Cancer Biology Division, National Centre for Cell Science, Ganeshkhind Road, Pune, Maharashtra 411007, India; Department of Biotechnology, Savitribai Phule Pune University, Ganeshkhind Road, Pune, Maharashtra 411007, India.
Laboratory of Cancer Biology and Genetics, Centre for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Biochim Biophys Acta Rev Cancer. 2022 Jul;1877(4):188753. doi: 10.1016/j.bbcan.2022.188753. Epub 2022 Jun 22.
Cancer metastasis is the primary cause of morbidity and mortality in cancer as it remains the most complicated, devastating, and enigmatic aspect of cancer. Several decades of extensive research have identified several key players closely associated with metastasis. Among these players, cytoskeletal linker Ezrin (the founding member of the ERM (Ezrin-Radixin-Moesin) family) was identified as a critical promoter of metastasis in pediatric cancers in the early 21st century. Ezrin was discovered 40 years ago as a aminor component of intestinal epithelial microvillus core protein, which is enriched in actin-containing cell surface structures. It controls gastric acid secretion and plays diverse physiological roles including maintaining cell polarity, regulating cell adhesion, cell motility and morphogenesis. Extensive research for more than two decades evinces that Ezrin is frequently dysregulated in several human cancers. Overexpression, altered subcellular localization and/or aberrant activation of Ezrin are closely associated with higher metastatic incidence and patient mortality, thereby justifying Ezrin as a valuable prognostic biomarker in cancer. Ezrin plays multifaceted role in multiple aspects of cancer, with its significant contribution in the complex metastatic cascade, through reorganizing the cytoskeleton and deregulating various cellular signaling pathways. Current preclinical studies using genetic and/or pharmacological approaches reveal that inactivation of Ezrin results in significant inhibition of Ezrin-mediated tumor growth and metastasis as well as increase in the sensitivity of cancer cells to various chemotherapeutic drugs. In this review, we discuss the recent advances illuminating the molecular mechanisms responsible for Ezrin dysregulation in cancer and its pleiotropic role in cancer progression and metastasis. We also highlight its potential as a prognostic biomarker and therapeutic target in various cancers. More importantly, we put forward some potential questions, which we strongly believe, will stimulate both basic and translational research to better understand Ezrin-mediated malignancy, ultimately leading to the development of Ezrin-targeted cancer therapy for the betterment of human life.
癌症转移是癌症发病率和死亡率的主要原因，因为它仍然是癌症最复杂、最具破坏性和最神秘的方面。几十年来的广泛研究已经确定了几个与转移密切相关的关键参与者。在这些参与者中，细胞骨架连接蛋白 Ezrin（ERM（Ezrin-Radixin-Moesin）家族的创始成员）在 21 世纪初被确定为儿科癌症转移的关键促进剂。Ezrin 是在 40 年前作为肠上皮微绒毛核心蛋白的次要成分被发现的，它富含含有肌动蛋白的细胞表面结构。它控制胃酸分泌，发挥多种生理作用，包括维持细胞极性、调节细胞黏附、细胞运动和形态发生。二十多年的广泛研究表明，Ezrin 在几种人类癌症中经常失调。Ezrin 的过表达、亚细胞定位改变和/或异常激活与更高的转移发生率和患者死亡率密切相关，因此 Ezrin 作为癌症有价值的预后生物标志物是合理的。Ezrin 在癌症的多个方面发挥着多方面的作用，通过重组细胞骨架和调节各种细胞信号通路，在复杂的转移级联中发挥着重要作用。目前使用遗传和/或药理学方法的临床前研究表明，Ezrin 的失活导致 Ezrin 介导的肿瘤生长和转移的显著抑制以及癌症细胞对各种化疗药物的敏感性增加。在这篇综述中，我们讨论了阐明导致癌症中 Ezrin 失调的分子机制及其在癌症进展和转移中的多效性作用的最新进展。我们还强调了它作为各种癌症预后生物标志物和治疗靶点的潜力。更重要的是，我们提出了一些潜在的问题，我们坚信这些问题将激发基础和转化研究，以更好地理解 Ezrin 介导的恶性肿瘤，最终为改善人类生活开发针对 Ezrin 的癌症治疗方法。
