TP53/miR-129/MDM2/4/TP53 feedback loop modulates cell proliferation and apoptosis in retinoblastoma

Retinoblastoma (RB) is commonly-seen cancer in children. The p53 pathway dysfunction, which can lead to elevated MDM2 or MDM4 (p53 antagonists) protein expression, is frequently observed in almost all human cancers, including RB. The present study attempted to investigate the underlying mechanism from the perspective of non-coding RNA regulation. Here, we demonstrated that p53 and miR-129 were positively correlated with each other in RB. miR-129 directly targeted MDM2/4 to inhibit expression, therefore counteracting MDM2/4-mediated p53 signaling suppression and modulating RB cell proliferation and apoptosis. Moreover, p53 could activate the transcription of miR-129 via binding to the miR-129 promoter region, therefore forming a regulatory loop with MDM2/4 to affect RB progression. Altogether, the p53/miR-129/MDM2/4/p53 regulatory loop can modulate RB cell growth. We provide a solid experimental basis for developing novel therapies for RB.

视网膜母细胞瘤（Retinoblastoma, RB）是儿童常见的恶性肿瘤。p53通路功能异常可导致MDM2或MDM4（p53拮抗剂）的蛋白表达上调，该现象在包括RB在内的几乎所有人类恶性肿瘤中均较为常见。本研究旨在从非编码RNA调控的视角探究其潜在分子机制。本研究证实，在RB中p53与miR-129呈正相关关系。miR-129可直接靶向MDM2/4并抑制其表达，从而抵消MDM2/4介导的p53信号通路抑制作用，并调节RB细胞的增殖与凋亡。此外，p53可通过结合miR-129的启动子区域激活其转录，进而与MDM2/4形成调控环路，影响RB的疾病进展。综上，p53/miR-129/MDM2/4/p53调控环路可调控RB细胞的生长。本研究为开发RB的新型治疗策略提供了坚实的实验依据。