doi:10.1507/endocrj.EJ21-0106 Review

Emerging role of signal transducer and activator of transcription 3 (STAT3) in pituitary adenomas

Cyndy Liu1), Tae Nakano-Tateno1), Motoyasu Satou1), 2), Constance Chik1) and Toru Tateno1)

1) Division of Endocrinology and Metabolism, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada 2) Department of Biochemistry, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan

Abstract. Pituitary adenomas are benign tumours that can cause an individual various clinical manifestations including tumour mass effects and/or the diverse effects of abnormal pituitary hormone secretion. Given the morbidity and limited treatment options for pituitary adenomas, there is a need for better biomarkers and treatment options. One molecule that is of specific interest is the signal transducer and activator of transcription 3 (STAT3), a transcription factor that plays a critical role in mediating cytokine-induced changes in expression. In addition, STAT3 controls cell proliferation by regulating mitochondrial activity. Not only does activation of STAT3 play a crucial role in tumorigenesis, including pituitary tumorigenesis, but a number of studies also demonstrate pharmacological STAT3 inhibition as a promising treatment approach for many types of tumours, including pituitary tumours. This review will focus on the role of STAT3 in different pituitary adenomas, in particular, -producing adenomas and null cell adenomas. Furthermore, how STAT3 is involved in the cell proliferation and hormone regulation in pituitary adenomas and its potential role as a molecular therapeutic target in pituitary adenomas will be summarized.

Key words: Signal transducer and activator of transcription 3 (STAT3), Pituitary adenomas, Biomarker

Introduction lactin (PRL)-producing pituitary adenomas and somato‐ statin analogues are used post transsphenoial surgery and Pituitary adenomas are common, occurring in almost occasionally primary medical therapy for GH-producing 17% of the population over the lifetime [1, 2]. They rep‐ adenomas. Both classes of medications have been used resent approximately 10% of all intracranial tumours [3]. as second- or third-line therapy for other types of pitui‐ They have the ability to cause a plethora of problems, tary adenomas. However, these methods are not suited including headaches (neurological problems), hormone for every patient and thus research is currently being hypersecretion (endocrinological problems) and loss of conducted in order to identify potential biomarkers that vision (ophthalmological problems). Currently, there are can act as a therapeutic target and/or predict pituitary few treatment options for pituitary adenomas including tumour behaviours. In this review, we examined the surgery, radiotherapy and medical therapy. Transsphenoi‐ potential role of signal transducer and activator of tran‐ dal surgery is the first treatment option for most of the scription 3 (STAT3), a transcription factor that plays a patients with adrenocorticotropic hormone (ACTH)-, critical role in mediating cytokine-induced changes in growth hormone (GH)-, thyroid-stimulating hormone in pituitary adenomas, as this molecule (TSH)-producing pituitary adenoma and non-functioning has been found to be overexpressed and/or overactivated pituitary macroadenomas. Dopamine agonists and somat‐ in a wide variety of tumours, including pituitary adenomas. ostatin analogues are two main classes of medications used for medical therapy for pituitary adenomas. In STAT3 general, dopamine agonists are first-line medical therapy primarily for hormonal and tumour size control for pro‐ STAT are part of cytoplasmic inducible transcription factors that are responsible for transducing Submitted Feb. 6, 2021; Accepted Jun. 14, 2021 as EJ21-0106 extracellular signals to the nucleus from the surface of Released online in J-STAGE as advance publication Jul. 10, 2021 the cell [4-9]. There are seven members of the STAT Correspondence to: Toru Tateno MD, PhD, Room 9-112J, Clinical Sciences Building, 11350-83 Avenue, University of Alberta, family: STAT1, STAT2, STAT3, STAT4, STAT5A, Edmonton, AB, Canada T6G 2G3. STA5B and STAT6 [4-7, 10]. Within the STAT family, E-mail: [email protected] STAT3 is responsible for the expression of relating

©The Japan Endocrine Society 2 Liu et al.

to cancer progression. Additionally, STAT3 can upregu‐ Potential Link between STAT3 and late genes that promote anti-apoptosis, angiogenesis, Pituitary Carcinomas metastasis, and cell cycle progression as well as down regulating growth suppressor genes [4-6, 10, 11]. The Currently, there are no articles discussing the direct tyrosine phosphorylated STAT3 (pY-STAT3) regulates link between STAT3 and pituitary carcinomas. Addition‐ the transcription of target genes, and the phosphorylation ally, there are few molecular studies of pituitary carcino‐ of the serine residue in 727 (pS-STAT3) increases mito‐ mas, presumably due to the rarity of this type of pituitary chondrial function, resulting in enhanced cell growth. tumour. One study analyzed the patterns of gene expres‐ sion in pituitary carcinomas and pituitary adenomas STAT3 Expression in Human Pituitary through high-density oligonucleotide arrays, reverse Tumours transcriptase-quantitative PCR and expression [21]. The results showed higher expression of galectin-3 Previous studies suggest the importance of STAT3 in a gene in pituitary carcinomas compared to pituitary ade‐ variety of cancers as well as in vitro and in vivo models nomas which indicate its potential important role in the of pituitary adenomas, which will be reviewed in detail development of pituitary carcinomas. Galectin-3 was in later sections. The highest STAT3 expression level is seen to increase phosphorylation of tyrosine STAT3 [22]. detected in GH-producing pituitary adenomas by immu‐ Higher expression levels of galectin-3 is associated with nohistochemistry, suggesting the specific role of STAT3 enhanced cancer cell proliferation and resistance to che‐ in this type of pituitary adenoma [12]. With regard to pS- motherapy [23]. Silencing of galectin-3 in cultured STAT3 in human pituitary adenoma tissues, we exam‐ human osteosarcomas resulted in decreased cell migra‐ ined pS-STAT3 expression levels in 23 pituitary tion and invasion abilities as well as inhibition of phos‐ adenoma tissues by immunohistochemistry [13]. Most of phorylated STAT3 expression [24]. These studies exhibit the somatotroph adenomas have strong immunoreactivity the potential link from STAT3 expression to development for pS-STAT3. Expression profiles of STAT3 and its of pituitary carcinomas with a focus on the expression of upstream molecules in sporadic pituitary null cell adeno‐ galectin-3. However, more studies are required in order mas have also been investigated. Feng J et al. reported to confirm the direct link between STAT3 expression and the association between activation of the IL6-R/JAK2/ pituitary carcinoma development. STAT3/MMP9 pathway and invasiveness of pituitary null cell adenomas based on clinicopathological features STAT3 in the Normal in 52 patients [14]. As previously mentioned, a study conducted on 23 pituitary adenoma tissues reveals strong Normal pituitary cells were reported to have the lower STAT3 serine phosphorylation in human somatotroph STAT3 expression compared to somatotroph adenoma adenomas but negative or weak immunoreactivity in cells and non-functioning pituitary adenoma cells [12]. other types of pituitary adenomas [13]. Another study Currently, there are no publications indicating a direct investigates the role of STAT3 gene promoter methyla‐ impact on pituitary development by the STAT family. tion and mRNA expression in 102 patients with pituitary However, certain signaling pathways involved in regulat‐ adenomas [15]. Low STAT3 methylation status is associ‐ ing pituitary development also control the activity of ated with invasive pituitary adenomas as only 12.1% of STATs. Such a pathway is the FGF signaling pathway, invasive pituitary adenomas have methylated STAT3 thus linking the plausible implication of the STAT family gene promoters. Additionally, PRL, IGF-1, ACTH and in pituitary development [25]. Further examples suggest‐ more than one hormone hypersecretion is more com‐ ing the involvement of STAT family in pituitary develop‐ monly found in adenomas with unmethylated STAT3. As ment include research concerning leukemia inhibitory the specific rs744166 STAT3 polymorphism is associated factor (LIF) [26]. The LIF-related cytokines presumably with an increased risk of cancer development [16-19], act through promoting activity of the JAK family and polymorphisms of STAT3 has been examined in order to this allows the phosphorylation of STAT family members uncover any associations between STAT3 rs744166 and to occur. Evidence indicates that LIF stimulates proopio‐ pituitary adenoma characteristics such as invasiveness, melanocortin (POMC) in fetal pituitary corticotrophs, hormonal activity, and recurrence [20]. The STAT3 offering support that it has a role in pituitary develop‐ rs744166 G/G genotype is associated with recurrence of ment [25]. In relation to the STAT family, the study pituitary adenomas. Taken together, these studies support offered support for the hypothesis that multiple STAT the potential role of STAT3 as a biomarker for treatment family members are involved in mediating LIF effects in of different pituitary adenomas. AtT20 cells. This was seen as STAT1 and STAT3 tyrosyl phosphorylation was influenced by LIF in AtT20 cells

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Table 1 Pituitary adenoma cell lines Cell line Hormone Origin Species Reference GH1 GH, PRL Mammosomatotroph adenoma Rat [28] GH3 GH, PRL Mammosomatotroph adenoma Rat [29] GH4C1 GH, PRL Mammosomatotroph adenoma Rat [29] MtT/SM GH, PRL Mammosomatotroph adenoma Rat [30] MMQ PRL Lactotroph adenoma Rat [31] PRL235 PRL Lactotroph adenoma Rat [32] RC-4B/C GH, PRL, ACTH, FSH, LH, TSH Mixed Rat [33] AtT20 ACTH Corticotroph adenoma Mouse [34] HP75 FSH, LH, gonadotropin α-subunit Gonadotroph adenoma Human [35] GH, Growth hormone; PRL, ; ACTH, Adrenocorticotropic hormone; FSH, Follicle-stimulating hormone; LH, luteinizing hormone; TSH, thyroid stimulating hormone

which further supports the involvement of STAT lines [36, 37]. families- through multiple signaling pathways in pitui‐ tary development. Roles of STAT3 in the Regulation of Insight into the importance of STAT3 was further pro‐ Pituitary Hormones vided in studies using knockout mice. Activity of STAT3 was found early within the development of the mouse Analysis of the GH gene reveals several prospective therefore suggesting its importance in early embryogen‐ STAT3 binding sites in the promoter region of the GH esis. This is further supported by results showing gene [12], indicating that GH could potentially be a STAT3-deficient mice dying earlier in embryogenesis. direct STAT3 target. The involvement of tyrosine phos‐ Additionally, in STAT3-deficient T cells, it was discov‐ phorylated STAT3 in GH production has been demon‐ ered that they exhibit a reduced proliferative response to strated using in vitro models. Not only did and IL-6 which can be attributed to the defect in IL-6- IGF-1 play a role in the negative-feedback system at the mediated suppression of apoptosis [27]. Further studies pituitary gland to inhibit GH expression [38], they also using pituitary-specific STAT3 knockout mice and/or activate pY-STAT3 and inhibit GH expression in rat transgenic mice expressing a constitutively active form mammosomatotroph pituitary adenoma cells, GH4 cells of STAT3 (STAT3-CA) in pituitary cells are required to [13]. In addition, genetic STAT3 down-regulation or uncover the role of STAT3 in pituitary development. overexpression of dominant negative form of STAT3 (STAT3-Y705F) results in increased GH production in STAT3 in Experimental Models of GH4 cells. In contrast, introduction of STAT3-CA Pituitary Adenomas increased GH expression and reduced PRL expression in rat mammosomatotroph GH3 cells. Also, pharmacologi‐ Several lines of evidence support the emerging roles cal inhibition of STAT3 suppressed GH production but of STAT3 in the pituitary tumorigenesis and pituitary augmented PRL production [12]. Zhou C et al. reported hormone regulation. STAT3 acts as a transcriptional fac‐ that a specific STAT3 inhibitor, S3I-201, suppresses GH tor in pituitary adenomas, which regulates several genes mRNA expression and GH secretion in primary cells responsible for hormone regulation and cell proliferation from human somatotroph adenomas in a concentration- of pituitary adenomas. STAT3 also regulates mitochon‐ dependent manner [12]. A recent study demonstrated that drial functions, which are associated with cell prolifera‐ atiprimod, a novel compound belonging to the azaspirane tion and resistance to analogues. The class of cationic amphiphilic drugs, can reduce GH following sections review the roles of STAT3 using in expression in GH3 cells [39]. Furthermore, GH was vitro and in vivo models of pituitary adenomas. Repre‐ shown to activate pY-STAT3 [40]. These findings sug‐ sentative transformed immortalized pituitary adenoma gest that enhanced GH production itself may accelerate cell lines [28-35] (Table 1) have been used to investigate its expression, and therefore pharmacological inhibition the regulation of hormone production and secretion, cell of STAT3 would be a novel therapeutic approach to sup‐ proliferation, migration, invasion, and apoptosis. Cell press enhanced GH production. responses to hormones might vary among different cell pY-STAT3 is activated by a novel germline mutation

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of Aryl Hydrocarbon Interacting Protein (AIP) The Effects of Pituitary-targeting Drugs gene, which is associated with familial pituitary adeno‐ on STAT3 mas [41]. The deletion of the AIP gene by clustered reg‐ ularly interspaced short palindromic repeats (CRISPR) A limited number of studies reported the effects of can enhance pY-STAT3, resulting in an increase in GH pituitary-targeting drugs on pY-STAT3, which may secretion in GH3 cells [41]. Another mutation of the AIP explain mechanisms underlying the suppressive effects gene associated with familial isolated pituitary adenoma of these drugs on hormone production and pituitary was reported to suppress STAT3 tyrosine phosphoryla‐ tumour cell growth. An et al. reported the inhibitory tion in GH3 cells [42]. effect of metformin, an antidiabetic drug, on GH secre‐ There are a limited number of studies investigating the tion in vitro and in vivo [48], which is mediated by inhi‐ role of STAT3 in the regulation of other pituitary hor‐ bition of STAT3 signaling. Bromocriptine can reduce pY- mones. Tomida M et al. demonstrated that cytokines, STAT3 in the skeletal muscle tissues in a concentration- including LIF and IL-6, phosphorylate STAT3 tyrosine dependent manner [49]. reduced STAT3 and inhibit PRL secretion in rat pituitary MtT/SM cells tyrosine phosphorylation in GH3 cells [50]. Also, pasir‐ [43]. Overexpression of STAT3-CA leads to disruption eotide, a somatostatin analog with higher affinity to of the negative-feedback system in AtT-20 cells [44]. 5 compared to octreotide, inhibits However, STAT3 serine phosphorylation has no impact STAT3 serine phosphorylation and its translocation to on hormone regulation [12, 13, 44]. mitochondria via phosphatase 2A. These findings sug‐ gest that can be a better treatment option for Involvement of STAT3 in the Pituitary Cell pituitary adenomas with serine-phosphorylated STAT3 Proliferation [46]. Further studies are required to determine the effects of these therapeutic agents on the STAT3 pathway in With regard to the effect of pY-STAT3 on pituitary cell pituitary adenomas and establish a better treatment proliferation, overexpression of STAT3 as well as approach based on the phosphorylation status of STAT3. STAT3-CA were reported to enhance pituitary adenoma cell proliferation [12, 13]. GH3 cells with pY-STAT3 Roles of STAT3 in Normal Cells and activated by deletion of AIP gene lead to increased cell Cancer Cells proliferation [41]. The roles of microRNAs (miRs) in the regulation of STAT3 in pituitary adenomas were reported The following sections review the roles of STAT3 in by Grzywa et al. [45]. miR-410-3p can upregulate cell normal cells and cancer cells as well as STAT3 inhibi‐ proliferation and invasiveness via STAT3 in AtT-20 cells tors, which have been under development in recent years. and RC-4B/C cells but inhibit them in GH3 cells. Addi‐ tionally, enhanced STAT3 serine phosphorylation via Src STAT3 Pathway by FGFR4R388 leads to STAT3 translocation to the mitochondria [13]. The mitochondrial serine STAT3 can In terms of the STAT3 pathway, cytokines, such as enhance mitochondrial function, resulting in increased interleukin-6 (IL-6), bind to their receptors and lead to pituitary adenoma cell proliferation [13, 46]. Further the homodimerization of (gp130) [51, studies using mouse models of pituitary adenomas are 52]. The dimerization of gp130 results in activation of required to determine if STAT3 is involved in the initia‐ janus kinases (JAKs) that phosphorylate tyrosine resi‐ tion and/or progression of pituitary adenoma. dues [4-6, 53]. Within the JAK family, JAK1 and JAK2 With regard to pharmacological STAT3 inhibition, a are the ones mainly associated with STAT3 [4-6, 54]. STAT3 inhibitor, S3I-201, can reduce GH-producing STAT3 activity occurs for the most part due to pY- pituitary adenoma cell growth in vitro and in vivo in a STAT3 which allows functional dimers to be formed and concentration-dependent manner [12]. Also, another binding to DNA, hence regulating transcription of target STAT3 inhibitor, atiprimod was reported to induce genes [4-6, 55]. caspase-dependent apoptosis by targeting STAT3 in GH3 STAT3 can also go through various post-translational cells [39]. BP-1-102, which can inhibit STAT3 phosphor‐ modifications and one of these modifications is pS- ylation, dimerization, and DNA-binding activity, sup‐ STAT3. Serine phosphorylation is mediated by several presses cell proliferation and induces apoptosis in AtT20 kinases such as mitogen-activated protein kinases cells [47]. Taken together, pharmacological inhibition of (MAPKs), protein kinase C epsilon (PKCε), and the STAT3 would be a promising approach to suppress pitui‐ mammalian target of rapamycin (mTOR) and these occur tary tumour growth. downstream of activation of STAT3 by cytokines [56]. In addition, STAT3 serine phosphorylation can modify

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STAT3 activation through inhibition of the tyrosine found in human neoplasms [90-95]. miRs are non-coding phosphorylation and is responsible for important factors RNAs that can have oncogenic or tumour suppressor within the mitochondria organelle [57-59]. pS-STAT3 properties depending on the malignancy. The use of enhances mitochondrial function, leading to promotion miRs to inhibit STAT3 through interactions with of cell growth [57-62]. upstream kinases or negative modulators can promote apoptosis [96, 97]. Negative Regulators of STAT3 Serine phosphorylation of STAT3 also plays an impor‐ tant role in cell survival as phosphorylated serine STAT3 The major endogenous negative regulators of STAT3 can promote aerobic glycolysis. When translocated to the include protein inhibitor of activated STAT3 (PIAS3), mitochondria, the serine phosphorylated form of STAT3 suppressor of cytokine signaling (SOCS), and protein can regulate respiration and control signaling within the tyrosine phosphatase (PTPs) [63-71]. Most notably, in organelle and lead to increased cancer growth, indicating tumours with increased levels of phosphorylated STAT3, the importance of STAT3 in tumour development there is a lower level of Src homology region 2 (SH2)- [57-62]. containing protein tyrosine phosphatase (SHP) 2 thus supporting how SHP2 can act as a tumour suppressor STAT3 Inhibitors for Cancer [72]. Overexpression and/or hyperactivation of STAT3 are STAT3 in Cancer found in a variety of cancers. Aggressive cancer behav‐ iours may be associated with the status of phosphoryl‐ STAT3 has been identified as an oncogenic transcrip‐ ated tyrosine and/or serine STAT3. This led to studies of tion factor that is involved in malignant transformation. inhibition of STAT3 as a therapeutic target for cancer In a variety of cancer cells [73-80], there is upregulation treatment. Studies using different STAT3 inhibitors rang‐ and constitutive activation of STAT3, which can be ing from proteins to drugs, small molecules and allo‐ linked to cell proliferation, angiogenesis, invasion, anti- steric inhibitors are summarized in Table 2. apoptosis, immune invasion and metastasis. Additionally, S3I-201 is a chemical inhibitor of STAT3 activity by most transformed cells are reliant on STAT3 for prolifer‐ blocking dimerization and STAT3 DNA-binding and ation and survival, suggesting that STAT3 remains an transcriptional activities. S3I-201 has been shown to sup‐ ideal therapeutic target [81]. press tumour growth and induce apoptosis in breast can‐ Activators of STAT3 include growth factors, cytokines cer cells and pituitary adenoma cells [12, 98, 99]. and hormones, which are regulated and terminated by CYD0618 [100], MM-206 [101], C188 [102] and K116 negative feedback loops. There are four mechanisms [103] are allosteric STAT3 inhibitors, which reduce can‐ involved in the activation of STAT3 which include: dis‐ cer growth in vitro and/or in vivo (Table 2). Although the rupting the negative regulation system, positive feedback allosteric STAT3 inhibitors have high selectivity, they mechanism, excessive stimulation by upstream kinases have some drawbacks [104]. Most of these inhibitors and somatic mutations within STAT3 [82]. have relatively low aqueous solubility and bioavailabil‐ PIAS3 are directly involved with STAT3 by interact‐ ity. Mutations of allosteric sites in STAT3 may lead to ing and limiting downstream transcriptional events [64, resistance to the allosteric STAT3 inhibitors. Whether 83]. Reduced SOCS3 expression is related to constitu‐ allosteric STAT3 inhibitors are of use in the difficult to tively active STAT3, which promotes tumour develop‐ manage pituitary adenomas is presently unknown and ment in a variety of cancers [64]. As well, PTPs can likely merits additional investigation. negatively control STAT3 signaling through dephospho‐ Pyrimethamine [105-107], OPB-51602 and rylation of their binding partners as described through OPB-31121 [10, 108-111] are small molecule STAT3 the loss of SHP1 in cancers [64]. inhibitors that are currently undergoing clinical trials for Dysregulated positive feedback systems lead to activa‐ various malignancies (Table 2). Although STAT3 is a tion of STAT3 by receptor tyrosine kinases resulting in potential therapeutic target, preclinical studies and/or cancer cell growth. Small molecules, such as NF-kB clinical trials with various STAT3 inhibitors are currently [84], IL-6 [85, 86], plasminogen activator inhibitor 1 underway to define their roles in specific cancers. (PAI1) [87], are involved in the activated STAT3 path‐ way in cancer. Changes in upstream kinases, such as Future Directions JAK, Src, EGFR, can lead to constitutive activation of STAT3 and thus promotes malignancies [85, 88, 89]. In summary, lines of evidence discussed in this review Mutations that drive constitutive activation of STAT3 are support the importance of STAT3 in the pituitary

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Table 2 STAT3 Inhibitors STAT3 inhibitors Type of inhibitor Types of cancer References Small molecule STAT3 S3I-201 Breast cancer and GH-secreting pituitary adenomas [12, 98, 99] activation inhibitors CYD0618 Allosteric inhibitors Ovarian cancer and breast cancer [100] MM-206 Allosteric inhibitors Acute myeloid leukemia [101] C188 Allosteric inhibitors Breast cancer [102] K116 Allosteric inhibitors Breast cancer and prostate cancer [103] Small molecule STAT3 Pyrimethamine Chronic lymphocytic and small lymphocytic leukemia [105-107] activation inhibitors Nasopharyngeal carcinoma, advanced cancer, multiple myeloma, Small molecule STAT3 OPB-51602 non-Hodgkin lymphoma, acute myeloid leukemia, chronic myeloid [10] activation inhibitors leukemia and malignant solid tumour Small molecule STAT3 Leukemia, advanced cancer, solid tumour, non-Hodgkin’s lymphoma, OPB-31121 [108-111] activation inhibitors multiple myeloma, and hepatocellular carcinoma

Fig. 1 STAT3 pathway in pituitary adenomas. Multiple ligands including hormones, cytokines and growth factors can activate the cytokine/growth factor receptors and activate the STAT signaling pathway. Phosphorylated tyrosine STAT3 translocates into the nucleus and regulates target gene expression. Phosphorylated serine STAT3 translocates into the mitochondria, promoting mitochondrial functions, leading to enhanced cell proliferation. Regulators of STAT3 and the specific mechanisms that they target including PTP, SOC3, PIAS, PP2A, JAK2, and Src are also indicated. Current medical therapies for pituitary adenomas, including octreotide and pasireotide, which act preferentially on SSTR2 and SSTR5 respectively are also depicted. STAT3 inhibitors suppress activation of STAT3.

tumorigenesis and hormone regulation in pituitary ade‐ studies are still required to confirm the relevance and nomas as depicted in Fig. 1 and Table 3. STAT3 regu‐ importance of STAT3 in pituitary adenomas. lates cellular functions in pituitary adenomas, including cell proliferation and hormone regulation, suggesting Conflict of Interest STAT3 as a potential biomarker and molecular therapeu‐ tic target for pituitary adenomas. As pituitary tumours The author(s) declared no potential conflicts of inter‐ are located outside the blood-brain-barrier, novel drugs est with respect to the authorship and/or publication of targeting STAT3 can be delivered to pituitary tumours. this article. Studies in the form of basic, preclinical, and clinical

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Table 3 The roles of STAT3 in pituitary tumorigenesis and hormone production/secretion Pituitary tumour growth, STAT3 Hormone production/secretion Pituitary adenoma models References invasion, recurrence correlation with Human null cell adenomas [14] invasiveness Human somatotroph ↑cell-growth ↑GH [12] adenoma cells pY-STAT3 ↑cell-growth ↑GH GH3 cells [12, 41] ↑cell-growth ↓GH GH4 cells [13] unknown ↓PRL MtT/SM cells [43] no effect ↑ACTH AtT20 cells [44] ↑cell-growth unknown AtT20 cells [47] strong immunoreactivity in Human somatotroph unknown [13] human somatotroph adenomas adenomas pS-STAT3 ↑cell-growth no effect GH4 cells [13, 46] ↑cell-growth no effect AtT20 cells [44] correlation with PRL, IGF-1, Low STAT3 methylation correlation with and/or ACTH Human pituitary adenomas [15] status invasiveness immunoreactivity STAT3 rs744166 G/G correlation with recurrence unknown Human pituitary adenomas [16] genotype

Acknowledgment published showing the involvement of STAT3/5 in the transcriptional regulation of the POMC gene in cortico‐ This project was supported by Start-up funds from the troph adenomas (Araki T, Tone Y, Yamamoto M, University of Alberta and by a grant from the University Kameda H, Ben-Shlomo A, et al. Two distinctive POMC Hospital Foundation. Liu C. is a recipient of Summer promoters modify gene expression in Cushing’s disease. Research Studentship from Alberta Innovates. J Clin Endocrinol Metab. (2021) Jun 1; dgab387 Epub ahead of print). Note

During the peer review of this article, a new paper was

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