MiRNA Signatures Related to Invasiveness and Recurrence in Patients With Non-Functioning Pituitary Neuroendocrine Tumors

Abstract

Purpose: This preliminary study aimed to analyze and identify differentially expressed miRNAs in Bulgarian patients with non-functioning pituitary neuroendocrine tumors (NFPitNET). The relationship between deregulated miRNAs and tumor invasiveness, recurrence, and size was determined.

Methods: Twenty patients with NFPitNET were selected and fresh pituitary tumor tissues were collected. RNA containing miRNAs were isolated using miRNAeasy mini kit and analyzed by quantitative real-time polymerase chain reaction (PCR) using LNA miRNA Cancer-Focus PCR Panel (Qiagen).

Results: Three miRNAs (miR-210-3p, miR-149-3p, and miR-29b-3p) were deregulated in invasive compared to non-invasive NFPitNETs. Differential expression of four-miRNA signatures – miRNA-17, miR-19, miR-106a, and miR-20, correlated with patient recurrence.

Conclusion: This prospective pilot study selected a unique miRNA expression profile, that correlates with invasiveness and recurrence in non-functioning pituitary neuroendocrine tumors. Moreover, some of the selected miRNAs are reported for the first time in patients with this disease, shedding light on the molecular mechanisms involved in pituitary pathogenesis. The identified miRNAs demonstrate potential as biomarkers, deserving further investigation in a larger cohort to validate their clinical applicability.

Keywords

miRNA - non-functioning pituitary neuroendocrine tumors - invasion - recurrence

Publication History

Received: 27 July 2023
Received: 29 January 2024

Accepted: 06 February 2024

Accepted Manuscript online:
14 February 2024

Article published online:
15 April 2024

• References

• 1 Ezzat S, Asa SL, Couldwell WT. et al. The prevalence of pituitary adenomas: A systematic review. Cancer 2004; 101: 613-619
• 2 Chanson P, Raverot G, Castinetti F. et al. Management of clinically non-functioning pituitary adenoma. Ann Endocrinol (Paris) 2015; 76: 239-247
• 3 Raverot G, Burman P, McCormack A. et al. European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas. Eur J Endocrinol 2018; 178: G1-G24
• 4 Dekkers OM, Pereira AM, Roelfsema F. et al. Observation alone after transsphenoidal surgery for nonfunctioning pituitary macroadenoma. J Clin Endocrinol Metab 2006; 91: 1796-1801
• 5 Ragel BT, Couldwell WT. Pituitary carcinoma: A review of the literature. Neurosurg Focus 2004; 16: E7
• 6 Ezzat S, Asa SL. Mechanisms of disease: The pathogenesis of pituitary tumors. Nat Clin Pract Endocrinol Metab 2006; 2: 220-230
• 7 Wei Z, Zhou C, Liu M. et al. MicroRNA involvement in a metastatic non-functioning pituitary carcinoma. Pituitary 2015; 18: 710-721
• 8 Bartel DP. Metazoan MicroRNAs. Cell 2018; 173: 20-51
• 9 Paranjape T, Slack FJ, Weidhaas JB. MicroRNAs: Tools for cancer diagnostics. Gut 2009; 58: 1546-1554
• 10 Zhang B, Pan X, Cobb GP. et al. microRNAs as oncogenes and tumor suppressors. Dev Biol 2007; 302: 1-12
• 11 Ciafrè SA, Galardi S, Mangiola A. et al. Extensive modulation of a set of microRNAs in primary glioblastoma. Biochem Biophys Res Commun 2005; 334: 1351-1358
• 12 Gadelha M, Kasuki J, Dénes J. et al. MicroRNAs: Suggested role in pituitary adenoma pathogenesis. J Endocrinol Invest 2013; 36: 889-895
• 13 Melmed S. Pathogenesis of pituitary tumors. Nat Rev Endocrinol 2011; 7: 257-266
• 14 Di Ieva A, Butz H, Niamah M. et al. MicroRNAs as biomarkers in pituitary tumors. Neurosurgery 2014; 75: 181-188
• 15 Butz H, Likó I, Czirják S. et al. MicroRNA profile indicates downregulation of the TGFβ pathway in sporadic non-functioning pituitary adenomas. Pituitary 2011; 14: 112-124
• 16 Wu S, Gu Y, Huang Y. et al. Novel biomarkers for non-functioning invasive pituitary adenomas were identified by using analysis of microRNAs expression profile. Biochem Genet 2017; 55: 253-267
• 17 Gruppetta M, Mercieca C, Vassallo J. Prevalence and incidence of pituitary adenomas: A population based study in Malta. Pituitary 2013; 16: 545-553
• 18 Yoshino H, Yonemori M, Miyamoto K. et al. microRNA-210-3p depletion by CRISPR/Cas9 promoted tumorigenesis through revival of TWIST1 in renal cell carcinoma. Oncotarget 2017; 8: 20881-20894
• 19 Vicchio TM, Aliquò F, Ruggeri RM. et al. MicroRNAs expression in pituitary tumors: Differences related to functional status, pathological features, and clinical behavior. J Endocrinol Invest 2020; 43: 947-958
• 20 Zhao P, Cheng J, Li B. et al. Up-regulation of the expressions of MiR-149-5p and MiR-99a-3p in exosome inhibits the progress of pituitary adenomas. Cell Biol Toxicol 2021; 37: 633-651
• 21 Yan B, Guo Q, Fu FJ. et al. The role of miR-29b in cancer: Regulation, function, and signaling. Onco Targets Ther 2015; 8: 539-548
• 22 Xia J, Li S, Ma D. et al. MicroRNA-29-3p regulates the β-catenin pathway by targeting IGF1 to inhibit the proliferation of prolactinoma cells. Mol Med Rep 2021; 23: 1-9
• 23 García-Martínez A, López-Muñoz B, Fajardo C. et al. Increased E2F1 mRNA and miR-17-5p expression is correlated to invasiveness and proliferation of pituitary neuroendocrine tumours. Diagnostics 2020; 10: 1-13
• 24 Ma Q, Peng Z, Wang L. et al. MiR-19a correlates with poor prognosis of clear cell renal cell carcinoma patients via promoting cell proliferation and suppressing PTEN/SMAD4 expression. Int J Oncol 2016; 49: 2589-2599
• 25 Wang W, Liu L, Tian Y. miR-19-3p targets PTEN to regulate cervical cancer cell proliferation, invasion, and autophagy. Genet Res (Camb) 2023; 2023: 4784500
• 26 Lu WD, Zuo Y, Xu Z. et al. MiR-19a promotes epithelial-mesenchymal transition through PI3K/AKT pathway in gastric cancer. World J Gastroenterol 2015; 21: 4564-4573
• 27 Niu Y, Zhou H, Liu Y. et al. MiR-16 regulates proliferation and apoptosis of pituitary adenoma cells by inhibiting HMGA2. Oncol Lett 2019; 17: 2491-2497
• 28 Cabana-Domínguez J, Arenas C, Cormand B. et al. MiR-9, miR-153 and miR-124 are down-regulated by acute exposure to cocaine in a dopaminergic cell model and may contribute to cocaine dependence. Transl Psychiatry 2018; 8: 173
• 29 Gangisetty O, Jabbar S, Wynne O. et al. MicroRNA-9 regulates fetal alcohol-induced changes in D2 receptor to promote prolactin production. J Endocrinol 2017; 235: 1-14
• 30 He Z, Chen L, Wang Q. et al. MicroRNA-186 targets SKP2 to induce p27Kip1-mediated pituitary tumor cell cycle deregulation and modulate cell proliferation. Korean J Physiol Pharmacol 2019; 23: 171-179
• 31 Németh K, Darvasi O, Likó I. et al. Comprehensive analysis of circulating miRNAs in the plasma of patients with pituitary adenomas. J Clin Endocrinol Metab 2019; 104: 4151-1468
• 32 Lu B, Liu GL, Yu F. et al. MicroRNA-16/VEGFR2/p38/NF-KB signaling pathway regulates cell growth of human pituitary neoplasms. Oncol Rep 2018; 39: 1235-1244
• 33 Belaya Z, Khandaeva P, Nonn L. et al. Circulating plasma microRNA to differentiate Cushing’s disease from ectopic ACTH syndrome. Front Endocrinol (Lausanne) 2020; 11: 1-8
• 34 Zhao S, Li J, Feng J. et al. Identification of serum miRNA-423-5p expression signature in somatotroph adenomas. Int J Endocrinol 2019; 2019
• 35 Licursi V, Conte F, Fiscon G. et al. MIENTURNET: An interactive web tool for microRNA-target enrichment and network-based analysis. BMC Bioinformatics 2019; 20: 545
• 36 Wang Y, Cheng T, Lu M. 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
• 37 Kowarik M, Onofri C, Colaco T. et al. Platelet-derived growth factor (PDGF) and PDGF receptor expression and function in folliculostellate pituitary cells. Exp Clin Endocrinol Diabetes 2010; 118: 113-120
• 38 Yao X, Liu Q, Zhao S. et al. Expression and clinical significance of MDM2 in non-functioning PitNETs. Medicina (Kaunas) 2023; 59: 373
• 39 Yao X, Gao H, Li C. et al. Analysis of Ki67, HMGA1, MDM2, and RB expression in nonfunctioning pituitary adenomas. J Neuroonco 2017; 132: 199-206
• 40 Cohen JI. Herpesviruses in the activated phosphatidylinositol-3-kinase-δ syndrome. Front Immunol 2018; 9: 237