Progression Of Pituitary Adenomas Research Articles

The diverging role of O-GlcNAc transferase in corticotroph and somatotroph adenomas.

Molecular mechanisms involved in the pathogenesis and tumor progression of pituitary adenomas (PA) remain incompletely understood. Corticotroph and somatotroph PA are associated with a high clinical burden, and despite improved surgical outcomes and medical treatment options, they sometimes require multiple surgeries and radiation. Preliminary data suggested a role for O-GlcNAc Transferase (OGT), the enzyme responsible for the O-GlcNAcylation of proteins. O-GlcNAcylation and OGT have been found elevated in other types of tumors. We evaluated 60 functioning and nonfunctioning PA (NFPA) from operated patients and postmortem normal and tumoral pituitary tissue by immunohistochemistry. We performed transcriptomic analyses to explore the relevance of the O-GlcNAc Transferase (OGT) in PAs. We detected OGT in immunobiological analysis and define its level in PA tissue in patients. OGT was strongly associated with PA hormone secretory capacity in functioning PA and with tumor growth in NFPAs. In NFPAs, OGT was positively associated with tumor size but not with cavernous sinus invasion (Knosp grading). In GH-secreting PA, OGT expression was negatively correlated with circulating Insulin-like Growth Factor 1 level. In adrenocorticotropic hormone (ACTH)-secreting PA, OGT expression was positively associated with circulating ACTH levels. OGT did not correlate with tumor size in secreting PAs. OGT levels were higher in gonadotroph PA compared to normal glands. O-GlcNAcylation can be downregulated in non-cancerous tumors such as GH-secreting adenomas. Future studies are warranted to elucidate the role of OGT in the pathogenesis of PAs.

Retraction Note: LncRNA PCAT6 regulates the progression of pituitary adenomas by regulating the miR-139-3p/BRD4 axis

Retraction Note: LncRNA PCAT6 regulates the progression of pituitary adenomas by regulating the miR-139-3p/BRD4 axis

MiR-200b-3p accelerates progression of pituitary adenomas by negatively regulating expression of RECK.

MicroRNA (miR)-200b-3p has been associated with many tumors, but its involvement in pituitary adenoma is unclear. This study investigated the molecular mechanism underlying miR-200b-3p regulation in pituitary adenomas to provide a theoretical basis for treatment. Bioinformatics was used to analyze pituitary adenoma-related genes and screen new targets related to RECK and miRNA. As well, the relationship between miR-200b-3p and RECK protein was verified using a double-luciferase reporter gene assay. The expression of miR-200b-3p in clinical samples was analyzed by in situ hybridization. Transfection of the miR-200b-3p inhibitor and small interfering-RECK (si-RECK) was verified by qPCR. GH3 cell viability and proliferation were detected using CCK8 and EdU assays. Apoptosis was detected by flow cytometry and western blotting. Wound healing and Transwell assays were used to detect cell migration and invasion. The effects of miR-200b-3p and RECK on GH3 cells were verified using salvage experiments. miR-200b-3p was highly expressed in pituitary tumor tissue. Inhibitors of miR-200b-3p inhibited cell proliferation promoted cell apoptosis, inhibited invasion and migration, and inhibited the expression of matrix metalloproteinases. Interestingly, miR-200b-3p negatively regulated RECK. The expression of RECK in pituitary adenoma tissues was lower than that in neighboring tissues. Si-RECK rescued the function of miR-200b-3p inhibitors in the above cellular behaviors, and miR-200b-3p accelerated the development of pituitary adenoma by negatively regulating RECK expression. In summary, this study investigated the molecular mechanism by which miR-200b-3p regulates the progression of pituitary adenoma through the negative regulation of RECK. The findings provide a new target for the treatment of pituitary adenoma.

CircDDX17 inhibits invasive progression of pituitary adenomas by sponging miR-1279 and regulating CADM2 expression.

Increasing evidence has revealed that circDDX17 plays significant regulatory roles in tumor progression. In the present study, we investigated the role of circDDX17 in pituitary adenomas (PAs). Reverse transcription-quantitative PCR was performed to detect the expression of Circular RNA DDX17 (circDDX17), microRNA-1279 (miR-1279), and cell adhesion molecule 2 (CADM2) in PA tissues. Cell abilities of migration and invasion were examined by wound healing and transwell assays. Dual-luciferase reporter, RNA immunoprecipitation, and RNA pull-down assays were applied to confirm the associations among circDDX17, miR-1279, and CADM2. Xenograft tumor experiments were performed to investigate the roles of circDDX17 in vivo. In the present study, we found that circDDX17 was downregulated in PA tissues correlated with invasion, tumor size, and progression-free survival of patients with PA. Enforced expression of circDDX17 significantly inhibited migration and invasion through miR-1279. Notably, CADM2 was verified as the direct binding target of miR-1279, and silencing the expression of CADM2 reverses the tumor suppressing effects induced by circDDX17 overexpression. We demonstrated that circDDX17 upregulated the expression of CADM2 by sponging miR-1279, which suppressed the invasive biological behaviors of PA. CircDDX17 may serve as a tumor suppressor and potential promising biomarker and effectively therapeutic target for the management of PA.

A disintegrin and metalloproteinase 22 activates integrin β1 through its disintegrin domain to promote the progression of pituitary adenoma.

Approximately 35% of pituitary adenoma (PA) display an aggressive profile, resulting in low surgical total resection rates, high recurrence rates, and worse prognosis. However, the molecular mechanism of PA invasion remains poorly understood. Although "a disintegrin and metalloproteinases" (ADAMs) are associated with the progression of many tumors, there are no reports on ADAM22 in PA. PA transcriptomics databases and clinical specimens were used to analyze the expression of ADAM22. PA cell lines overexpressing wild-type ADAM22, the point mutation ADAM22, the mutated ADAM22 without disintegrin domain, and knocking down ADAM22 were generated. Cell proliferation/invasion assays, flow cytometry, immunohistochemistry, immunofluorescence, co-immunoprecipitation, mass spectrometry, Reverse transcription-quantitative real-time PCR, phos-tag SDS-PAGE, and Western blot were performed for function and mechanism research. Nude mice xenograft models and rat prolactinoma orthotopic models were used to validate in vitro findings. ADAM22 was significantly overexpressed in PA and could promote the proliferation, migration, and invasion of PA cells. ADAM22 interacted with integrin β1 (ITGB1) and activated FAK/PI3K and FAK/ERK signaling pathways through its disintegrin domain to promote PA progression. ADAM22 was phosphorylated by PKA and recruited 14-3-3, thereby delaying its degradation. ITGB1-targeted inhibitor (anti-itgb1) exerted antitumor effects and synergistic effects in combination with somatostatin analogs or dopamine agonists in treating PA. ADAM22 was upregulated in PA and was able to promote PA proliferation, migration, and invasion by activating ITGB1 signaling. PKA may regulate the degradation of ADAM22 through post-transcriptional modification levels. ITGB1 may be a potential therapeutic target for PA.

Tumor-Associated Fibroblast-Derived Exosomal circDennd1b Promotes Pituitary Adenoma Progression by Modulating the miR-145-5p/ONECUT2 Axis and Activating the MAPK Pathway.

TAF participated in the progression of various cancers, including PA via the release of soluble factors. Exosomes belonged to extracellular vesicles, which were revealed as a crucial participator in intercellular communication. However, the expression pattern and effect of TAF-derived exosomes remained largely unknown in PA. In the present study, we performed in silico analysis based on public RNA-seq datasets to generate the circRNA/miRNA regulatory network. The qRT-PCR, Western blotting, RNA pull-down, and luciferase assay were performed to investigate the effect of TAF-derived exosomes. TAF-derived exosomal circDennd1b was significantly upregulated in PA and promoted the proliferation, migration, and invasion of PA cells via sponging miR-145-5p in PA cells. In addition, miR-145-5p directly regulated One Cut homeobox 2 (ONECUT2/OC2) expression and inhibited the promoting effect of ONECUT2 on PA. We further demonstrated that ONECUT2 transcriptionally increased fibroblast growth factor receptor 3 (FGFR3) expression, which further activates the mitogen-activated protein kinases (MAPK) pathway, thus promoting PA progression. Moreover, the suppression of TAFs by ABT-263 and ONECUT2 by CSRM617 inhibited the growth of PA. In conclusion, our study illustrated that TAF-derived exosomal circDennd1b affected PA progression via regulating ONECUT2 expression, which provides a potential therapeutic strategy against aggressive PA.

Tamoxifen Exerts Anticancer Effects on Pituitary Adenoma Progression via Inducing Cell Apoptosis and Inhibiting Cell Migration.

Although pituitary adenomas are histologically benign, they are often accompanied by multiple complications, such as cardiovascular disease and metabolic dysfunction. In the present study, we repositioned the Food and Drug Administration -approved immune regulator tamoxifen to target STAT6 based on the genomics analysis of PAs. Tamoxifen inhibited the proliferation of GH3 and AtT-20 cells with respective IC50 values of 9.15 and 7.52 μM and increased their apoptotic rates in a dose-dependent manner. At the molecular level, tamoxifen downregulated phosphorylated PI3K, phosphorylated AKT and the anti-apoptotic protein Bcl-2 and increased the expression of pro-apoptotic proteins p53 and Bax in GH3 and AtT-20 cells. Furthermore, tamoxifen also inhibited the migration of both cell lines by reprogramming tumor-associated macrophages to the M1 phenotype through STAT6 inactivation and inhibition of the macrophage-specific immune checkpoint SHP1/SHP. Finally, administration of tamoxifen (20, 50, 100 mg·kg−1·d−1, for 21 days) inhibited the growth of pituitary adenomas xenografts in nude mice in a dose-dependent manner. Taken together, tamoxifen is likely to be a promising combination therapy for pituitary adenomas and should be investigated further.

EIF1A depletion restrains human pituitary adenoma progression

EIF1A encodes a translation initiation factor in eukaryocyte and aberrant expression of EIF1A is deemed to be associated with dysfunctions in intracranial diseases. The goal of this research was to explore the impacts of EIF1A on progression of human pituitary adenoma (PA). We employed immunohistochemistry to assess the expression of EIF1A in PA and para-carcinoma tissues. After constructing EIF1A-knockdown cell models via lentivirus infection, we examined cell proliferation through CCK-8 assay and Celigo cell counting assay. Flow cytometry was utilized to detect cell apoptosis and the migration ability of experimental cells was estimated using wound-healing assay and Transwell assay. The activity of the apoptosis-related factor, Caspase 3, was also examined via Caspase 3 activity assay. Lastly, in vivo xenograft mouse models were established to verify findings derived from in vitro cell models. Our results affirmed upregulation of EIF1A in PA cells and revealed that depletion of EIF1A could seriously limit cell proliferation and weaken the capacity of cell migration, and also enhance apoptosis of tumor cells. Mechanistically, degradation in cell growth mediated by EIF1A knockdown may involve in activation of MAPK signaling but inactivation of PI3K/AKT signaling pathway. This study indicates EIF1A plays a prominent role in facilitating tumor cell proliferation and migration which may further contribute to PA progression.

LINC01116 boosts the progression of pituitary adenoma via regulating miR-744–5p/HOXB8 pathway

Pituitary adenoma (PA) is one of the common intracranial tumors. In order to optimize status quo, seeking out potential biomarkers for pituitary adenoma diagnosis and treatment is urgent and important. Long non-coding RNAs (lncRNAs) have been related with progression of various cancers. Based on this reason and unknown role of long intergenic non-protein coding RNA 1116 (LINC01116) in pituitary adenoma, we aimed to explore the function and molecular mechanism of LINC01116 in pituitary adenoma. The RT-qPCR analysis showed that LINC01116 was abnormally overexpressed in pituitary adenoma cells. Down-regulated LINC01116 effectively suppressed cell proliferation and migration as well as epithelial–mesenchymal transition (EMT) progression in pituitary adenoma. Additionally, LINC01116 could competitively sponge miR-744–5p as shown by RIP, RNA pull down and luciferase reporter assays. Similarly, we also proved that homeobox B8 (HOXB8) was the target gene of miR-744–5p in pituitary adenoma cells. In the end, the rescue assays unmasked that HOXB8 could effectually reverse inhibition effect of LINC016 knockdown on pituitary adenoma cells proliferation, migration and EMT, further suggesting that LINC01116 expedited the pituitary adenoma progression by up-regulating HOXB8. Taken together, LINC01116 boosted the progression of pituitary adenoma cells via regulating miR-744–5p/HOXB8 pathway.

CircNFIX promotes progression of pituitary adenoma via CCNB1 by sponging miR-34a -5p

Previous studies have shown that CCNB1 affects the invasiveness of pituitary adenomas, and it is of great significance to find the upstream mechanism of regulating CCNB1.In this study, we explored a significantly overexpressed circRNA in invasive pituitary adenomas. Based on bioinformatics analysis and mechanism experiments, we determined that circNFIX (has-circ_0005660) affects cell invasion, migration and proliferation in pituitary adenomas by sponging miR-34a-5p through CCNB1. In pituitary adenoma tissues, the expression of circNFIX and CCNB1 was upregulated, while miR-34a-5p expression was downregulated. The silencing of circNFIX or overexpression of miR-34a-5p inhibited cell invasion, migration and proliferation. Inhibition of miR-34a-5p expression reversed the inhibitory effect of circNFIX silencing on the progression of pituitary adenoma. In conclusion, CircNFIX affects cell invasion, migration, and proliferation in pituitary adenomas by sponging miR-34a-5p through CCNB1. Therefore, circNFIX is expected to serve as a potential target for the treatment of pituitary adenomas.

MCM7 as a marker of postsurgical progression in non-functioning pituitary adenomas.

Current markers predicting tumour progression of pituitary adenomas after surgery are insufficient. Our objective was to investigate if minichromosome maintenance protein 7 (MCM7) expression predicts tumour progression in non-functioning pituitary adenomas (NFPAs). In a cohort study of surgically treated NFPAs, two groups with distinctly different behaviour of a residual tumour were selected: one group requiring reintervention due to tumour progression (reintervention group, n = 57) and one with residual tumours without progression (radiologically stable group, n = 40). MCM7, Ki-67, oestrogen receptor-α expression, mitotic index and tumour subtype were assessed by immunohistochemistry, and their association with tumour progression requiring reintervention was analysed. Median (IQR) MCM7 expression was 7.4% (2.4-15.2) in the reintervention group compared with 2.0% (0.6-5.3) in the radiologically stable group (P <0.0001). Cox regression analysis showed an association between high (>13%) MCM7 expression and reintervention (HR: 3.1; 95% CI:1.7-5.4; P = 0.00012). The probability for reintervention within 6 years for patients with high MCM7 was 93%. Ki-67 expression >3% (P = 0.00062), age ≤55 years (P = 0.00034) and mitotic index≥1 (P = 0.024) were also associated with reintervention. Using a receiver operating characteristics curve, a predictive model for reintervention with all the above predictors yielded an area under the curve of 82%. All eight patients with both high MCM7 and high Ki-67 needed reintervention. This cohort study shows that expression of MCM7 is a predictor for clinically significant postoperative tumour progression. Together with age, Ki-67 and mitotic index, MCM7 might be of added value as a predictive marker when managing patients with NFPA after surgery.

RETRACTED ARTICLE: LncRNA PCAT6 regulates the progression of pituitary adenomas by regulating the miR-139-3p/BRD4 axis

BackgroundDysregulated lncRNA PCAT6 was discovered in many cancers excluding pituitary adenomas (PA). Therefore, we explored the role of PCAT6 in PA in this research.MethodsAbnormally expressed miRNAs were analyzed by bioinformatics and RT-qPCR. The target and regulator of miR-139-3p were determined by bioinformatics, dual-luciferase reporter assay, or RIP. The correlation among PCAT6, miR-139-3p, and BRD4 was further analyzed. The viability, apoptosis, cell cycle distribution of PA cells, as well as their ability to invade, migrate, and proliferate, were tested after transfection through CCK-8, flow cytometry, transwell, wound healing, and colony formation assays. After construction of transplanted-tumor model in nude mice, cell apoptosis in the tumor was detected by TUNEL. The expressions of PCAT6, BRD4, miR-139-3p, and apoptosis-related factors in PA tissues, cells, or tumor tissues were detected by RT-qPCR, Western blot, or IHC.ResultsPCAT6 and BRD4 were high-expressed but miR-139-3p was low-expressed in PA. Both the 3′-untranslated regions of PCAT6 and BRD4 mRNAs were demonstrated to contain a potential binding site for miR-139-3p. PCAT6 was positively correlated to BRD4, and miR-139-3p was negatively correlated to PCAT6 and BRD4. MiR-139-3p mimic, shPCAT6 and siBRD4 inhibited the viability, migration, invasion, and proliferation of PA cells while inducing apoptosis. MiR-139-3p mimic and shPCAT6 inhibited the cell cycle progression of PA cells, decreased the weight and volume of the xenotransplanted tumor, and reduced the levels of Bcl-2 and BRD4 while enhancing the levels of Bax, miR-139-3p, and Cleaved caspase-3. MiR-139-3p inhibitor caused the opposite effect of miR-139-3p mimic and further reversed the effect of shPCAT6 on on PA cells.ConclusionPCAT6 regulated the progression of PA via modulating the miR-139-3p/BRD4 axis, which might provide a novel biomarker for the prevention, diagnosis, and treatment of PA.

Dysregulated miR-137 and its target EGFR contribute to the progression of pituitary adenomas

Pituitary adenomas (PAs) hypersecrete hormones or cause mass effect symptoms, with 10%–35% patients showing resistance to standard therapies. Targeting epidermal growth factor receptor (EGFR) has significantly improved the clinical outcome in many cancers. In this study, immunochemistry results showed that EGFR associated H-scores in 116 PA samples were higher than those in pituitary glands, and that p21, p27-and Wif-1 associated H-scores were lower (P < 0.05 for all). Patients with high levels of EGFR had increased PA invasion, lower total resection, and lower p21 and p27 expression than those with low levels of EGFR expression. Dual-luciferase reporter gene assays showed that EGFR was the target gene of miR-137, and miR-137 mimic could inhibit the cell proliferation of GH3 cells and induce apoptosis and G1-phase arrest of GH3 cells. A combination of miR-137 mimic and AZD9291 had stronger inhibition on GH3 cells compared with miR-137 mimic or AZD9291 alone; furthermore, miR-137 inhibitor partially reversed the inhibition of AZD9291. p21 and p27 were shown to be involved in the miR-137- and AZD9291-mediated effects on GH3 cells. In all, activation of EGFR in PAs was related to tumor invasive behavior, which reduced the total resection of PAs in patients. A combination of miR-137 and AZD9291 provided a potential treatment for PAs, especially for patients who show resistance to standard treatment.

LncRNA SNHG7 sponges miR-449a to promote pituitary adenomas progression.

This study aimed to characterize the expression status and potentially mechanistic involvement of SNHG7 in pituitary adenoma. Relative expression of SNHG7 and miR-449a was analyzed by real-time PCR. Cell viability was measured with Cell Counting Kit-8 (CCK-8). Cell apoptosis was determined by PI/Annexin V double staining followed by flow cytometry analysis. Cell invasion and migration were analyzed by wound healing and transwell assays, respectively. The regulatory action of miR-449a on SNHG7 was interrogated by luciferase reporter assay. We also investigated the pro-tumor activity of SNHG7 with the MMQ xenograft tumor mouse model. We identified the aberrant up-regulation of SNHG7 in pituitary adenoma both in vivo and in vitro, which associated with poor survival outcome. siRNA-mediated SNHG7-knockdown decreased cell viability, increased apoptosis and compromised migration and invasion. We further predicted and validated that SNHG7 negatively regulated miR-449a via sponging. Concurrent inhibition of miR-449a restored cell viability, apoptosis, migration and invasion influenced by SNHG7-deficiency. Most importantly, we demonstrated that SNHG7-silencing delayed xenograft tumor progression, which was accompanied with increased miR-449a and decreased Ki67 intensity. Our study highlighted the essential oncogenic properties of the SNHG7/miR-449a axis in pituitary adenoma.

26. GENETIC CHARACTERIZATION OF SELLAR METASTASIS FROM PRIMARY BRONCHIAL CARCINOID TUMOR OF NEUROENDOCRINE PATHOLOGY

Metastasis to the pituitary gland and surrounding sellar region from systemic tumors is a rare occurrence. Patients may present with signs of endocrine dysfunction secondary to pituitary involvement, as well as mass effect-related symptoms including headaches and visual deficits. Despite a small but accumulating body of literature describing the clinical and histopathological correlates for sellar metastases from systemic tumors, the genetic alterations underlying sellar spread have not been previously described. We describe a 68 year-old female with history of a resected lung carcinoid tumor, followed by chemoradiation, who was diagnosed with a sellar lesion on surveillance PET-CT and subsequent brain MRI. Her tumor was resected via an endoscopic endonasal approach, and final pathology was consistent with neuroendocrine origin, including positive immunohistochemistry for synpatophysin, CK7, TTF-1, and CAM5.2 with a Ki-67 index of 8–12%. Whole-exome sequencing of the sellar specimen demonstrated large-scale deletions of chromosomes 3, 6, and 9 and focal deletions on chromosomes 1,2, 11, 15, and 16. Mutational signature analysis was enriched for COSMIC Signature 4, seen in multiple primary lung cancers. Among 91 total somatic alterations, 7 had been previously associated with oncogenesis (MYO18A, PTCH1, BCOR, CLIC6, TLL2, COL1A1, PTPRK). Notably, mutations in BCOR and PTCH1 have been previously implicated in both systemic neuroendocrine tumors as well as primary tumors of the pituitary gland, while MYO18A, FGF4, and PTPRK mutations had not been reported in systemic neuroendocrine tumors but have been implicated in tumor migration and pituitary adenoma progression. In summary, these data demonstrated an expected mutational pattern indicating a systemic lung neuroendocrine origin but also revealed new mutations previously implicated in primary pituitary pathologies that may have evolutionarily drove divergence from the primary tumor. Further genome studies of these rare lesions may yield further insight into the genetic alterations underlying metastasis to the sellar region.

MiR-448 targets BLC2 and inhibits the growth of pituitary adenoma cells.

There is an increasing body of evidence indicating the important roles of miRNAs in the progression of pituitary adenoma. Recent studies have shown decreased expression and tumor suppressive function of miR-448 in cancers; however, the clinical significance of miR-448 in pituitary adenoma has remained largely unknown. In our study, we found that miR-448 was down-regulated in pituitary adenoma tissues and cell lines. Overexpression of miR-448 significantly inhibited the proliferation and migration of pituitary adenoma cells. Increased cell apoptosis was also observed with overexpression of miR-448. To further understand the mechanisms behind the regulation of pituitary adenoma by miR-448 in, the targets of miR-448 were predicted using the bioinformatics tools. B cell lymphoma 2 (BCL2) was identified as a target of miR-448. MiR-448 bound the 3'-untranslated region (UTR) of BCL2 and inhibited the expression of BCL2 in pituitary adenoma cells. There was a consistent and significantly negative correlation between the level of miR-448 and BCL2 in pituitary adenoma tissues. When BCL2 was highly expressed, the inhibitory impact of miR-448 on the proliferation and apoptosis of pituitary adenoma cells was significantly inhibited. Collectively, our findings emphasize the significance of the miR-448-BCL2 axis in the development of pituitary adenoma, highlighting the potential therapeutic significance of miR-448 in pituitary adenoma.

MiR-219a-2-3p suppresses cell proliferation and promotes apoptosis by targeting MDM2/p53 in pituitary adenomas cells.

Pituitary adenomas constitute one of the most common intracranial tumors. MicroRNAs play an important role in development and progression of pituitary adenomas. In this study, we showed that miR-219a-2-3p was significantly down-regulated in pituitary adenomas cells. Overexpression of miR-219a-2-3p suppressed the proliferation and promoted apoptosis of pituitary adenomas cells. After bioinformatics analysis, we found that MDM2 was one of the downstream targets of miR-219a-2-3p. Further researches showed that miR-219a-2-3p could reduce the protein level of MDM2 by binding to the 3'-UTR of MDM2 and promoted p53 expression. Then, we overexpressed both miR-219a-2-3p and MDM2 in the same group and found that it could counteract the effect of overexpressing miR-219a-2-3p alone on proliferation and apoptosis of pituitary adenoma cells. Taken together, these results suggested that miR-219a-2-3p regulated the proliferation and apoptosis by targeting MDM2/p53 in pituitary adenomas. Therefore, miR-219a-2-3p may serve as a novel marker and therapeutic target for pituitary adenomas.

Construction of lncRNA regulatory networks reveal the key lncRNAs associated with Pituitary adenomas progression.

Pituitary adenomas (PA) is one of the most frequent types of intracranial neoplasms. Long noncoding RNAs (lncRNAs) played important roles in the progression of human cancers, including PA. However, the roles of lncRNAs in PA remained to be further investigated. We performed analysis of GSE26966 dataset to identify differently expressed lncRNAs in PA. Co-expression network, lncRNA-RNA binding proteins network, and competing endogenous RNA networks were constructed. Moreover, we performed RT-qPCR assay to validate four key lncRNAs expression in PA. This study identified differently expressed mRNAs and lncRNAs by using GSE26966 database. Furthermore, we constructed lncRNA-mRNA co-expression, lncRNA-RBP interaction and ceRNA networks. Bioinformatics analysis showed these lncRNAs were involved in regulating mechanical stimulus, gene expression, JAK-STAT cascade, cell cycle arrest, FoxO signaling, HIF-1 signaling, Insulin signaling, Oxytocin signaling, and MAPK signaling. We also showed KCNQ1OT1, SNHG7, MEG3, and SNHG5 were down-regulated in PA. Our findings could provide a novel insight to understand the mechanisms of lncRNAs underlying PA pathogenesis and identify new biomarkers for PA.

Reduction of miR-212 contributes to pituitary adenoma cell invasion via targeting c-Met.

The current study aimed to evaluate the expression and role of miR-212 in the progression of pituitary adenoma (PA), thereby providing a theoretical basis and potential therapy methods for PA patients. Our data showed that miR-212 levels were significantly reduced in PA tissues than normal pituitary tissues. However, no significant difference was identified in the serum of PA patients and healthy control. In addition, the expression of miR-212 in invasive PA was significantly lower than that in noninvasive and normal pituitary tissues. Moreover, the level of miR-212 was decreased with the increase of tumor invasion. Meanwhile, the expression of miR-212 in giant adenomas was significantly lower than that in macroadenomas and microadenomas. Furthermore, inhibition of miR-212 significantly enhanced the proliferation and invasive capacity of GH3 cells. Dual luciferase reporter assay and western blot analysis confirmed that c-Met was a target gene of miR-212. More importantly, upregulation of c-Met significantly prompted PA cell proliferation mainly as a result of the enhanced level of phosphorylation of AKT. This effect could be abolished when c-Met was silenced in GH3 cells. In summary, reduced miR-212 expression in PA contributed to abnormal cancer cell proliferation and invasion mainly by targeting c-Met.

Long Non-Coding RNA Plasmacytoma Variant Translocation 1 (PVT1) Enhances Proliferation, Migration, and Epithelial-Mesenchymal Transition (EMT) of Pituitary Adenoma Cells by Activating β-Catenin, c-Myc, and Cyclin D1 Expression.

BackgroundAs a kind of benign tumor, pituitary adenomas have attracted increasing attention from researchers. The plasmacytoma variant translocation 1 (PVT1) is a molecule in the lncRNA family protein that has been proven to play critical roles in many cancers; however, no study has explored the special biological roles of PVT1 in pituitary adenoma.Material/MethodsThe qRT-PCR assay was conducted to evaluate PVT1 expressions in various cell lines and tissues. Loss of function assays were carried out to detect the influence of silenced PVT1 on the proliferation, migration, and epithelial-mesenchymal transition (EMT) of pituitary adenoma cells. Western blotting was used to identify correlation between β-catenin and PVT1.ResultsThe PVT1 expressions were significantly enhanced in tissues of pituitary adenoma and cancer cells. Cell migration and proliferation were inhibited when the PVT1 gene was knocked down. Knockdown of PVT1 repressed the migration and EMT of pituitary adenoma cells. The PVT1 downregulation obviously blocked Wnt/β-catenin signaling pathway activity. PVT1 aggravated progression of pituitary adenoma through initiating the Wnt/β-catenin signaling pathway.ConclusionsPVT1 exerts an oncogenic role through activating Wnt/β-catenin signaling in pituitary adenoma cells. The present results may provide a potential therapeutic target or approach for treating pituitary adenomas.