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AIP-related pituitary adenoma predisposition

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of AIP-related pituitary adenoma predisposition. Core disease mechanisms, mol...

2026-04-22
Asta Model: Asta Scientific Corpus Retrieval 20 citations

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of AIP-related pituitary adenoma predisposition. Core disease mechanisms, mol...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 20
  • Snippets retrieved: 20

Relevant Papers

[1] AIP mutations in Brazilian patients with sporadic pituitary adenomas: a single-center evaluation

  • Authors: P. B. Araújo, L. Kasuki, Carlos Henrique de Azeredo Lima, L. Ogino, A. Camacho et al.
  • Year: 2017
  • Venue: Endocrine Connections
  • URL: https://www.semanticscholar.org/paper/e16e8321121c727ca387d8f7b4e5ca239d95e542
  • DOI: 10.1530/EC-17-0237
  • PMID: 29074612
  • PMCID: 5704447
  • Citations: 12
  • Influential citations: 1
  • Summary: The study identified two mutations exclusively found in Brazilians and also shows, for the first time, loss of heterozygosity in tumor DNA from an acromegaly patient harboring the A299V AIPmut.
  • Evidence snippets:
  • Snippet 1 (score: 0.601) > Although most pituitary adenomas occur sporadically, with only 5% of all cases being related to inherited syndromes (1), the mechanisms underlying pituitary tumorigenesis in a non-familial setting are poorly understood. Somatic mutations and other genetic and/or epigenetic abnormalities have been related to SPA, but a minor subgroup of these adenomas can have a germline mutation in a predisposing gene with no known familial history of pituitary adenoma (2). Germline aryl hydrocarbon receptor-interacting protein (AIP) gene mutations (AIPmut) were first described by Vierimaa and coworkers in 2006 (3). This study has found AIPmut in seemingly sporadic acromegaly patients and in familial isolated pituitary adenomas (FIPA) (3), which is characterized by the presence of pituitary adenomas in two or more members of the same family in the absence of other syndromic clinical features. > AIP appears to act as a tumor suppressor gene (TSG) (3). It is a cytoplasmic protein and a co-chaperone of heat-shock protein 90 (HSP90), and several studies demonstrated the involvement of AIP in various nuclear receptor signaling pathways, such as in estrogen receptor α (ERA) and glucocorticoid receptor (GR) signaling pathways (4,5,6). However, the exact molecular mechanisms by which AIPmut promotes pituitary adenomas are unclear. There is evidence that a failure to inhibit cyclic adenosine monophosphate (cAMP) synthesis underlies the development of pituitary adenomas in AIPmut patients (7). The observation of loss of heterozygosity (LOH) at the chromosome 11q13 in pituitary adenomas containing AIPmut provides another argument for the role of these genetic mutations in pituitary tumorigenesis (3,8). Functional evaluation of AIPmut has shown reduced ability to inhibit cell proliferation and disruption of the protein-protein interaction between AIP and phosphodiesterase-4A5 (PDE4A5) (9).

[2] Landscape of Molecular Events in Pituitary Apoplexy

  • Authors: Prakamya Gupta, P. Dutta
  • Year: 2018
  • Venue: Frontiers in Endocrinology
  • URL: https://www.semanticscholar.org/paper/55e86f595e73f18ecf8b038db544a8418d4e7264
  • DOI: 10.3389/fendo.2018.00107
  • PMID: 29615979
  • PMCID: 5869273
  • Citations: 21
  • Summary: The various proteins/cytokines/growth factors and signaling molecules which are involved in the pathogenesis of pituitary apoplexy and their potential role as biomarkers or as therapeutic targets are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.577) > Pituitary apoplexy is currently defined as a clinical symptom that can be confirmed radiologically or pathologically. Due to scanty literature in the field, this review proposes the possible underlying pathways responsible for pituitary apoplexy in terms of analyzing a bunch of molecular targets, i.e., VEGF, TNF-α, HIF-1α, MMP-2/9, PTTG, and Ki-67. The analysis of possible constituents of pituitary apoplexy pathways is seemingly relative not encircling the long list of predefined molecules. However, including basic molecular studies of cell damage, namely intrinsic (cellular suicide, e.g., apoptosis) and extrinsic (external threat from surrounding) pathways will help in deciphering the exact mechanism of pituitary apoplexy. Moreover, unknown genes, cytokines, proteins might be involved in two major phenomena such as hemorrhage and infarction by being most effective pathogenetic mechanisms of pituitary apoplexy. > Despite extensive research on pituitary adenoma, there is scanty literature on the etio-pathogenesis of apoplectic pituitary adenoma. Genomics, proteomic, and metabolomics study on large sample sizes are needed to better understand the mechanism and thus may help in the management of patients with pituitary apoplexy.

[3] Novel Insights into Pituitary Tumorigenesis: Genetic and Epigenetic Mechanisms

  • Authors: Vinaya Srirangam Nadhamuni, M. Korbonits
  • Year: 2020
  • Venue: Endocrine Reviews
  • URL: https://www.semanticscholar.org/paper/73f7cd16dd35ae141782ba38f0bb1d6f046e86cc
  • DOI: 10.1210/endrev/bnaa006
  • PMID: 32201880
  • PMCID: 7441741
  • Citations: 76
  • Influential citations: 1
  • Summary: Insights from the recent developments in the regulation of pituitary tumorigenesis are summarized and best studied in the emerging multiomics studies.
  • Evidence snippets:
  • Snippet 1 (score: 0.514) > • An increasing number of genes with germline mutations are known now to be associated with pituitary tumors, some causing syndromic disease while others isolated pituitary adenomas. > • Gain-of-function somatic mutations are common in somatotropinomas in the GNAS gene and in corticotropinomas in USP8. > • Other, less common somatic variants recently identified through next generation sequencing need to be confirmed in independent cohorts and elucidated through functional studies in the future. > • Epigenetic modifications (DNA methylation, histone modification, and noncoding RNAs) can greatly influence tumorigenesis and tumor characteristics such as subtype differentiation and local invasion. > • An integrated multiomics approach to characterize genetic and epigenetic pathways allows better understanding the molecular mechanisms that underlie pituitary tumorigenesis within and across the various subtypes and may lead to the identification of better prognostic factors. > although mostly identified as de novo mutation, has also been described in families (three kindreds described so far in the literature (25)(26)(27)(28)). However, patients with a suggestive family history with no known genetic cause form the majority of patients with FIPA. AIP mutation-positive pituitary tumors. The AIP gene maps to chromosome 11q13. 2 (29)(30)(31). The cAMP/ protein kinase A/phosphodiesterase pathway plays a key role in somatotroph physiology and acromegaly-related genetic syndromes (Fig. 3). Not surprisingly, therefore, a link has been found between this pathway and AIP at several levels: at the inhibitory Gαi-2 protein (32,33), at cAMP (34), at phosphodiesterase 4A (35)(36)(37), at protein kinase A (38,39), downstream of somatostatin receptors, and Zac1 (40,41) levels. AIP has also found interact and inhibit the endoplasmatic reticulum calcium channel ryanodine receptor in C. elegans (31), another pathway closely linked with hormone release, with somatic variants identified in calcium-related pathways in somatotrop

[4] Aggressive prolactinoma in a child related to germline mutation in the ARYL hydrocarbon receptor interacting protein (AIP) gene.

  • Authors: L. Naves, M. Jaffrain-Rea, S. Vencio, C. Jacomini, L. Casulari et al.
  • Year: 2010
  • Venue: Arquivos brasileiros de endocrinologia e metabologia
  • URL: https://www.semanticscholar.org/paper/cdacdb557de8fdaa8d5577e9fd5d2969047ecc9c
  • DOI: 10.1590/S0004-27302010000800017
  • PMID: 21340166
  • Citations: 19
  • Summary: Germline mutations in the AIP gene may be involved in the predisposition to pituitary adenoma formation, as cause or co-factor in pathogenesis of aggressive tumors in young patients.
  • Evidence snippets:
  • Snippet 1 (score: 0.502) > C linically relevant pituitary adenomas have a preva- lence of 1 case per 1064-1289 of the population and prolactinomas are the most common comprising 57%-66% of the total (1,2). As with all pituitary adenomas, prolactinomas are unfrequent in childhood, only about 3.5%-8.5% of pituitary adenomas are diagnosed before the age of 20 years and an indolent course may mean that tumors occurring in adolescents are not actually diagnosed until early adulthood (3,4). > Clinical presentation in childhood is variable and symptoms related to tumor growth are the most prevalent. In young children, decrease in growth velocity is a rare symptom, what could contribute to subclinical disease evolution and the delay in diagnosis. Impairment of gonadal axis is the most frequent endocrine disorder in late childhood and adolescence, leading to delayed puberty (4-6). > First-line treatment of prolactinomas relies on dopamine agonists, such as, cabergoline, and relative or complete resistance is very uncommon. Clinical factors associated with tumor aggressiveness and resistance to dopamine agonists include young age at onset, male gender, large tumor size or cavernous sinus invasion at diagnosis (7)(8)(9)(10). > Despite many genetic abnormalities being described, the molecular pathophysiology of prolactinomas, particularly those with an aggressive clinical course, remains largely obscure. Recently, germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene, were reported to be involved in the predisposition to pituitary adenoma formation (11,12). > Patients with AIP mutations have pituitary adenomas at a younger age, which are often large at diagnosis, suggesting an aggressive phenotype. These tumors usually occur in the familial isolated pituitary adenomas (FIPA) setting (13,14) and sporadic pituitary tumors firstly appeared to be very rare (15)(16). Recently, AIP mutations related to sporadic tumors have been increasingly reported in young patients (17,18).

[5] Childhood Multiple Endocrine Neoplasia (MEN) Syndromes: Genetics, Clinical Heterogeneity and Modifying Genes

  • Authors: F. Lanzaro, Delia De Biasio, Francesco Giustino Cesaro, E. Stampone, I. Tartaglione et al.
  • Year: 2024
  • Venue: Journal of Clinical Medicine
  • URL: https://www.semanticscholar.org/paper/bfd33b0ef807e95dcdeccab919ca54b88638745d
  • DOI: 10.3390/jcm13185510
  • PMID: 39336996
  • PMCID: 11432259
  • Citations: 3
  • Summary: Understanding factors and genetic variants that control cellular functions and the expression of disease genes should provide insights into fundamental disease processes, providing implications for counseling and therapeutic and prophylactic possibilities.
  • Evidence snippets:
  • Snippet 1 (score: 0.494) > As described before, the MEN1 phenotype varies between patients in terms of tumor localization, age of onset, and clinical aggressiveness, even between affected members within the same family. Additional co-segregating modifying factors, such as germline mutations in other genes, or epigenetic changes or post-translational protein modifications, likely contribute to the interfamilial variability of MEN 1 [18]. > For example, the gene encoding for the aryl hydrocarbon receptor interacting protein (AIP) is located on 11q13, near the MEN1 gene but approximately 3 mb away. Inactivating mutations and deletions in the AIP gene predispose individuals to low-penetrance pituitary adenomas. Concurrent deletions involving these genes may contribute to predisposition to MEN1 and pituitary adenoma [71], as has been already postulated for the pathogenesis of the brown fat tumor hibernoma [72]. Although no preclinical models or clinical direct evidence have been produced in the MEN1 setting, patients with particularly aggressive pituitary adenomas associated with MEN1 syndrome might be considered for either AIP gene analysis or expression and functional protein assessments, which could help explain the aggressive phenotype. > The aryl hydrocarbon receptor-interacting protein (AIP) is a relatively understudied HSP90 and HSC70 co-chaperone, consisting of 330 amino acids, with a potential role as both a tumor suppressor and an oncogene involved in the cAMP-phosphodiesterase pathway. Common AIP variants (AIPvar) include nonsense and missense mutations, deletions, insertions, splice-site and promoter mutations, and large deletions, most of which lead to a truncated protein or, less commonly, affect the tetratricopeptide repeat (TPR) domains or the C-terminal α-helix.

[6] Expression and Clinical Significance of miR-26a and Pleomorphic Adenoma Gene 1 (PLAG1) in Invasive Pituitary Adenoma

  • Authors: Chuan-ting Yu, Jixia Li, Fengnan Sun, Jinpeng Cui, Huali Fang et al.
  • Year: 2016
  • Venue: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research
  • URL: https://www.semanticscholar.org/paper/4615a7684601a27e4dac6bda9456ff79de0942bc
  • DOI: 10.12659/MSM.898908
  • PMID: 28012286
  • PMCID: 5207015
  • Citations: 28
  • Summary: MiR-26a can facilitate occurrence of pituitary tumor and invasiveness, probably via inhibiting PLAG1 expression.
  • Evidence snippets:
  • Snippet 1 (score: 0.474) > Pituitary tumors are monoclonal tumors originating from residual epithelial cells of anterior/posterior pituitary and cranial-pharyngeal tissues, and account for about 10~15% of all intracranial tumors. A previous study has confirmed the benign nature of most pituitary tumors. Clinically, however, about onethird of all pituitary tumors showed invasive growth, which is a biological behavioral of malignant tumors. Such pituitary adenomas often show aggressive growth toward peripheral tissues/nerves, and thus are termed invasive pituitary tumors. Invasive pituitary tumors have rapid progression, are difficult to completely removal during surgery, and have higher shortterm recurrence rate after surgery, making clinical treatment a major challenge. The invasive growth of pituitary tumor is one important factor causing the recurrence of disease, further affecting clinical treatment efficacy and prognosis. Recent studies have focused on the mechanism directing pituitary tumor proliferation, activation of oncogenes, and inactivation of tumor suppression genes, but the biological mechanism affecting tumor invasion/migration is still not fully understood. For instance, CCND1 gene, a proto-oncogene, plays a role in pituitary tumorigenesis and invasiveness and its polymorphism in patients with different types of sporadic pituitary adenomas were determined [21]. Hypoxia can increase the expression of DDR1, a newly discovered kind of tyrosine kinase receptor on the cell surface, which in turn promotes pituitary adenoma cell proliferation and invasion [22]. In particular, a recent finding showed that the expression of Cold-Inducible RNA-Binding Protein (CIRP) in pituitary adenomas is closely related with tumor proliferation and invasion, and its significantly elevated expression level indicates post-operative recurrence [23]. Therefore, understanding the invasion/migration mechanism and identifying the specific molecular marker for acquiring invasion/migration property are of critical importance for early diagnosis of pituitary tumors, broadening clinical treatment strategy, improving treatment efficacy, and guiding individualized treatment. With the advancement of molecular biology, the pathogenesis mechanism of IPA has been illustrated from the molecular level by some scholars.

[7] Isolated familial somatotropinoma: 11q13-loh and gene/protein expression analysis suggests a possible involvement of aip also in non-pituitary tumorigenesis

  • Authors: R. Toledo, B. Mendonca, M. Fragoso, I. Soares, M. Almeida et al.
  • Year: 2010
  • Venue: Clinics
  • URL: https://www.semanticscholar.org/paper/7baae2cb07fdafba37f12c628dd34c158b8096be
  • DOI: 10.1590/S1807-59322010000400010
  • PMID: 20454499
  • PMCID: 2862671
  • Citations: 35
  • Summary: The finding of AIP inactivation in the adrenocortical tumor suggests that further investigation of the potential role of this recently identified tumor suppressor gene in non-pituitary tumors, mainly in those tumors in which the cAMP and the 11q13 locus are implicated, is likely to be worthwhile.
  • Evidence snippets:
  • Snippet 1 (score: 0.472) > Acromegaly/gigantism is characterized by excess of growth hormone (GH) largely due to GH-secreting pituitary adenomas. 1 Although most cases are sporadic, familial forms may occur in association with inherited syndromes such as Multiple Endocrine Neoplasia type 1 (MEN1), Carney complex (CNC), pituitary adenoma predisposition (PAP) and familial isolated pituitary adenoma (FIPA), which includes isolated familial somatotropinoma (IFS). [2][3][4] Germline mutations and somatic inactivation of the aryl hydrocarbon receptor-interacting protein (AIP) gene have been recently identified in patients with PAP. 2 The role of AIP in FIPA patients has been confirmed, and more than thirty different AIP inactivating mutations have been identified throughout the gene. 5 GH-, GH/PRL-and PRLsecreting pituitary adenomas are the most common clinical features of AIP mutation carriers, although ACTH-secreting and non-functioning pituitary adenomas have also been reported. 5,6 AIP mutations account for approximately 15% of families with FIPA and 50% of IFS families. 3,5 While AIP mutations appear to be very rare in cases with sporadic pituitary disease, 7,8,9 they are more frequently found in children and adolescents with GH-secreting tumors, even in the absence of family history. 10 Although no systematic clinical surveys of non-pituitary neoplasia have been reported, concomitant non-pituitary tumors, including thyroid, adrenal and MEN1-related tumors were reported in a subset of AIP mutation-positive PAP and FIPA families 10,11 and Prof. Albert Beckers, FIPA Meeting, Liège 2009 (unpublished data). The fact that AIP interacts with phosphodiesterases type 4A (PDE4A) and type 2A (PDE2A) implicates this gene in the cyclic AMP (cAMP) signaling cascade, 12,13 a cellular pathway known to be disrupted in pituitary, but also in thyroid and ad

[8] Macroprolactinoma in a Patient With Schizophrenia: A Therapeutic Challenge

  • Authors: E. Voelz, L. Matias, M. Student, M. Medeiros, Murilo D Pimentel
  • Year: 2021
  • Venue: Journal of the Endocrine Society
  • URL: https://www.semanticscholar.org/paper/696f918472b1dded0b3170d8b7f6ddd4f0946979
  • DOI: 10.1210/jendso/bvab048.1206
  • PMCID: 8090302
  • Citations: 1
  • Summary: It is necessary to analyze prolactin levels, imaging tests and the prescription of antipsychotic medications for correct analysis and evaluation of prolact inomas in schizophrenic patients.
  • Evidence snippets:
  • Snippet 1 (score: 0.469) > Background: Germline mutations in the Aryl hydrocarbon receptor-Interacting Protein (AIP) gene are associated with pituitary adenomas in young patients usually in the setting of Familial Isolated Pituitary Adenomas (FIPA). The majority of these adenomas are somatotropinomas followed by prolactinomas, and rarely non-secreting adenomas. AIP-mutation-related prolactinomas predominantly affect men, as opposed to sporadic prolactinomas, that typically affect women. Clinical Case: We previously described an AIP gene mutation in two patients affected by prolactinomas. During the past years, we continued our study and have identified two more male patients with macroprolactinomas originally from the same small village and harboring the same AIP gene mutation. These male patients aged 19 to 44 years at the time of diagnosis. Two of them had neurological manifestations as the first clinical manifestation of the disease, one was studied because of hypogonadism and two patients had visual field defects. All of them had prolactin levels above 1000 ng/dl (mean 2946.5±948.7 ng/dl, reference range 10-21). In the imaging exams (CT/MRI) they presented pituitary adenomas larger than 20 mm (macroprolactinomas) and in two of the cases, the adenomas were even larger than 40 mm (giant prolactinomas). In order to exclude mutations most often associated with prolactinomas, DNA samples were obtained and analyzed by Next Generation Sequencing (NGS) using TruSightCancer Gene Set (Illumina) methodology. Investigation of significant deletions and/or duplications was performed using the MLPA (Multiplex ligation-dependent probe amplification) technique. None of the patients were positive for mutations of Multiple Endocrine Neoplasia type 1 (MEN1) gene. A variant of the AIP gene c.47G>A, expecting to lead to a substitution of arginine by histidine at position 16 (p.Arg16His) of the AIP was found in these four patients, including a father and his son.

[9] Aryl hydrocarbon receptor (AHR) is a potential tumour suppressor in pituitary adenomas

  • Authors: Robert Formosa, J. Borg, J. Vassallo, J. Vassallo
  • Year: 2017
  • Venue: Endocrine-Related Cancer
  • URL: https://www.semanticscholar.org/paper/d93ab1b8deb2488ce89e9c686679c1c6ecf1118b
  • DOI: 10.1530/ERC-17-0112
  • PMID: 28649092
  • PMCID: 5541251
  • Citations: 28
  • Influential citations: 1
  • Summary: Functional studies support a mechanistic pathway for the putative tumour suppressive role of AHR specifically in PA, possibly through its role as a cell cycle co-regulator, even in the absence of exogenous ligands.
  • Evidence snippets:
  • Snippet 1 (score: 0.464) > Pituitary adenomas (PA) represent the commonest cranial neoplasms and vary in size, type and aggressiveness.Clinically relevant PAs result in symptoms due to hormonal hypersecretion, intracranial mass effects or secondary hypopituitarism and locally occur with an average prevalence of approximately 76/100,000 (Gruppetta et al. 2013).The vast majority of PAs are sporadic in origin with only a small number of significant genetic mutations identified in relatively rare familial cases and endocrine syndromes.The heterogenous nature of PAs poses challenges in the elucidation of the molecular mechanisms driving their formation and progression 24:8 (Asa et al. 2017).This contrasts significantly with current knowledge in relation to malignant tumours. > Certain key pathways have already garnered a great deal of attention, including the cAMP secondary messenger signalling pathway, the Wnt signalling pathway and the pI3K/Akt signalling pathways (Chambers et al. 2013, Formosa & Vassallo 2014, Monsalves et al. 2014, Peverelli et al. 2014).However, even collectively, these molecular pathways do not cater for the entirety of the mechanisms that are responsible for the development and/or progression of PAs, making our understanding of the disease as yet limited.Several studies using highthroughput techniques including microarray studies and large-scale sequencing have identified a number of interesting pathways (Moreno et al. 2005, Morris et al. 2005, Evans et al. 2008, Jiang et al. 2010, Newey et al. 2013, Valimaki et al. 2015).In an attempt to uncover more molecular mechanisms driving Pas, we screened RNA profiles expressions of local tumours to uncover common altered pathways among a heterogeneous set of PAs.A consistently altered pathway observed implicated xenobiotic signalling. > The AHR is a ligand-activated transcription factor containing the basic helix-loop-helix (bHLH)/PAS domain mediating the response to a variety of environmental toxins (Burbach et al. 1992).

[10] The Mechanism and Pathways of Dopamine and Dopamine Agonists in Prolactinomas

  • Authors: Xiaoshuang Liu, Chao Tang, Guodao Wen, C. Zhong, Jin Yang et al.
  • Year: 2019
  • Venue: Frontiers in Endocrinology
  • URL: https://www.semanticscholar.org/paper/cb3b81abdb92e83c8be21aa966cb4926c31e4cd2
  • DOI: 10.3389/fendo.2018.00768
  • PMID: 30740089
  • PMCID: 6357924
  • Citations: 49
  • Influential citations: 2
  • Summary: The main aim of this paper is to review the different pathways of dopamine and its agonists in prolactinomas to help to gain a better understanding of their functions and drug resistance mechanisms.
  • Evidence snippets:
  • Snippet 1 (score: 0.461) > Pituitary adenomas (PAs) are common intracranial neoplasms. Typically, PAs are classified as either clinically non-functioning PAs or functioning PAs with characteristic clinical and endocrine symptoms, such as acromegaly and hyperprolactinemia or Cushing disease (1,2). > Prolactinomas are the most common type of functioning PAs, which can cause headache, visual dysfunction, hypopituitarism, and hyperprolactinemia (3). The clinical features of hyperprolactinemia include impotence in males and oligo/amenorrhea in females (4,5). The normalization of serum prolactin (PRL) levels and shrinkage of tumors are among the major goals of treatment in patients with prolactinomas (6). Dopamine agonists (DAs), such as bromocriptine (BRC) and cabergoline (CAB) are the first-line drugs for the treatment of patients with idiopathic hyperprolactinemia and prolactinomas (3,7). The lactotroph adenoma cells express dopamine receptors, and DAs effectively suppress prolactin secretion and shrink the tumor by binding the cell-surface dopamine receptors in most patients (7,8). This suggests that a "gene-network" may exist to regulate the activation of dopamine receptors, and may be involved in the mechanism of action of DAs for the treatment prolactinomas. > Although, two main DAs, namely BRC and CAB, have been approved as first-line drugs for the treatment of patients with hyperprolactinemia, a minority of patients with prolactinoma were resistant or intolerant to BRC, but responded adequately to CAB (9,10). Currently, a better understanding of the pathophysiology of prolactinomas and the precise mechanisms of action of DAs in prolactinomas is greatly needed, especially considering that different pharmacological compounds act on lactotroph cells through different intracellular molecular pathways.

[11] Dopamine and Somatostatin Analogues Resistance of Pituitary Tumors: Focus on Cytoskeleton Involvement

  • Authors: E. Peverelli, D. Treppiedi, E. Giardino, E. Vitali, A. Lania et al.
  • Year: 2015
  • Venue: Frontiers in Endocrinology
  • URL: https://www.semanticscholar.org/paper/2151b0fde86089f4889837a105353c2a28daa73e
  • DOI: 10.3389/fendo.2015.00187
  • PMID: 26733942
  • PMCID: 4686608
  • Citations: 36
  • Influential citations: 2
  • Summary: An overview of the known molecular events involved in SS and DA resistance is provided, focusing on the role played by FLNA in DRD2 and SSTRs receptors expression and signaling in PRL- and GH-secreting tumors.
  • Evidence snippets:
  • Snippet 1 (score: 0.460) > FiGURe 1 | Schematic representation of the possible molecular mechanisms involved in drug resistance of pituitary tumors. DA-resistance in PRL-secreting tumors might be related to a defective expression of DRD2 or to an altered expression of specific splice variants. Genetic alterations of DRD2 or possible alterations in the molecules involved in receptor internalization or signal transduction culminating in the inhibitory action on PRL secretion and cell proliferation might also be involved. SS-resistance of GH-secreting tumors, besides to reduced SSTR2 and/or SSTR5 expression, rarely associated with mutations of SSTR2 and SSTR5 genes, but it has been correlated with the expression of truncated variatns of SSTR5 (SST5TMD4). Asterisk indicates the only mutational change found in the SSTR5 gene (R240W, in the third intracellular loop). Alterations in signal transduction may include G proteins, AIP, or arrestins. tumorigenic somatotroph cells is the cause of gigantism during childhood and acromegaly in adults, with significant morbidity due to clinical complications involving cardiovascular, respiratory, and metabolic systems. Adenocorticotroph hormone (ACTH)secreting tumors cause Cushing's disease (hypercortisolism), and TSH-secreting tumors present with signs and symptoms of hyperthyroidism. Non-functioning pituitary tumors (NFPAs) are hormonally inactive, and patients with this tumor type often present with neurological symptoms due to the mass effect. > Pituitary tumors frequently preserve responsiveness to hypophysiotropic factors, including dopamine (DA) and somatostatin (SS), ubiquitous peptides that physiologically inhibit hormone secretion and cell proliferation at both the pituitary and the periphery levels, and thus are considered as molecules with therapeutical potential (1).

[12] Molecular subtypes of adamantinomatous craniopharyngiomas

  • Authors: Wenhao An, Shouwei Li, Yihua An, Zhixiong Lin
  • Year: 2025
  • Venue: Neuro-Oncology
  • URL: https://www.semanticscholar.org/paper/143003e08778ae31fc11732445c3ba4c90c178de
  • DOI: 10.1093/neuonc/noaf030
  • PMID: 39898434
  • PMCID: 12187517
  • Citations: 9
  • Influential citations: 1
  • Summary: This review focuses on summarizing and synthesizing the molecular mechanisms and potential subtypes of ACP, aiming to provide theoretical support for future research on the molecular subtyping of ACP.
  • Evidence snippets:
  • Snippet 1 (score: 0.456) > Growth pattern of the tumor around the arachnoid sleeve near the pituitary stalk -Q type: tumor originating from the area below the sellar diaphragm -S type: tumor originating from the suprasellar pituitary stalk area -T type: tumor originating from the infundibular tubercle region of multiple signaling pathways and molecular mechanisms, including Wnt/β-catenin, MAPK, SHH, and others, which play significant roles in the formation and progression of ACPs. In recent years, with the application of high-resolution technologies such as single-cell RNA sequencing, researchers have gradually revealed significant heterogeneity within ACP tumors. 101 This internal heterogeneity also leads to considerable differences in the clinical presentations of patients with ACP. 102 For example, the age of onset varies widely, affecting both children and adults; radiologically, ACP can present in various forms, including cystic, solid, or a combination of cystic and solid components. 103 These diverse presentations contrast sharply with the traditional view of ACP as a tumor driven solely by single-gene mutations. More notably, different patients also exhibit significant variability in their responses to drug treatments. 104 For example, some patients respond well to anti-inflammatory therapy and achieve disease control, whereas others may show no significant response to the same treatment. 15 These findings further suggest that ACP might exist in different molecular subtypes, each with distinct mechanisms of onset, progression, and treatment response. Tumor classification has gradually shifted from histological to molecular subtyping, and new molecular subtyping is not only the basis for precision therapy but also crucial for elucidating tumor mechanisms, identifying prognostic factors, and developing personalized treatment strategies. 105,106 esearch on the molecular subtyping of ACP has evolved from the discovery of single-gene mutations to comprehensive multiomics analyses. 8][109] Subsequently, specific epigenetic markers, such as DNA methylation and histone modifications, were identified, revealing different patterns among numerous ACP patients. 110

[13] Benzene and 2-ethyl-phthalate induce proliferation in normal rat pituitary cells

  • Authors: Laura Tapella, A. Sesta, M. Cassarino, V. Zunino, M. Catalano et al.
  • Year: 2016
  • Venue: Pituitary
  • URL: https://www.semanticscholar.org/paper/26fa892152dc373704774d4f86a3d83030c7433b
  • DOI: 10.1007/s11102-016-0777-3
  • PMID: 27853917
  • PMCID: 5427103
  • Citations: 19
  • Influential citations: 1
  • Summary: These findings indicate that benzene and 2-ethyl-phthalate activate AhR/AIP expression and stimulate proliferation in normal rat pituitary cells, the first demonstration that pollutants can induce normal pituitsary cells to proliferate.
  • Evidence snippets:
  • Snippet 1 (score: 0.453) > AhR is a cytosolic transcription factor first identified through its dioxin-binding capacity and, indeed, mediates a variety of responses to toxic halogenated aromatic hydrocarbons [22]. AIP acts as chaperone to AhR and facilitates activation of AhR; in turn, activated AhR translocates into the nucleus, heterodimerizes with AhRnuclear translocator (ARNT) and acts upon target genes [46]. The role of this pathway in carcinogenesis is the focus of increasing interest [23] and, indeed, a link to pituitary tumorigenesis was recently detected as germline mutations in AIP were shown to predispose to development of pituitary adenomas [21]. Several studies followed upon this first report in an attempt to clarify the pathogenesis of AIPmutated pituitary tumors but the exact mechanism remains elusive [47,48]. In fact, expression and cellular localization of AIP, AhR and ARNT appear variable with some tumors presenting low AIP, absent nuclear AhR staining and loss of ARNT expression, others increased AIP expression or nuclear AhR staining [49][50][51]. A most recent study in fibroblasts from patients with four different AIP mutations showed that AhR expression was unaffected but that AhR target genes, i.e. CYP1B1, AhR repressor (AHRR), were either reduced or increased depending on the AIP variant [52]. From a clinical viewpoint, patients carrying AIP mutations are more often young, male and with large GH-or mixed GH-and prolactin-secreting tumors [48,53,54]. Interestingly, the AhR gene itself appears to contribute to severity of acromegaly as polymorphisms and variants in AhR have been associated with more aggressive disease [55,56]. > Altogether, it is clear that the AhR-AIP pathway is involved in pituitary tumorigenesis and our findings shed further light into this concept.

[14] Deciphering USP8’s pivotal role in cancer: mechanisms, clinical insights and contrasts with its function in pituitary adenomas

  • Authors: Li-ping Song, Dexu Kong, Lina Yang
  • Year: 2025
  • Venue: Journal of Translational Medicine
  • URL: https://www.semanticscholar.org/paper/a17537fe741b548059ecdbc5aaae7b918a826eb0
  • DOI: 10.1186/s12967-025-07530-y
  • PMID: 41331709
  • PMCID: 12777360
  • Summary: This review systematically summarizes USP8’s context-dependent roles in cancer biology, dissects the mechanistic basis for its divergent effects in cancers and pituitary adenoma, and highlights its clinical value as a differential biomarker and unifying therapeutic target across tumor types.
  • Evidence snippets:
  • Snippet 1 (score: 0.444) > As a core member of the ubiquitin-specific protease (USP) family, USP8 functions as a pivotal deubiquitinating enzyme that orchestrates fundamental biological processes. Its dysregulation has been firmly established as a key driver in the initiation and progression of cancers, while its activating mutations also play a determinant role in the pathogenesis of Cushing's disease-associated pituitary adenomas-specifically promoting adenoma growth and excessive ACTH secretion. This review systematically synthesizes three interconnected dimensions of USP8 research to construct a comprehensive understanding of its role in tumor biology and related disorders. First, it dissects the context-dependent molecular mechanisms through which USP8 exerts divergent biological effects across tumor types, with a focus on how its modulation of substrate proteins such as EGFR shapes distinct pathogenic cascades. Second, it delineates the clinical utility of USP8 as a diagnostic and prognostic biomarker, highlighting its potential to guide treatment decision-making. Third, it evaluates the translational potential of USP8 as a therapeutic target, underscoring its relevance for developing targeted interventions across disease entities. > A central innovative insight of this review lies in its identification of a cross-disease functional linkage for USP8. Through integrated analysis of existing evidence, we demonstrate that USP8 activates distinct molecular pathways via its shared substrate EGFR, ultimately driving disparate biological outcomes in cancers and benign pituitary adenomas. This finding not only provides a novel mechanistic framework for unifying research on cancers and pituitary adenoma but also expands the therapeutic landscape by positioning USP8 as a common target with relevance across diverse pathological contexts. Such a cross-disease perspective addresses a long-standing gap in the field, where cancer and benign pituitary adenoma research involving USP8 has largely proceeded in isolation. > Beyond bridging the divide between cancer and benign pituitary adenoma biology, USP8 serves as a central regulatory node that coordinates multiple cancer-related biological processes, modulates key tumor-associated molecular mechanisms, and offers actionable insights for translational medicine and clinical practice.

[15] Somatic Deletion in Exon 10 of Aryl Hydrocarbon Receptor Gene in Human GH-Secreting Pituitary Tumors

  • Authors: A. Re, F. Ferraù, C. Cafiero, F. Spagnolo, V. Barresi et al.
  • Year: 2020
  • Venue: Frontiers in Endocrinology
  • URL: https://www.semanticscholar.org/paper/f9be55a775b0bff5854394553f4bc757f74a73b0
  • DOI: 10.3389/fendo.2020.591039
  • PMID: 33281746
  • PMCID: 7689685
  • Citations: 7
  • Summary: This is the first demonstration of a recurrent somatic deletion in the exon 10 of the AHR gene in somatotropinomas, and the functional impact of this genetic finding needs to be clarified.
  • Evidence snippets:
  • Snippet 1 (score: 0.442) > AHR is a ligand-activated transcription factor that can bind over 400 different endogenous and exogenous compounds, including several endocrine disrupting chemicals and environmental contaminants (17)(18)(19). AHR activation leads to the transactivation of genes encoding phase I and II xenobiotics metabolizing enzymes, thus representing a key factor of the intracellular detoxification systems (20). The AHR has been therefore studied mainly in the context of environmental pollutants processing as transcriptional regulator of genes involved in the metabolism and/or excretion of toxins such as dioxin TCDD (21). Moreover, AHR is directly or indirectly involved in many other biologically relevant processesvia the so-called non-canonical pathwayssuch as cell cycle regulation and cell contact inhibition, potentially contributing to tumorigenesis (22)(23)(24). A limited number of studies has focused on the impact of AHR signaling in PA. Jaffrain-Rea in 2009 reported that the AHR and its partner AIP were downregulated in aggressive somatotropinomas as compared to non-invasive adenomas suggesting their involvement in the acquisition of an aggressive phenotype (25). Subsequently, several groups focused their attention on the uncovered link between AHR and/or AIP expression and the molecular mechanisms underlying pituitary adenoma pathogenesis. AIP, a co-chaperone protein that acts as a tumor suppressor in pituitary cells (26), is critical for AHR stabilization and function. AIP gene germline mutations have been found in young patients with familial or apparently sporadic aggressive pituitary adenomas, mostly secreting GH and/or PRL, and less responsive to conventional medical treatments (27). Moreover, although it is still a matter of debate, AIP mutations also affect the AHR signaling, since they can alter the AHR and phosphodiesterase (PDE)4A5 interaction and consequently the cAMP pathway, affecting pituitary function and tumorigenesis (22,28).

[16] Phenotype-Genotype Association Analysis of ACTH-Secreting Pituitary Adenoma and Its Molecular Link to Patient Osteoporosis

  • Authors: Renzhi Wang, Yakun Yang, Miaomiao Sheng, Dechao Bu, Fengming Huang et al.
  • Year: 2016
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/5b1f65eaaabf469aee5b143df5e58601a2eecc95
  • DOI: 10.3390/IJMS17101654
  • PMID: 27690016
  • PMCID: 5085687
  • Citations: 7
  • Summary: A novel analysis linking disease clinical characteristics and whole transcriptomic changes, using Pearson Correlation Coefficient to discover a molecular network mechanism for osteoporosis in CD patients is developed and it is reported that osteoporeosis is distinguished from the phenotype and genotype analysis.
  • Evidence snippets:
  • Snippet 1 (score: 0.442) > Adrenocorticotrophin (ACTH)-secreting pituitary adenoma, also known as Cushing disease (CD), is rare and causes metabolic syndrome, cardiovascular disease and osteoporosis due to hypercortisolism. However, the molecular pathogenesis of CD is still unclear because of a lack of human cell lines and animal models. Here, we study 106 clinical characteristics and gene expression changes from 118 patients, the largest cohort of CD in a single-center. RNA deep sequencing is used to examine genotypic changes in nine paired female ACTH-secreting pituitary adenomas and adjacent nontumorous pituitary tissues (ANPT). We develop a novel analysis linking disease clinical characteristics and whole transcriptomic changes, using Pearson Correlation Coefficient to discover a molecular network mechanism. We report that osteoporosis is distinguished from the phenotype and genotype analysis. A cluster of genes involved in osteoporosis is identified using Pearson correlation coefficient analysis. Most of the genes are reported in the bone related literature, confirming the feasibility of phenotype-genotype association analysis, which could be used in the analysis of almost all diseases. Secreted phosphoprotein 1 (SPP1), collagen type I α 1 chain (COL1A1), 5′-nucleotidase ecto (NT5E), HtrA serine peptidase 1 (HTRA1) and angiopoietin 1 (ANGPT1) and their signalling pathways are shown to be involved in osteoporosis in CD patients. Our discoveries provide a molecular link for osteoporosis in CD patients, and may open new potential avenues for osteoporosis intervention and treatment.

[17] CCNB1 affects cavernous sinus invasion in pituitary adenomas through the epithelial–mesenchymal transition

  • Authors: Bin Li, Jianhua Cheng, Hongyun Wang, Sida Zhao, Haibo Zhu et al.
  • Year: 2019
  • Venue: Journal of Translational Medicine
  • URL: https://www.semanticscholar.org/paper/ce00533d98ea744f75ca3e7bec07198a28fabd0f
  • DOI: 10.1186/s12967-019-2088-8
  • PMID: 31585531
  • PMCID: 6778375
  • Citations: 22
  • Summary: High CCNB1 expression in pituitary adenoma affects cavernous sinus invasion through EMT, and downregulation ofCCNB1 led to reduced cell invasion and migration in Transwell experiments.
  • Evidence snippets:
  • Snippet 1 (score: 0.439) > Pituitary adenoma is one of the most common nervous system tumours, accounting for approximately 10-15% of intracranial tumours. The incidence of pituitary adenomas has increased in recent years [1,2]. Some pituitary adenomas are invasive, leading to the enclosure and compression of important adjacent structures, including the cavernous sinus, making surgery and treatment difficult. Pituitary adenomas that invade the cavernous sinus area account for 6-10% of all pituitary adenomas [3]. These refractory pituitary adenomas adversely affect patient survival and quality of life [4,5]. The clinical diagnosis and treatment of pituitary adenomas that invade the cavernous sinus are fraught with difficulties and challenges, such as difficulties in preoperative classification, inaccurate predictions of prognosis, incomplete tumour resections, postoperative recurrences and drug resistance. Therefore, exploring the biological characteristics of pituitary adenomas that invade the cavernous sinus and studying the molecular biological mechanism involved in their occurrence and development will help to resolve the abovementioned difficulties in clinical diagnosis and treatment, thus improving the pituitary adenoma cure rate, reducing the recurrence of pituitary adenoma, and improving the prognosis of patients. Cyclin B1, which is encoded by the CCNB1 gene, belongs to the cyclin family of cell cycle proteins. Previous studies have demonstrated that the CCNB1 gene is highly expressed in pituitary adenomas and is associated with invasiveness, suggesting that the CCNB1 gene plays an important role in the genesis and development of pituitary adenomas [6]. Similarly, CCNB1 was shown to be closely involved in the pathogenesis of pituitary adenomas in Zhang's research [7]. > Our subsequent research found that suppressing the CCNB1 gene can regulate the proliferation and apoptosis of pituitary tumour cells and activate the epithelialmesenchymal transition (EMT) process. These findings may provide important knowledge for understanding the biological mechanisms of CCNB1 in the development and progression of pituitary adenoma.

[18] Endocrine disrupting chemicals: effects on pituitary, thyroid and adrenal glands

  • Authors: Filippo Egalini, L. Marinelli, Mattia Rossi, G. Motta, N. Prencipe et al.
  • Year: 2022
  • Venue: Endocrine
  • URL: https://www.semanticscholar.org/paper/4a981ef0d60e8b2a306c63b75946f54e7d0c1d5b
  • DOI: 10.1007/s12020-022-03076-x
  • PMID: 35604630
  • PMCID: 9637063
  • Citations: 47
  • Influential citations: 1
  • Summary: Current evidence regarding the detrimental effects of EDCs on pivotal endocrine glands like pituitary, thyroid and adrenal ones are summarized and the known and the hypothesized mechanisms of endocrine dysfunction brought by EDCs are directed at.
  • Evidence snippets:
  • Snippet 1 (score: 0.436) > The pituitary gland is a potential target of EDCs, which can result in an alteration of the pituitary hormonereleasing patterns. The hypophysis seems to be vulnerable through direct and hypothalamic-mediated processes exerted by these compounds [1,17]. However, EDCs mechanisms of action are still not fully figured out: over the entire lifespan of the individual, they could interfere with endogenous hormonal function, affecting the homeostatic system, or alter the genomic expression, e.g., through DNA methylation [1,12]. > A growing body of evidence is suggesting that EDCs can have an influence on tumorigenesis. Researchers described a link between EDCs and cancer burden, particularly with testicular, breast and prostate cancer [1]. Pituitary gland seems to be a potential target of these compounds, too. First epidemiological studies reported a higher incidence of pituitary adenomas due to previous exposure to dioxin [18] and a higher incidence of growth hormone-(GH-)secreting adenomas in a highly industrialized area nearby Messina, Italy [19]. Moreover, in vitro studies succeeded in demonstrating correlations between pollutants and stimulation of pituitary cells: benzene and phthalates increased cell proliferation via a deregulation of aryl hydrocarbon receptor (AHR) and AHR-interacting protein (AIP) [20], a tumor suppressor pathway that seems to be involved with other xenobiotics, such as polycyclic aromatic hydrocarbons and PCBs [21]. The involvement of AIP seems to play a key role: in fact, previous studies had already linked AIP gene mutations with familial isolated pituitary adenoma syndrome, familial somatotropinomas, and with apparently sporadic acromegaly [22,23]. Moreover, in clinical practice AIP gene mutations are associated with an aggressive disease phenotype, which is less responsive to conventional medical treatment, as somatostatin analogues [19].

[19] Special issue on molecular genetics in endocrinology.

  • Authors: M. Azevedo, Regina S. Moisés, S. Antonini
  • Year: 2012
  • Venue: Arquivos brasileiros de endocrinologia e metabologia
  • URL: https://www.semanticscholar.org/paper/2b94ca494ba86e4ddc902f5bd7c5686098e2ac8f
  • DOI: 10.1590/S0004-27302012000800001
  • PMID: 23295283
  • Summary: This special issue aims at describing clinical cases in which molecular research was performed, thus opening opportunities for the publication of novel mutations, and for the presentation of clinical particularities in patients with mutations that have already been described.
  • Evidence snippets:
  • Snippet 1 (score: 0.428) > (6). > A number of genetic alterations have been correlated with disorders in growth and sexual development, and in some cases, the genetic profile may predict the phenotype and clinical outcome. From chromosome anomalies to point mutations, studies by Maciel-Guerra and cols. ( 7 16) illustrates the contribution of microRNA detection strategies in the prediction of outcomes, by describing a patient with an aggressive papillary thyroid carcinoma. > In pituitary diseases, better knowledge of the mechanisms involved in tumorigenesis may provide more effective medical therapy. The association of mutations in the AIP gene in patients with familial pituitary adenomas has pointed out a possible role of AIP protein alterations in the development of sporadic pituitary tumors. In this issue, Kasuki and cols. ( 17) investigated the AIP expression in GH-secreting tumors in correlation with response to medical treatment. Boguszewski and cols. ( 18) describe an interesting case in which the two types of multiple endocrine neoplasm coexist, and discuss the genetic findings associated with this condition, whereas multiple endocrine neoplasia type 2 is revisited by Blom and cols. (19) in a description of the rare S891A RET mutation in a patient with medullary thyroid carcinoma. In addition, genetic studies in oncogenic osteomalacia by Chang and cols. (20), and in Frasier (Guaragna and cols. [21]), Cowden's (Lima and cols. [22]) and hyperinsulinism/hyperammonemia (Corrêa-Giannella and cols. [23]) syndromes are presented in this issue. > In the past, knowledge about molecular genetics was important in the management of only a restricted group of patients. Currently, this strategy has become critical for proper monitoring of a large number of patients in different settings (24). Accordingly, the practitioner should be familiar with the indications and potential limitations of genetic testing. > We are honored to participate as invited editors in this Special Edition of ABEM, having the opportunity of getting in contact with high-quality articles.

[20] Cushing’s disease

  • Authors: F. Castinetti, I. Morange, B. Conte‐Devolx, T. Brue
  • Year: 2012
  • Venue: Orphanet Journal of Rare Diseases
  • URL: https://www.semanticscholar.org/paper/db0a10b862c990be7a0af1fc851042e1c8faad85
  • DOI: 10.1186/1750-1172-7-41
  • PMID: 22710101
  • PMCID: 3458990
  • Citations: 47
  • Influential citations: 1
  • Summary: A review summarizes potential pathophysiological mechanisms, diagnostic approaches, and therapies for Cushing’s disease, which is a rare disease responsible for increased morbidity and mortality.
  • Evidence snippets:
  • Snippet 1 (score: 0.428) > Most of these are somatotroph or lactotroph, but corticotroph adenomas have been described in 5-10% of cases. AIP (Aryl hydrocarbon receptor Interacting Protein) mutations have been reported in familial pituitary adenomas: secretion profile is usually somatotroph or lactotroph, whereas very rare cases of CD have also been reported [15]. > Potentially involved molecular mechanisms Triggering signals leading to Cushing's disease remain unclear. Oncogenes do not appear to be involved, as somatic mutations are usually not present in corticotroph adenomas cells. Recent studies in mice identified a potential role of loss of function of Brg1 (brahma-related gene 1) and HDAC2 (Histone Deacetylase 2) in the pathogenesis of Cushing's disease. Both proteins form a complex with the glucocorticoid receptor and the orphan nuclear receptor nuclear growth factor IB (NGFI-B) to repress POMC secretion. Interestingly, about 50% of corticotroph adenomas do not express these proteins anymore. The loss of Brg1 could lead to overexpression of cyclin E, leading to increased cell proliferation and sporadic hyperplasia or tumors. Interestingly, tumors with a loss of nuclear localization of Brg1 seem to be more responsive to anticortisolic drugs in vitro compared to the ones with a complete loss of Brg1 oncogene [16,17]. > Transcription factors involved in progenitors proliferation and differentiation during pituitary embryogenesis could also be involved in pituitary tumorigenesis. TPIT deficiency is known to result in congenital isolated corticotroph deficiency. Patients with other pituitary transcription factors mutations (PROP1, LHX3, LHX4, HESX1) usually present combined pituitary hormone deficiencies including inconstant corticotroph deficiency. As some of these factors are still expressed at adult age, and their role is not precisely known, it could be tempting to speculate on potential roles of an overexpression of these proteins in pituitary adenomas ontogenesis.

Notes

  • This provider combines search_papers_by_relevance with snippet_search.
  • No synthesis or second-stage model call is performed.