{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T05:12:02Z","timestamp":1779340322908,"version":"3.51.4"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T00:00:00Z","timestamp":1779321600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Aims and objectives<\/jats:title>\n                    <jats:p>Retinoblastoma is the most common pediatric intraocular malignancy, although it remains a rare disease overall, yet the molecular targets and therapeutic vulnerabilities sustaining its most aggressive proliferative cell states remain incompletely defined. We aimed to identify actionable molecular regulators and potential therapeutic targets of malignant retinoblastoma progression using integrated single-cell transcriptomics and functional validation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed single-cell RNA sequencing data from 189,431 cells derived from 13 retinoblastoma tumors and 3 normal fetal retina samples. Data integration was performed using Harmony, followed by clustering, differential expression, and functional enrichment analyses. BIRC5 function was evaluated through overexpression and siRNA-mediated knockdown in retinoblastoma cell lines (Y79, WERI-Rb1), with assessment of proliferation, migration, invasion, and cell cycle\u2013related proteins.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Clustering identified 10 retinal cell types, including cone precursor-like, cone-like, and two MKI67\n                      <jats:sup>+<\/jats:sup>\n                      proliferative RB subpopulations enrichment of G2\/M-phase genes and chromosomal instability pathways. MKI67\n                      <jats:sup>+<\/jats:sup>\n                      cells2 displayed hyperactivated cell cycle genes, chromosomal instability, and mitotic checkpoint dysregulation. BIRC5 (survivin) was selectively overexpressed in 93.7% of MKI67\n                      <jats:sup>+<\/jats:sup>\n                      cells2 (mean expression 1.733 \u00b1 0.643), while minimally expressed in other retinal cells. Functional assays demonstrated that BIRC5 overexpression promoted proliferation, invasion, migration, and CCND1\/CDK4 activation, while suppressing CHEK2\u2013p21\u2013mediated checkpoint control. Conversely, BIRC5 knockdown induced G1 cell cycle arrest and increased apoptotic activity, accompanied by activation of checkpoint pathways.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study defines BIRC5 as a cell-state\u2013specific regulator of malignant proliferation in retinoblastoma and provides a mechanistic rationale for targeting survivin in highly proliferative tumor subpopulations.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1854143","type":"journal-article","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T04:52:48Z","timestamp":1779339168000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["BIRC5 drives cell-cycle dysregulation and represents a novel molecular target in retinoblastoma"],"prefix":"10.3389","volume":"16","author":[{"given":"Yingtong","family":"Chen","sequence":"first","affiliation":[{"name":"The Second Clinical Medical College of Jinan University, Department of Ophthalmology, Shenzhen People\u2019s Hospital","place":["Shenzhen, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaohan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pathology, Shengjing Hospital, China Medical University","place":["Shenyang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fuhua","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Shenzhen People\u2019s Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University)","place":["Shenzhen, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoya","family":"Wang","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical College of Jinan University, Department of Ophthalmology, Shenzhen People\u2019s Hospital","place":["Shenzhen, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiang","family":"Wang","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical College of Jinan University, Department of Ophthalmology, Shenzhen People\u2019s Hospital","place":["Shenzhen, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Di","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Beijing Children\u2019s Hospital, Capital Medical University, National Center for Children\u2019s Health","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaowei","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Pediatric Research, Shenzhen Children\u2019s Hospital","place":["Shenzhen, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chengyue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Beijing Children\u2019s Hospital, Capital Medical University, National Center for Children\u2019s Health","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huibin","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Shenzhen People\u2019s Hospital (The First Affiliated Hospital, Southern University of Science and Technology; The Second Clinical Medical College, Jinan University)","place":["Shenzhen, Guangdong, 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