Investigative ophthalmology & visual science · 2025
SOX4 as a Key Oncogene Driving Tumor Invasion in Retinoblastoma.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Nie Jiahe, Tang Junjie, Zhang Zhihui, Sun Hetian, Wang Xinyue, Wang Longxiang, Wang Meng, Huang Weifeng, Gao Yang, Li Jinmiao, Cheng Chao, Su Shicai, Chen Shuxia, Ai Siming, Mao Yuxiang, Zhang Ping, Liu Yaoming, Lu Rong
Аннотация
PURPOSE: This study aims to explore the role of SRY-related HMG box transcription factor 4 (SOX4) in promoting invasion in retinoblastoma (RB) and to elucidate the underlying oncogenic pathways.
METHODS: SOX4 expression in human retina, intraocular RB, and extraocular RB samples was evaluated using bulk RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq), with further evaluation in RB cell lines (Y79, WERI-RB1). Small interfering RNA-mediated knockdown was performed in RB cell lines, followed by functional assays including CCK-8, EdU, colony formation, and transwell assays. An orthotopic xenograft model with SOX4 knockdown was utilized to assess tumor invasion. RNA-seq was performed on SOX4 knockdown (si-SOX4) and control (si-NC) Y79 cells to explore downstream signaling pathways.
RESULTS: RNA-seq and scRNA-seq data revealed that SOX4, E2F3, and DEK were significantly upregulated in RB tissues compared to normal retina. Notably, SOX4 expression was particularly elevated in extraocular RB tissues, especially in MKI67+ photoreceptorness-decreased cells. Knockdown of SOX4 in RB cell lines caused decreased proliferation, colony formation, migration, and reversal of epithelial-to-mesenchymal transition markers (N-cadherin, E-cadherin, vimentin). In vivo, SOX4 knockdown resulted in fewer cases of anterior chamber involvement and eyeball wall invasion in an orthotopic xenograft model. RNA-seq analysis revealed that SOX4 knockdown altered the Wnt/β-catenin and cyclin D1 signaling pathways.
CONCLUSIONS: SOX4 plays a critical role in driving local invasion in RB, and targeting SOX4 may provide new insights into the molecular mechanisms of RB invasion, potentially leading to improved therapeutic strategies for RB treatment.
METHODS: SOX4 expression in human retina, intraocular RB, and extraocular RB samples was evaluated using bulk RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq), with further evaluation in RB cell lines (Y79, WERI-RB1). Small interfering RNA-mediated knockdown was performed in RB cell lines, followed by functional assays including CCK-8, EdU, colony formation, and transwell assays. An orthotopic xenograft model with SOX4 knockdown was utilized to assess tumor invasion. RNA-seq was performed on SOX4 knockdown (si-SOX4) and control (si-NC) Y79 cells to explore downstream signaling pathways.
RESULTS: RNA-seq and scRNA-seq data revealed that SOX4, E2F3, and DEK were significantly upregulated in RB tissues compared to normal retina. Notably, SOX4 expression was particularly elevated in extraocular RB tissues, especially in MKI67+ photoreceptorness-decreased cells. Knockdown of SOX4 in RB cell lines caused decreased proliferation, colony formation, migration, and reversal of epithelial-to-mesenchymal transition markers (N-cadherin, E-cadherin, vimentin). In vivo, SOX4 knockdown resulted in fewer cases of anterior chamber involvement and eyeball wall invasion in an orthotopic xenograft model. RNA-seq analysis revealed that SOX4 knockdown altered the Wnt/β-catenin and cyclin D1 signaling pathways.
CONCLUSIONS: SOX4 plays a critical role in driving local invasion in RB, and targeting SOX4 may provide new insights into the molecular mechanisms of RB invasion, potentially leading to improved therapeutic strategies for RB treatment.