissue expression profile of MicroRNAs in primary hyperparathyroidism caused by sporadic parathyroid adenomas. JBMR Plus 5, e10431 (2021).

    Article  CAS  PubMed  Google Scholar 

  101. Li, A. et al. MicroRNA array analysis finds elevated serum miR-1290 accurately distinguishes patients with low-stage pancreatic cancer from healthy and disease controls. Clin. Cancer Res. 19, 3600–3610 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Vicentini, C. et al. Clinical application of microRNA testing in neuroendocrine tumors of the gastrointestinal tract. Molecules 19, 2458–2468 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Thorns, C. et al. Global microRNA profiling of pancreatic neuroendocrine neoplasias. Anticancer. Res. 34, 2249–2254 (2014).

    PubMed  Google Scholar 

  104. Bocchini, M. et al. Circulating has-miR-5096 predicts 18F-FDG PET/CT positivity and modulates somatostatin receptor 2 expression: a novel miR-based assay for pancreatic neuroendocrine tumors. Front. Oncol. 13, 1136331 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Melone, V. et al. Identification of functional pathways and molecular signatures in neuroendocrine neoplasms by multi-omics analysis. J. Transl. Med. 20, 306 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Kooblall, K. G. et al. miR-3156-5p is downregulated in serum of MEN1 patients and regulates expression of MORF4L2. Endocr. Relat. Cancer 29, 557–568 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Modlin, I. M. et al. A multianalyte PCR blood test outperforms single analyte ELISAs (chromogranin A, pancreastatin, neurokinin A) for neuroendocrine tumor detection. Endocr. Relat. Cancer 21, 615–628 (2014).

    Article  CAS  PubMed  Google Scholar 

  108. Lu, B. et al. MicroRNA-16/VEGFR2/p38/NF-κB signaling pathway regulates cell growth of human pituitary neoplasms. Oncol. Rep. 39, 1235–1244 (2018).

    CAS  PubMed  Google Scholar 

  109. Belaya, Z. et al. Circulating plasma microRNA to differentiate cushing’s disease from ectopic ACTH syndrome. Front. Endocrinol. 11, 331 (2020).

    Article  Google Scholar 

  110. Zhang, Q., Wang, Y., Zhou, Y., Zhang, Q. & Xu, C. Potential biomarkers of miRNA in non-functional pituitary adenomas. World J. Surg. Oncol. 19, 270 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Beylerli, O. et al. Differential non-coding RNAs expression profiles of invasive and non-invasive pituitary adenomas. Non-coding RNA Res. 6, 115–122 (2021).

    Article  CAS  Google Scholar 

  112. Lutsenko, A. et al. Circulating plasma microRNA in patients with active acromegaly. J. Clin. Endocrinol. Metab. 107, 500–511 (2022).

    Article  PubMed  Google Scholar 

  113. Niedra, H. et al. Case report: micro-RNAs in plasma from bilateral inferior petrosal sinus sampling and peripheral blood from corticotroph pituitary neuroendocrine tumors. Front. Endocrinol. 13, 748152 (2022).

    Article  Google Scholar 

  114. Amaral, F. C. et al. MicroRNAs differentially expressed in ACTH-secreting pituitary tumors. J. Clin. Endocrinol. Metab. 94, 320–323 (2009).

    Article  CAS  PubMed  Google Scholar 

  115. Zhang, J. et al. MicroRNA-143 shows tumor suppressive effects through inhibition of oncogenic K-Ras in pituitary tumor. Int. J. Clin. Exp. Pathol. 10, 10969–10978 (2017).

    PubMed  PubMed Central  Google Scholar 

  116. Michael, M. Z., SM, O. C., van Holst Pellekaan, N. G., Young, G. P. & James, R. J. Reduced accumulation of specific microRNAs in colorectal neoplasia. Mol. Cancer Res. 1, 882–891 (2003).

    CAS  PubMed  Google Scholar 

  117. Turai, P. I., Nyírő, G., Butz, H., Patócs, A. & Igaz, P. MicroRNAs, long non-coding RNAs, and circular RNAs: potential biomarkers and therapeutic targets in pheochromocytoma/paraganglioma. Cancers 13, 1522 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Butz, H. Circulating noncoding RNAs in pituitary neuroendocrine tumors-two sides of the same coin. Int. J. Mol. Sci. 23, 5122 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Morotti, A. et al. The long non-coding BC200 is a novel circulating biomarker of parathyroid carcinoma. Front. Endocrinol. 13, 869006 (2022).

    Article  Google Scholar 

  120. Zhang, Y. et al. Exosome-transmitted lncRNA H19 inhibits the growth of pituitary adenoma. J. Clin. Endocrinol. Metab. 104, 6345–6356 (2019).

    Article  PubMed  Google Scholar 

  121. Sanchez, A., Lhuillier, J., Grosjean, G., Ayadi, L. & Maenner, S. The long non-coding RNA ANRIL in cancers. Cancers 15, 4160 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Wu, Z. R. et al. Inhibition of mTORC1 by lncRNA H19 via disrupting 4E-BP1/Raptor interaction in pituitary tumours. Nat. Commun. 9, 4624 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Campolo, F. et al. Platelet-derived circRNAs signature in patients with gastroenteropancreatic neuroendocrine tumors. J. Transl. Med. 21, 548 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. MacLellan, S. A., MacAulay, C., Lam, S. & Garnis, C. Pre-profiling factors influencing serum microRNA levels. BMC Clin. Pathol. 14, 27 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  125. Ammerlaan, W. & Betsou, F. Intraindividual temporal miRNA variability in serum, plasma, and white blood cell subpopulations. Biopreserv. Biobank 14, 390–397 (2016).

    Article  CAS  PubMed  Google Scholar 

  126. Shende, V. R., Goldrick, M. M., Ramani, S. & Earnest, D. J. Expression and rhythmic modulation of circulating microRNAs targeting the clock gene Bmal1 in mice. PLoS ONE 6, e22586 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Ameling, S. et al. Associations of circulating plasma microRNAs with age, body mass index and sex in a population-based study. BMC Med. Genomics 8, 61 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Giardina, S. et al. Changes in circulating miRNAs in healthy overweight and obese subjects: effect of diet composition and weight loss. Clin. Nutr. 38, 438–443 (2019).

    Article  CAS  PubMed  Google Scholar 

  129. Mantilla-Escalante, D. C. et al. Postprandial circulating miRNAs in response to a dietary fat challenge. Nutrients 11, 1326 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Li, F. et al. Long-term exercise alters the profiles of circulating Micro-RNAs in the plasma of young women. Front. Physiol. 11, 372 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Ferrero, G. et al. Intake of natural compounds and circulating microRNA expression levels: their relationship investigated in healthy subjects with different dietary habits. Front. Pharmacol. 11, 619200 (2020).

    Article  CAS  PubMed  Google Scholar 

  132. Perge, P., Nagy, Z., Decmann, Á., Igaz, I. & Igaz, P. Potential relevance of microRNAs in inter-species epigenetic communication, and implications for disease pathogenesis. RNA Biol. 14, 391–401 (2017).

    Article  PubMed  Google Scholar 

  133. Manca, S. et al. Milk exosomes are bioavailable and distinct microRNA cargos have unique tissue distribution patterns. Sci. Rep. 8, 11321 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Kornienko, A. E. et al. Long non-coding RNAs display higher natural expression variation than protein-coding genes in healthy humans. Genome Biol. 17, 14 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Li, L. et al. Comprehensive analysis of circRNA expression profiles in humans by RAISE. Int. J. Oncol. 51, 1625–1638 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. McDonald, J. S., Milosevic, D., Reddi, H. V., Grebe, S. K. & Algeciras-Schimnich, A. Analysis of circulating microRNA: preanalytical and analytical challenges. Clin. Chem. 57, 833–840 (2011).

    Article  CAS  PubMed  Google Scholar 

  137. Darvasi, O. et al. Limitations of high throughput methods for miRNA expression profiles in non-functioning pituitary adenomas. Pathol. Oncol. Res. 25, 169–182 (2019).

    Article  CAS  PubMed  Google Scholar 

  138. Li, F., Yang, Q., He, A. T. & Yang, B. B. Circular RNAs in cancer: limitations in functional studies and diagnostic potential. Semin. Cancer Biol. 75, 49–61 (2021).

    Article  CAS  PubMed  Google Scholar 

  139. Marabita, F. et al. Normalization of circulating microRNA expression data obtained by quantitative real-time RT-PCR. Brief. Bioinform. 17, 204–212 (2016).

    Article  PubMed  Google Scholar 

  140. Chevillet, J. R., Lee, I., Briggs, H. A., He, Y. & Wang, K. Issues and prospects of microRNA-based biomarkers in blood and other body fluids. Molecules 19, 6080–6105 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Faraldi, M. et al. Normalization strategies differently affect circulating miRNA profile associated with the training status. Sci. Rep. 9, 1584 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  142. Das, A. V. & Pillai, R. M. Implications of miR cluster 143/145 as universal anti-oncomiRs and their dysregulation during tumorigenesis. Cancer Cell Int. 15, 92 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Zhang, F. & Cao, H. MicroRNA-143-3p suppresses cell growth and invasion in laryngeal squamous cell carcinoma via targeting the k-Ras/Raf/MEK/ERK signaling pathway. Int. J. Oncol. 54, 689–701 (2019).

    CAS  PubMed  Google Scholar 

  144. Takai, T. et al. Synthetic miR-143 exhibited an anti-cancer effect via the downregulation of K-RAS networks of renal cell cancer cells in vitro and in vivo. Mol. Ther. 27, 1017–1027 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Max, K. E. A. et al. Plasma microRNA interindividual variability in healthy individuals, pregnant women, and an individual with a stably altered neuroendocrine phenotype. Clin. Chem. 67, 1676–1688 (2021).

    Article  PubMed  Google Scholar 

  146. Cai, S. et al. Single-molecule amplification-free multiplexed detection of circulating microRNA cancer biomarkers from serum. Nat. Commun. 12, 3515 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Mugoni, V. et al. Integrating extracellular vesicle and circulating cell-free DNA analysis using a single plasma aliquot improves the detection of HER2 positivity in breast cancer patients. J. Extracell. Biol. 2, e108 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Hücker, S. M. et al. Single-cell microRNA sequencing method comparison and application to cell lines and circulating lung tumor cells. Nat. Commun. 12, 4316 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Del Valle, I. et al. An integrated single-cell analysis of human adrenal cortex development. JCI Insight 8, e168177 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors acknowledge support from the Hungarian National Research, Development and Innovation Office (NKFIH) (grants K134215 and K146906 to P.I. and FK135065 to H.B.), TKP2021-EGA-24 from the National Research, Development and Innovation Fund by the Ministry of Innovation and Technology of Hungary financed under the (TKP2021-EGA) funding scheme. H.B.’s work is supported by the Bolyai Research Fellowship of the Hungarian Academy of Sciences and New National Excellence Program of the Ministry of Human Capacities (UNKP-22-5-SE-1). The National Tumour Biology Laboratory is funded by the Ministry of Innovation and Technology of Hungary (H.B. and A.P.). The authors thank B. Antal (Semmelweis University) for his help with the design of Figs. 2 and 3. B. Antal was supported by the National Academy of Scientist Education Program of the National Biomedical Foundation under the sponsorship of the Hungarian Ministry of Culture and Innovation.

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Butz, H., Patócs, A. & Igaz, P. Circulating non-coding RNA biomarkers of endocrine tumours. Nat Rev Endocrinol (2024). https://doi.org/10.1038/s41574-024-01005-8

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