The anterior pituitary gland plays a pivotal role in the endocrine system and comprises a diverse array of cells, including six primary hormone-secreting types: prolactin (PRL), growth hormone (GH), adrenocorticotrophic hormone (ACTH), thyrotrophic hormone (TSH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH). The hormones secreted by this gland control multiple body processes, such as growth, cell metabolism, and reproduction. The gland also hosts other non-secretory cells, such as follicular-stellate and endothelial cells, which contribute to its structural integrity and overall functionality [1, 2].
Pituitary neuroendocrine tumors (PitNETs) affect approximately 5% of people globally and pose significant challenges in neuroendocrinology [3–5]. They are a prevalent cause of brain tumors, distinguished by their hormonal overexpression profiles, which include the most common lactotroph and the rarer thyrotrophic tumors. The clinical manifestations of these tumors can be significant, with somatotroph adenomas leading to acromegaly in adults and gigantism in children due to excess growth hormone (GH) and insulin-like growth factor 1 (IGF-1) production [4].
As common functional PitNETs, somatotroph adenomas arise from PIT1 lineage cells and cause acromegaly due to excessive GH and IGF-1 levels. High GH/IGF-1 serum levels lead to comorbidities, including arthritis, facial changes, prognathism, and glucose intolerance [5, 6]. The treatment landscape for PitNETs typically involves surgery, which is successful in about 70% of cases. However, the effectiveness of pharmacological treatments, such as somatostatin analogs (SSAs), varies significantly among patients, highlighting the need for more detailed molecular insights to guide therapy choices [7–9]. Unfortunately, the factors determining a patient's positive or negative response to treatment with SSAs, such as pasireotide and temozolomide, remain unclear [7–9]. Despite advancements in histopathological categorization, the molecular basis of GH PitNETs remains inadequately understood, partly due to the scarcity of preclinical models and surgical specimens available for research [10].
In the last few years a more profound molecular characterization of PitNETs has revolutionized this field of research thanks to several molecular biology studies and omics approaches, strengthening prediction capacity of better understanding patient's responsiveness to pharmacological and/or surgical treatments [3, 11, 12]. In addition, recent developments in molecular biology, particularly those involving noncoding RNAs (ncRNAs) such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), have provided new perspectives on the pathogenesis of PitNETs. These ncRNAs play crucial roles in gene regulation, influencing cellular processes like proliferation and apoptosis, which are central to tumor development and progression. Their study has begun to unravel the complex molecular interactions underlying PitNETs, offering potential for novel diagnostic and therapeutic strategies [3, 13, 14].
Recent studies have proposed that noncoding RNAs can regulate the progression of pituitary tumors, including somatotropinomas, by altering the expression of genes involved in cell proliferation and apoptosis, among other processes. Specifically, somatotropinomas exhibit frequent variation in the expression of the following transcripts: mRNAs such as T-PIT, NF1, NR5A1 (SF1), PIT-1, PRKARIA, GPR101, DRD2; miRNAs associated with the long noncoding RNA MEG3 and miR532-let7 (miR-574, miR-195, miR-497-5p e let-7) cluster, and lncRNA such as H19. Recurrent alterations in the expression of coding genes, such as MEN1, MGMT, AIP, GNAS, USP48, and USP8, have also been found in other PitNET subtype [3, 13, 15, 16]. However, the specific role of noncoding RNAs in pituitary tumorigenesis and their potential use as therapeutic targets or predictive biomarkers for the treatment response in pituitary adenomas, including somatotropinomas, remains to be fully elucidated.
This introduction underscores the significance of advancing our understanding of the molecular characteristics of GH-secreting PitNETs. Leveraging cutting-edge techniques, such as Laser Capture Microscopy (LCM) from formalin-fixed paraffin-embedded (FFPE) tissues coupled with high-throughput RNA sequencing analysis, can help identify new biomarkers and therapeutic targets. Such efforts promise to refine precision medicine approaches for treating PitNETs, potentially leading to more effective and targeted interventions. By exploring the molecular landscape of these tumors, mainly through the analysis of ncRNA expression, we might provide novel information that are helpful in neuroendocrinology diagnosing and managing one of the most common intracranial tumors.