دورية أكاديمية
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The OTX2 Gene Induces Tumor Growth and Triggers Leptomeningeal Metastasis by Regulating the mTORC2 Signaling Pathway in Group 3 Medulloblastomas.

التفاصيل البيبلوغرافية
العنوان: The OTX2 Gene Induces Tumor Growth and Triggers Leptomeningeal Metastasis by Regulating the mTORC2 Signaling Pathway in Group 3 Medulloblastomas.
المؤلفون: Ampudia-Mesias E; Division of Hematology and Oncology, Department of Pediatrics, Medical School, University of Minnesota, Minneapolis, MN 55454, USA., Cameron CS; Division of Hematology and Oncology, Department of Pediatrics, Medical School, University of Minnesota, Minneapolis, MN 55454, USA., Yoo E; Division of Hematology and Oncology, Department of Pediatrics, Medical School, University of Minnesota, Minneapolis, MN 55454, USA.; Department of Pharmacy, Institute of Pharmaceutical Science and Technology, College of Pharmacy, Hanyang University, Ansan 15588, Gyeonggi-do, Republic of Korea., Kelly M; Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455, USA., Anderson SM; Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455, USA., Manning R; Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455, USA., Abrahante Lloréns JE; University of Minnesota Informatics Institute, University of Minnesota, Minneapolis, MN 55455, USA., Moertel CL; Division of Hematology and Oncology, Department of Pediatrics, Medical School, University of Minnesota, Minneapolis, MN 55454, USA., Yim H; Department of Pharmacy, Institute of Pharmaceutical Science and Technology, College of Pharmacy, Hanyang University, Ansan 15588, Gyeonggi-do, Republic of Korea., Odde DJ; Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455, USA., Saydam N; ExoMed Diagnostic, Minneapolis, MN 55404, USA., Saydam O; Division of Hematology and Oncology, Department of Pediatrics, Medical School, University of Minnesota, Minneapolis, MN 55454, USA.
المصدر: International journal of molecular sciences [Int J Mol Sci] 2024 Apr 17; Vol. 25 (8). Date of Electronic Publication: 2024 Apr 17.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Basel, Switzerland : MDPI, [2000-
مواضيع طبية MeSH: Gene Expression Regulation, Neoplastic* , Mechanistic Target of Rapamycin Complex 2*/metabolism , Mechanistic Target of Rapamycin Complex 2*/genetics , Medulloblastoma*/genetics , Medulloblastoma*/pathology , Medulloblastoma*/metabolism , Meningeal Neoplasms*/genetics , Meningeal Neoplasms*/pathology , Meningeal Neoplasms*/metabolism , Meningeal Neoplasms*/secondary , Otx Transcription Factors*/metabolism , Otx Transcription Factors*/genetics, Animals ; Female ; Humans ; Male ; Mice ; Cell Line, Tumor ; Cell Movement/genetics ; Cell Proliferation/genetics ; Cerebellar Neoplasms/genetics ; Cerebellar Neoplasms/pathology ; Cerebellar Neoplasms/metabolism ; Signal Transduction
مستخلص: Medulloblastoma (MB) encompasses diverse subgroups, and leptomeningeal disease/metastasis (LMD) plays a substantial role in associated fatalities. Despite extensive exploration of canonical genes in MB, the molecular mechanisms underlying LMD and the involvement of the orthodenticle homeobox 2 (OTX2) gene, a key driver in aggressive MB Group 3, remain insufficiently understood. Recognizing OTX2's pivotal role, we investigated its potential as a catalyst for aggressive cellular behaviors, including migration, invasion, and metastasis. OTX2 overexpression heightened cell growth, motility, and polarization in Group 3 MB cells. Orthotopic implantation of OTX2-overexpressing cells in mice led to reduced median survival, accompanied by the development of spinal cord and brain metastases. Mechanistically, OTX2 acted as a transcriptional activator of the Mechanistic Target of Rapamycin (mTOR) gene's promoter and the mTORC2 signaling pathway, correlating with upregulated downstream genes that orchestrate cell motility and migration. Knockdown of mTOR mRNA mitigated OTX2-mediated enhancements in cell motility and polarization. Analysis of human MB tumor samples (N = 952) revealed a positive correlation between OTX2 and mTOR mRNA expression, emphasizing the clinical significance of OTX2's role in the mTORC2 pathway. Our results reveal that OTX2 governs the mTORC2 signaling pathway, instigating LMD in Group 3 MBs and offering insights into potential therapeutic avenues through mTORC2 inhibition.
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فهرسة مساهمة: Keywords: LMD; OTX2; group 3 medulloblastoma; mTORC2
المشرفين على المادة: EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
0 (Otx Transcription Factors)
0 (OTX2 protein, human)
تواريخ الأحداث: Date Created: 20240427 Date Completed: 20240427 Latest Revision: 20240522
رمز التحديث: 20240523
مُعرف محوري في PubMed: PMC11050316
DOI: 10.3390/ijms25084416
PMID: 38674001
قاعدة البيانات: MEDLINE
الوصف
تدمد:1422-0067
DOI:10.3390/ijms25084416