{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T01:48:54Z","timestamp":1783648134516,"version":"3.55.0"},"reference-count":29,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2022,10,28]],"date-time":"2022-10-28T00:00:00Z","timestamp":1666915200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Natural Foundation project of The Applied Basic Research Program of Shanxi Province","award":["201901D111430"],"award-info":[{"award-number":["201901D111430"]}]},{"name":"Natural Foundation project of The Applied Basic Research Program of Shanxi Province","award":["11000022T00000423806"],"award-info":[{"award-number":["11000022T00000423806"]}]},{"name":"Natural Foundation project of The Applied Basic Research Program of Shanxi Province","award":["81601205"],"award-info":[{"award-number":["81601205"]}]},{"name":"Natural Foundation project of The Applied Basic Research Program of Shanxi Province","award":["81771489"],"award-info":[{"award-number":["81771489"]}]},{"name":"Beijing Municipal Health Commission","award":["201901D111430"],"award-info":[{"award-number":["201901D111430"]}]},{"name":"Beijing Municipal Health Commission","award":["11000022T00000423806"],"award-info":[{"award-number":["11000022T00000423806"]}]},{"name":"Beijing Municipal Health Commission","award":["81601205"],"award-info":[{"award-number":["81601205"]}]},{"name":"Beijing Municipal Health Commission","award":["81771489"],"award-info":[{"award-number":["81771489"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["201901D111430"],"award-info":[{"award-number":["201901D111430"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["11000022T00000423806"],"award-info":[{"award-number":["11000022T00000423806"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81601205"],"award-info":[{"award-number":["81601205"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81771489"],"award-info":[{"award-number":["81771489"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Natural Science Foundation of China","award":["201901D111430"],"award-info":[{"award-number":["201901D111430"]}]},{"name":"National Natural Science Foundation of China","award":["11000022T00000423806"],"award-info":[{"award-number":["11000022T00000423806"]}]},{"name":"National Natural Science Foundation of China","award":["81601205"],"award-info":[{"award-number":["81601205"]}]},{"name":"National Natural Science Foundation of China","award":["81771489"],"award-info":[{"award-number":["81771489"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Somatotroph adenomas are the leading cause of acromegaly, with the nearly sparsely granulated somatotroph subtype belonging to high-risk adenomas, and they are less responsive to medical treatment. The integrated stress response (ISR) is an essential stress-support pathway increasingly recognized as a determinant of tumorigenesis. In this study, we identified the characteristic profiling of the integrated stress response in translocation and translation initiation factor activity in somatotroph adenomas, normal pituitary, or other adenoma subtypes through proteomics. Immunohistochemistry exhibited the differential significance and the priority of eukaryotic translation initiation factor 2\u03b2 (EIF2\u03b2) in somatotroph adenomas compared with gonadotroph and corticotroph adenomas. Differentially expressed genes based on the level of EIF2\u03b2 in somatotroph adenomas were revealed. MetaSape pathways showed that EIF2\u03b2 was involved in regulating growth and cell activation, immune system, and extracellular matrix organization processes. The correlation analysis showed Spearman correlation coefficients of r = 0.611 (p &lt; 0.001) for EIF2\u03b2 and eukaryotic translation initiation factor 2 alpha kinase 1 (HRI), r = 0.765 (p &lt; 0.001) for eukaryotic translation initiation factor 2 alpha kinase 2 (PKR), r = 0.813 (p &lt; 0.001) for eukaryotic translation initiation factor 2 alpha kinase 3 (PERK), r = 0.728 (p &lt; 0.001) for GCN2, and r = 0.732 (p &lt; 0.001) for signal transducer and activator of transcription 3 (STAT3). Furthermore, the invasive potential in patients with a high EIF2\u03b2 was greater than that in patients with a low EIF2\u03b2 (7\/10 vs. 4\/18, p = 0.038), with a lower immune-cell infiltration probability (p &lt; 0.05). The ESTIMATE algorithm showed that the levels of activation of the EIF2 pathway were negatively correlated with the immune score in somatotroph adenomas (p &lt; 0.001). In in vitro experiments, the knockdown of EIF2\u03b2 changed the phenotype of somatotroph adenomas, including cell proliferation, migration, and the secretion ability of growth hormone\/insulin-like growth factor-1. In this study, we demonstrate that the ISR is pivotal in somatotroph adenomas and provide a rationale for implementing ISR-based regimens in future treatment strategies.<\/jats:p>","DOI":"10.3390\/ijms232113067","type":"journal-article","created":{"date-parts":[[2022,10,30]],"date-time":"2022-10-30T04:57:34Z","timestamp":1667105854000},"page":"13067","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Integrated Stress Response Is Tumorigenic and Constitutes a Therapeutic Liability in Somatotroph Adenomas"],"prefix":"10.3390","volume":"23","author":[{"given":"Zhenye","family":"Li","sequence":"first","affiliation":[{"name":"Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiyuan","family":"Chen","sequence":"additional","affiliation":[{"name":"Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China"},{"name":"Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohui","family":"Yao","sequence":"additional","affiliation":[{"name":"Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, China"},{"name":"Shanxi Provincial People\u2019s Hospital, Taiyuan 030000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Liu","sequence":"additional","affiliation":[{"name":"Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haibo","family":"Zhu","sequence":"additional","affiliation":[{"name":"Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yazhuo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China"},{"name":"Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Feng","sequence":"additional","affiliation":[{"name":"Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Gao","sequence":"additional","affiliation":[{"name":"Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, China"},{"name":"China National Clinical Research Center for Neurological Diseases, Beijing 100070, China"},{"name":"Key Laboratory of Central Nervous System Injury Research, Beijing 100070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1001\/jama.2016.19699","article-title":"Diagnosis and Treatment of Pituitary Adenomas: A Review","volume":"317","author":"Molitch","year":"2017","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1007\/s11154-020-09588-z","article-title":"Multidisciplinary Management of Acromegaly: A Consensus","volume":"21","author":"Giustina","year":"2020","journal-title":"Rev. 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