文章：

p53肿瘤抑制因子功能障碍诱导的肿瘤进展的肌动蛋白依赖性机制

Actin-Dependent Mechanism of Tumor Progression Induced by a Dysfunction of p53 Tumor Suppressor

原文发布日期：11 March 2024

DOI: 10.3390/cancers16061123

类型: Article

开放获取: 是

英文摘要：

Cancer cell aggressiveness, marked by actin cytoskeleton reconfiguration critical for metastasis, may result from an imbalanced ratio favoring γ-actin. Dysfunctional p53 emerges as a key regulator of invasiveness and migration in various cancer cells, both in vitro and in vivo. P53 inactivation (via mutants R175H, R248W, R273H, or TP53 repression) significantly enhanced the migration, invasion, and proliferation of human lung adenocarcinoma A549 cells in vitro and in vivo, facilitating intrapulmonary xenograft metastasis in athymic mice. Conversely, wild-type TP53 (TP53 WT) overexpression in p53-deficient non-small- cell lung cancer (NSCLC) H1299 cells substantially reduced proliferation and migration in vitro, effectively curbing orthotopic tumorigenicity and impeding in vivo metastasis. These alterations in cell motility were closely associated with actin cytoskeleton restructuring, favoring γ-actin, and coincided with ERK1/2-mediated signaling activation, unveiling an innovative regulatory mechanism in malignancy progression. Cancer cell aggressiveness, driven by actin cytoskeleton reorganization and a shift towards γ-actin predominance, may be regulated by p53 dysfunction, thereby providing novel insight into tumor progression mechanisms.

摘要翻译： 

癌细胞侵袭性以肌动蛋白细胞骨架重构为标志，这一过程对转移至关重要，可能源于γ-肌动蛋白比例失衡导致的失衡状态。功能失调的p53在多种癌细胞（包括体外和体内实验）中成为侵袭和迁移的关键调节因子。p53失活（通过R175H、R248W、R273H突变体或TP53抑制）显著增强了人肺腺癌A549细胞在体外和体内的迁移、侵袭及增殖能力，促进了无胸腺小鼠肺内异种移植转移。相反，在p53缺陷的非小细胞肺癌H1299细胞中过表达野生型TP53（TP53 WT）显著降低了体外增殖和迁移，有效抑制了原位肿瘤形成并阻碍了体内转移。这些细胞运动性的改变与肌动蛋白细胞骨架重构（偏向γ-肌动蛋白）密切相关，并与ERK1/2介导的信号激活同时发生，揭示了恶性肿瘤进展中的创新调控机制。由肌动蛋白细胞骨架重组和γ-肌动蛋白主导转变驱动的癌细胞侵袭性可能受p53功能障碍调控，从而为肿瘤进展机制提供了新的见解。

原文链接：

Actin-Dependent Mechanism of Tumor Progression Induced by a Dysfunction of p53 Tumor Suppressor