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Integrase interactor 1 (INI1) loss is associated with a poor prognosis of skull base chordoma, while the molecular mechanism remains generally unclear. Hence, we herein explored the regulatory mechanism underlying INI1 action in skull base chordoma. We exploited transcriptomic sequencing of 48 skull base chordomas to analyze the INI1-correlated genes, and we found that EZH2 was negatively correlated with INI1. As EZH2 regulated the expression of the repressive histone mark H3K27me3, we applied chromatin immunoprecipitation (ChIP) sequencing of H3K27me3 to investigate the downstream molecules involved. ChIP sequencing and ChIP-qPCR revealed that H3K27me3 directly bound to the SIDT1 promoter, and qRT-PCR verified that H3K27me3 suppressed the transcription of SIDT1. The expression of SIDT1 in skull base chordoma was assessed using immunohistochemical staining and its low expression was associated with a poor prognosis in chordoma patients. When the potential tumor-suppressive effects ofSIDT1 were further investigatedby cytologic experiments, our results verified that SIDT1 played a tumor-suppressive role in chordoma both in vitro and in vivo. In conclusion, these findings suggested the INI1-EZH2-H3K27me3-SIDT1 axis as a possible novel therapeutic target in skull base chordoma.

Background Recently, a hotspot mutation in prolactinoma was observed in splicing factor 3b subunit 1 (SF3B1R625H), but its functional effects and mechanisms are poorly understood. Methods Using the CRISPR/Cas9 genome editing system and rat pituitary GH3 cells, we generated heterozygous Sf3b1R625H mutant cells. Sanger and whole-genome sequencing were conducted to verify the introduction of this mutation. Transcriptome analysis was performed in SF3B1-wild-type versus mutant human prolactinoma samples and GH3 cells. Quantitative PCR and minigene reporter assays were conducted to verify aberrant splicing. The functional consequences of SF3B1R625H were evaluated in vitro and in vivo. Critical makers of epithelial-mesenchymal transition and key components of relevant signaling pathways were detected by western blot, immunohistochemistry, and immunofluorescence, and were knocked down by siRNA-mediated silencing. Results Transcriptomic analysis of prolactinomas and heterozygous mutant cells revealed that the SF3B1R625H allele led to different alterations in splicing properties, affecting different genes in different species. Consistently between rat cells and human tumor samples, mutant SF3B1 promoted aberrant splicing and the suppression of DLG1. Additionally, mutant SF3B1 with knockdown of DLG1 expression promoted cell migration, invasion, and epithelial-mesenchymal transition by activating the PI3K/Akt pathway. Conclusions Our findings elucidate a mechanism through which mutant SF3B1 promotes tumor progression and may provide a potent molecular therapeutic target for prolactinomas with the SF3B1R625H mutation.

OBJECTIVE: Skull-base chordoma (SBC) is rare and one of the most challenging diseases to treat. We aimed to assess the optimal timing of adjuvant radiation therapy (RT) and evaluate the factors that influence resection and long-term outcomes.METHODS: In total, 284 patients with 382 surgeries were enrolled in this retrospective study. Postsurgically, 64 patients underwent RT before recurrence (pre-recurrence RT), and 47 patients underwent RT after recurrence. During the first attempt to achieve gross-total resection (GTR), when the entire tumor was resected, 268 patients were treated with an endoscopic midline approach, and 16 patients were treated with microscopic lateral approaches. Factors associated with the success of GTR were identified using c2 and logistic regression analyses. Risk factors associated with chordoma-specific survival (CSS) and progression-free survival (PFS) were evaluated with the Cox proportional hazards model.RESULTS: In total, 74.6% of tumors were marginally resected [GTR (40.1%); near-total resection (34.5%)]. History of surgery, large tumor volumes and tumor locations in the lower clivus were associated with a lower GTR rate. The mean follow-up period was 43.9 months. At last follow-up, 181 (63.7%) patients were alive. RT history, histologic subtype (dedifferentiated and sarcomatoid), non-GTR, no postsurgical RT, and the presence of metastasis were associated with poorer CSS. Patients with pre-recurrence RT had the longest PFS and CSS, while patients without postsurgical RT had the worst outcome.CONCLUSION: GTR is the goal of initial surgical treatment. Pre-recurrence RT would improve outcome regardless of GTR.

Background: Pituicytoma is an extremely rare low-grade glial tumor that is closely related to the neurohypophysis axis. Most studies of pituicytomas include only several cases. To better understand this disease, we reviewed a series of cases of pituicytomas. The diagnosis and treatment of pituicytoma must be further elucidated.Methods: Eleven patients with pituicytoma admitted to Beijing Tiantan Hospital from 2012 to 2019 were selected. The clinical features, including radiological and histological examination, surgical records and prognosis were reviewed. Sixty-eight other previously published cases of pituicytoma also were used to analyze the predictive factors for the results.Results: Our cohort included 4 males (36.37%) and 7 females (63.63%), with a mean age of 48.6 years. The tumor was located in the suprasellar region in 4 patients (36.37%), intrasellar region in 5 patients (45.45%), and intrasellar-suprasellar region in 2 patients (18.18%). All patients were misdiagnosed with other common tumors in the sellar region before the operation. During the operation, gross total resection of the tumor was achieved in 6 patients (54.55%), and subtotal resection was achieved in 5 patients (45.45%). The mean progression-free survival time was 33.72 months. Tumor progression after surgical resection occurred in 4 patients (36.37%). Among them, 72.73% of the patients with subtotal resection experienced progression, while 18.18% of the patients with gross total resection experienced progression. Combined with the 68 cases in the literature, gross total resection was an independent risk factor for progression-free survival time (PConclusion: Pituicytomas are more common in middle-aged people and in the sellar region. The clinical manifestations of pituicytomas are different, but no diagnostic clinical features have been identified other than an abnormally abundant blood supply. Currently, gross total resection is the best approach for the treatment of pituicytomas. More patients and longer follow-up periods were needed to further elucidate the biological features of pituicytomas.

Background: Pituicytomas are rare neurogenic tumors of the sellar region.The diagnosis and treatment of pituicytoma needs to be further elucidated.Patients and Methods: This research included 16 patients with pituicytomas that were pathologically diagnosed in Tiantan Hospital from 2012 to 2019. And 68 other previously published cases of pituicytoma to analyze the predictive factors of the results.Results: Our cohort included 7 males (43.75%) and 9 females (56.25%), with a mean age of 49 years. The tumor was located in the suprasellar in 7 cases (43.75%), intrasellar in 6 cases (37.5%), and intrasellar-suprasellar mixed in 3 cases (18.75%). All patients were misdiagnosed with other common tumors in the sellar region before the operation. During the operation, gross total resection (GTR) of the tumor was achieved in 9 cases (56.25%) and subtotal resection (STR) in 7 cases (43.75%). The mean progression-free survival time (PFS) was 34.63 months. Tumor progression after surgical resection occurred in 5 patients (31.25%). Among them, 57.14% of the patients with STR had progression, while 11.11% of the patients with GTR had progression. Combined with 68 cases in the literature, it was found that GTR was an independent risk factor for PFS(PConclusions: Pituicytomas are more common in middle-aged people and the suprasellar region. The clinical manifestations of pituicytomas are different, there are no diagnostic clinical features, and its blood supply is abnormally abundant. Currently, GTR is the best approach for the treatment of pituicytomas.

Pit-1 (POU1F1) is a POU-homeodomain transcription factor, and it is one of the most important tissue-specific transcription factors in pituitary development. Cyclin-dependent kinase 5 (CDK5) is a protein kinase that can phosphorylate many key transcription factors, but the mechanism under which CDK5 phosphorylates Pit-1 is unclear. To investigate whether CDK5 can regulate cell proliferation and promote hormone secretion through phosphorylation of Ser126-Pit-1 in prolactinomas, we generated an antibody that specifically recognizes phosphorylated serine at position 126 of Pit-1 (Ser126-Pit-1). We used western blotting to detect the level of Pit-1 phosphorylation and observed the proliferation and apoptosis of GH3 cells with different levels of Pit-1 phosphorylation by clone formation experiments, cell viability assays, and flow cytometry. ELISA was used to measure the level of PRL in the supernatant of GH3 cells. Tissue microarrays and immunohistochemistry were used to evaluate the expression of the phosphorylation level of Ser126-Pit-1 (pSer126-Pit-1) in prolactinomas. Our data indicated that Ser126-Pit-1 is specifically phosphorylated by CDK5 and high-level pSer-126-Pit-1 can promote cell proliferation and PRL secretion. In addition, a higher level of pSer-126-Pit-1 correlates with a worse prognosis in patients with prolactinoma. Our results show that CDK5 mediated Ser126-Pit-1 phosphorylation and regulated prolactinoma progression and PRL secretion.

Background: Pituitary neuroendocrine tumors (PitNETs) represent the neoplastic proliferation of the anterior pituitary gland. Transcription factors play a key role in the differentiation of PitNETs according to the 2017 WHO classification of tumors of endocrine organs. However, for a substantial proportion of PitNETs, the etiology is poorly understood.Methods: To analyze the diversity genes and pathways based on transcriptomic data of 172 patients by transcriptome sequencing, difference, correlation, and enrichment analysis. The transcriptomic data and clinical characteristics are applied to find the clinical significance of key genes by correlation analysis and ROC curve. Series functional experiments demonstrated the role of DLK1/MEG3 locus through antibody blocking and RNA interference in GH3, MMQ and ATT20 cell line.Results: In this study, we found the imprinting disorders of the 14q32.2 region and DLK1/MEG3 locus associated with the differentiation of PitNETs. As being specific feature change in somatotroph adenomas compared with other subtype adenomas, DLK1/MEG3 locus promoted somatotroph differentiation and inhibited tumor proliferation in PIT1(+) PitNET patients, furthermore, the level of DLK1 played a critical role in the trend of somatotroph differentiation or lactotroph differentiation in PIT1(+) PitNET patients. Anti-DLK1 monoclonal antibody blockade or siMEG3 both indicated that the DLK1/MEG3 domain significantly induced the synthesis and secretion of growth hormone/insulin-like growth factor-1 (GH/IGF-1) and inhibited cell growth and colony formation and that the loss of DLK1 activated the mTOR signaling pathway in high DLK1-expressing and PIT1(+) GH3 cell lines. There was a mild effect in the low DLK1-expressing and PIT1(+) MMQ cell lines and no effect in the PIT1(-) ATT20 cell line, regardless of whether anti-DLK1 monoclonal antibody blockade or siMEG3 was used. Conclusions: These findings emphasize that expression at the DLK1/MEG3 locus plays a key role in the differentiation of PitNETs in patients depending on the level of PIT1. In addition, these findings provide potential molecular target data for patient stratification and treatment in the future.

Background: For individually predicting preoperative response to Stereotactic radiotherapy for Nonfunctioning pituitary Adenoma with the use of a radiomics approach.Methods: 93 cases (training set: n = 62; test set: n = 31) were recruited with contrast-enhanced T1-weighted MRI (CE-T1) before stereotactic radiotherapy. All of these patients received another MRI scan to assess sensitivity of radiotherapy after 12 to 18 months. The shrinkage and no increase in tumor volume are regarded as sensitive to gamma knife radiotherapy. According to CE-T1 images, we extracted 1208 quantitative imaging features totally. Support vector machine (SVM) combined with recursive feature elimination (RFE) and grid-search trained a four-feature prediction mode verified with an assay of receiver operating characteristics (ROC) for an individual set of test. In addition, a ROC curves with individual feature and signature bar were constructed for prediction.Results: The cross-validation area under the curve (AUC) on the three-fold train set is 0.991,0.843 and 0.889. In terms of the test and training sets, T1-CE image features led to 0.897 and 0.914 AUC, separately. Conclusions: With the use of a radiomics method, the response to Stereotactic Radiotherapy for Nonfunctioning Pituitary Adenoma was primarily predicted before the operation. The built mode performed well, suggesting that radiomics is promising to preoperatively predict sensitivity to radiotherapy in NFPA.