Gherardini Lisa, Sharma Ankush, Taranta Monia, Cinti Caterina
Institute of Clinical Physiology, National Research Council of Italy, 53100 Siena, Italy.
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, 0450 Oslo, Norway.
Front Biosci (Landmark Ed). 2025 Apr 25;30(4):33386. doi: 10.31083/FBL33386.
Retinoblastoma (Rb) is a rare cancer, yet it is the most common eye tumor in children. It can occur in either a familial or sporadic form, with the sporadic variant being more prevalent, though its downstream effects on epigenetic markers remain largely unclear. Currently, the treatment for retinoblastoma typically involves aggressive chemotherapy and surgical resection. The identification of specific epigenetic characteristics of non-hereditary (sporadic) Rb has led to the development of advanced, high-throughput methods to explore its epigenetic profile. Our previous research demonstrated that treatment with the demethylating agent 5-Aza-2'-deoxycytidine (decitabine; DAC) induced cell cycle arrest and apoptosis in a well-characterized retinoblastoma model (WERI-Rb-1). Our analysis of time-dependent gene expression in WERI-Rb-1 cells following DAC exposure has led to the development of testable hypotheses to further investigate the epigenetic impact on the initiation and progression of retinoblastoma tumors.
Gene expression analysis of publicly available datasets from patients' primary tumors and normal retina have been compared with those found in WERI-Rb-1 cells to assess the relevance of DAC-driven genes as markers of primary retinoblastoma tumors. The effect of DAC treatment has been evaluated , both in subcutaneous xenografts and in orthotopic models. qPCR analysis of gene expression and Methylation-Specific PCR (MSP) was performed.
Our analysis of network maps for differentially expressed genes in primary tumors compared to DAC-driven genes identified 15 hub/driver genes that may play a pivotal role in the genesis and progression of retinoblastoma. DAC treatment induced significant tumor growth arrest in both subcutaneous and orthotopic xenograft retinoblastoma models. This was associated with changes in gene expression, either through the direct switching-on of epigenetically locked genes or through the indirect regulation of linked genes, suggesting the potential use of DAC as an epigenetic anti-cancer drug for the treatment of retinoblastoma patients.
There is a pressing need to develop innovative treatments for retinoblastoma. Our research revealed that DAC can effectively suppress the growth and progression of retinoblastoma in models, offering a potential new therapeutic approach to battle this destructive disease. This discovery highlights the impact of this epigenetic therapy in reprogramming tumor dynamics, and thus its potential to preserve both the vision and lives of affected children.
视网膜母细胞瘤（Rb）是一种罕见的癌症，但却是儿童中最常见的眼部肿瘤。它可以以家族性或散发性形式出现，散发性变体更为普遍，但其对表观遗传标记的下游影响在很大程度上仍不清楚。目前，视网膜母细胞瘤的治疗通常包括积极的化疗和手术切除。非遗传性（散发性）Rb特定表观遗传特征的鉴定导致了探索其表观遗传谱的先进高通量方法的发展。我们之前的研究表明，用去甲基化剂5-氮杂-2'-脱氧胞苷（地西他滨；DAC）处理可在一个特征明确的视网膜母细胞瘤模型（WERI-Rb-1）中诱导细胞周期停滞和凋亡。我们对DAC处理后WERI-Rb-1细胞中时间依赖性基因表达的分析导致了可测试假设的发展，以进一步研究表观遗传对视网膜母细胞瘤肿瘤发生和进展的影响。
已将来自患者原发性肿瘤和正常视网膜的公开可用数据集的基因表达分析与WERI-Rb-1细胞中的分析进行比较，以评估DAC驱动基因作为原发性视网膜母细胞瘤肿瘤标志物的相关性。在皮下异种移植模型和原位模型中均评估了DAC处理的效果，并进行了基因表达的qPCR分析和甲基化特异性PCR（MSP）。
我们对原发性肿瘤中差异表达基因与DAC驱动基因的网络图谱分析确定了15个可能在视网膜母细胞瘤的发生和进展中起关键作用的中心/驱动基因。DAC处理在皮下和原位异种移植视网膜母细胞瘤模型中均诱导了显著的肿瘤生长停滞。这与基因表达的变化有关，要么是通过表观遗传锁定基因的直接开启，要么是通过相关基因的间接调节，这表明DAC有可能作为一种表观遗传抗癌药物用于治疗视网膜母细胞瘤患者。
迫切需要开发针对视网膜母细胞瘤的创新治疗方法。我们的研究表明，DAC可以在模型中有效抑制视网膜母细胞瘤的生长和进展，为对抗这种破坏性疾病提供了一种潜在的新治疗方法。这一发现突出了这种表观遗传疗法在重新编程肿瘤动态方面的影响，因此其在保护受影响儿童的视力和生命方面的潜力。
