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Here, we investigated the causes and consequences of downregulated miR\u201099a\u20105p\/miR\u2010100\u20105p (functionally identical) and miR\u2010125b\u20105p levels in malignant GCTs regardless of age, site, or subtype. Quantitative RT\u2010PCR was used to assess miR\u201099a\u20105p\/miR\u2010100\u20105p, miR\u2010125b\u20105p, and associated gene expression in malignant GCT tissues\/cell lines [seminoma (Sem), yolk sac tumor (YST), embryonal carcinoma (EC)]. Cells were treated with demethylating 5\u2010azacytidine and pyrosequencing was performed. Combination miR\u2010100\u20105p\/miR\u2010125b\u20105p mimic replenishment was used to treat malignant GCT\u00a0cells. Global messenger RNA (mRNA) targets of the replenished miRNAs were identified and Metascape used to study pathway effects. We found that expression levels of miR\u201099a\u20105p\/miR\u2010100\u20105p and miR\u2010125b\u20105p, their respective pri\u2010miRNAs, and associated genes from chromosomes 11 and 21 (chr11\/chr21) were downregulated and highly correlated in malignant GCT\u00a0cells. Treatment with 5\u2010azacytidine caused upregulation of these miRNAs, with pyrosequencing revealing hypermethylation of their chr11\/chr21 loci, likely contributing to miR\u2010100\u20105p\/miR\u2010125b\u20105p downregulation. Combination miR\u2010100\u20105p\/miR\u2010125b\u20105p mimic replenishment resulted in growth inhibition in Sem\/YST cells, with miR\u2010100\u20105p\/miR\u2010125b\u20105p mRNA targets enriched in downregulated genes, which were involved in cell cycle (confirmed by flow cytometry) and signaling pathways. Knockdown of the miR\u2010100\u20105p\/miR\u2010125b\u20105p target <jats:italic>tripartite motif containing 71<\/jats:italic> (<jats:italic>TRIM71<\/jats:italic>kd) recapitulated miR\u2010100\u20105p\/miR\u2010125b\u20105p replenishment, with growth inhibition and cell cycle disruption of Sem\/YST\/EC cells. Further, replenishment led to reduced <jats:italic>lin\u201028 homolog A<\/jats:italic> (<jats:italic>LIN28A<\/jats:italic>) levels and concomitant increases in <jats:italic>let\u20107<\/jats:italic> (<jats:italic>MIRLET7B<\/jats:italic>) tumor suppressor miRNAs, creating a sustained reversion of cell phenotype. In summary, combination miR\u2010100\u20105p\/miR\u2010125b\u20105p mimic replenishment or <jats:italic>TRIM71<\/jats:italic>kd caused growth inhibition in malignant GCT\u00a0cells via cell cycle disruption. Further studies are now warranted, including mimic treatment alongside conventional platinum\u2010based chemotherapy.<\/jats:p>","DOI":"10.1002\/1878-0261.13757","type":"journal-article","created":{"date-parts":[[2024,11,11]],"date-time":"2024-11-11T00:29:16Z","timestamp":1731284956000},"page":"1203-1228","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Replenishing co\u2010downregulated mi<scp>R<\/scp>\u2010100\u20105p and mi<scp>R<\/scp>\u2010125b\u20105p in malignant germ cell tumors causes growth\u00a0inhibition through cell cycle disruption"],"prefix":"10.1002","volume":"19","author":[{"given":"Marta","family":"Ferraresso","sequence":"first","affiliation":[{"name":"Department of Pathology University of Cambridge  UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shivani","family":"Bailey","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Cambridge  UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luz","family":"Alonso\u2010Crisostomo","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Cambridge  UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dawn","family":"Ward","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Cambridge  UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christos","family":"Panayi","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Cambridge  UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zachary G. L.","family":"Scurlock","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Cambridge  UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harpreet K.","family":"Saini","sequence":"additional","affiliation":[{"name":"EMBL\u2010European Bioinformatics Institute (EMBL\u2010EBI)  Cambridge UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen P.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Cambridge  UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James C.","family":"Nicholson","sequence":"additional","affiliation":[{"name":"Department of Paediatrics University of Cambridge, Cambridge University Hospitals NHS Foundation Trust  UK"},{"name":"Department of Paediatric Haematology and Oncology Cambridge University Hospitals NHS Foundation Trust  UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anton 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