Banimohammad Majid, Khalafi Parsa, Gholamin Danial, Bangaleh Zahra, Akhtar Nahid, Solomon Abhishikt David, Prabhakar Pranav Kumar, Sanami Samira, Prakash Ajit, Pazoki-Toroudi Hamidreza
Physiology Research Center, Iran University of Medical Sciences, Tehran 1449614535, Iran.
Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran.
Explor Target Antitumor Ther. 2025 Apr 2;6:1002306. doi: 10.37349/etat.2025.1002306. eCollection 2025.
The purpose of this review was to provide a comprehensive review of the latest insights on the pathogenesis of uveal melanoma (UM) and its intracellular pathways. This article covers the epidemiology of UM, racial predispositions, cytogenetic and chromosomal alterations, gene mutations, key defective pathways, and their underlying mechanisms, as well as the application of hallmarks of cancer to UM. A key knowledge gap remains in identifying the most effective targeted therapy and determining the central pathway linking multiple signaling networks. UM is a malignant tumor arising from uveal melanocytes, predominantly affecting the choroid, with both genetic and epigenetic contributors. Key cytogenetic alterations include monosomy 3, chromosome 6p gain, chromosome 1p loss, and chromosome 8q gain. The most important UM-related signaling pathways are RAS/MAPK, PI3K/Akt/mTOR, Hippo-YAP, retinoblastoma (Rb), and p53 pathways. In the RAS/MAPK pathway, / mutations occur which account for more than 80% of UM cases. The PI3K/Akt/mTOR pathway promotes cyclin D1 overexpression and MDM2 upregulation, leading to p53 pathway inhibition. / mutations activate YAP via the Trio-RhoGTPase/RhoA/Rac1 signaling circuit in the Hippo-YAP pathway. Rb pathway dysregulation results from cyclin D1 overexpression or cyclin-dependent kinase inhibitor (CDKI) inactivation. In the p53 pathway, UM is characterized by mutations, MDM2 overexpression, and Bcl-2 deregulation. Eventually, the ARF-MDM2 axis serves as a critical link between the RAS and p53 pathways. Hallmarks of cancer, such as evasion of growth suppression and self-sufficiency in growth signals, are also evident in UM. Genetic and epigenetic alterations, including , and amplification, and mutations, play pivotal roles in UM pathobiology. Thus, UM exhibits a multifactorial pathology. By consolidating key mechanisms underlying UM pathogenesis, this review provides a comprehensive perspective on the involved pathways, offering insights that may facilitate the development of effective therapeutic strategies.
本综述的目的是全面回顾葡萄膜黑色素瘤（UM）发病机制及其细胞内信号通路的最新见解。本文涵盖了UM的流行病学、种族易感性、细胞遗传学和染色体改变、基因突变、关键缺陷信号通路及其潜在机制，以及癌症特征在UM中的应用。在确定最有效的靶向治疗方法以及确定连接多个信号网络的核心信号通路方面，仍存在关键的知识空白。UM是一种起源于葡萄膜黑色素细胞的恶性肿瘤，主要累及脉络膜，其发病涉及遗传和表观遗传因素。关键的细胞遗传学改变包括3号染色体单体、6号染色体短臂增加、1号染色体短臂缺失和8号染色体长臂增加。与UM最重要的信号通路是RAS/MAPK、PI3K/Akt/mTOR、Hippo-YAP、视网膜母细胞瘤（Rb）和p53信号通路。在RAS/MAPK信号通路中，/ 突变的发生占UM病例的80%以上。PI3K/Akt/mTOR信号通路促进细胞周期蛋白D1过表达和MDM2上调，导致p53信号通路受到抑制。/ 突变通过Hippo-YAP信号通路中的Trio-RhoGTPase/RhoA/Rac1信号回路激活YAP。Rb信号通路失调是由细胞周期蛋白D1过表达或细胞周期蛋白依赖性激酶抑制剂（CDKI）失活引起的。在p53信号通路中，UM的特征是 突变、MDM2过表达和Bcl-2失调。最终，ARF-MDM2轴是RAS和p53信号通路之间至关重要的联系。癌症特征，如逃避生长抑制和生长信号的自给自足，在UM中也很明显。遗传和表观遗传改变，包括 、 和 扩增以及 突变，在UM病理生物学中起关键作用。因此，UM表现出多因素病理学特征。通过巩固UM发病机制的关键机制，本综述提供了对相关信号通路的全面观点，为开发有效的治疗策略提供了思路。
