PO.MCB07.01 · 分子与细胞生物学
核心张力与调控：Fxr1通过ahnak介导头颈癌中的机械调控
Core tension and control: Fxr1 mediates mechanoregulation via ahnak in head and neck cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：头颈部鳞状细胞癌（HNSCC）是全球第六大常见癌症，其特征为侵袭性强、转移潜能高，且5年生存率持续偏低（约50%）。新出现的证据强调了细胞骨架重塑和细胞生物力学改变（包括硬度、粘弹性和可变形性）在促进癌细胞迁移和侵袭中的作用。然而，HNSCC中这些生物力学特性的分子调控因子仍不明确。
方法：我们研究了脆性X相关蛋白1（FXR1）这一RNA结合蛋白在调节癌细胞肿瘤生物力学和侵袭中的作用。在HNSCC细胞系中进行FXR1敲低（KD），随后进行转录组学、细胞骨架和生物力学分析。进行了功能实验，包括细胞运动性、硬度以及体外和同基因小鼠模型中的肿瘤生长，以确定FXR1在口腔癌中的致瘤作用。
结果：FXR1沉默显著上调了AHNAK——一种与细胞骨架组织相关的大型支架蛋白。这种上调与F-actin聚合减少、片状伪足形成受损、细胞硬度降低以及口腔癌细胞的侵袭和迁移特性减弱相关。同时敲低FXR1和AHNAK可部分恢复F-actin结构、片状伪足形成和细胞硬度，提示FXR1相关蛋白网络之间存在功能性相互作用。在机制上，进一步的证据表明FXR1 KD通过LATS2激活了Hippo信号通路，导致磷酸化YAP（P-YAP）在胞质中积累，提示FXR1在机械转导中的作用。在体内，WT和FXR1 KD来源的异种移植物在同基因小鼠模型中显示出显著降低的肿瘤体积，并伴有免疫细胞激活。
结论：FXR1通过抑制AHNAK和增强F-actin动力学来促进HNSCC进展，从而增加细胞硬度、侵袭和迁移。我们的研究结果揭示了一个调控肿瘤生物力学和口腔肿瘤侵袭性的新型FXR1-AHNAK-F-actin轴，提供了新的机制见解，并将FXR1确定为HNSCC中一个有前景的治疗靶点。
查看英文原文 English abstract
Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer globally and is marked by aggressive invasion, high metastatic potential, and a persistently low 5-year survival rate (~50%). Emerging evidence highlights the roles of cytoskeletal remodeling and altered cellular biomechanics, including stiffness, viscoelasticity, and deformability, in promoting cancer cell migration and invasion. However, the molecular regulators of these biomechanical properties in HNSCC remain poorly defined.
Methods : We investigated the role of Fragile X-Related Protein 1 (FXR1), an RNA-binding protein, in modulating tumor biomechanics and invasion in cancer cells. FXR1 knockdown (KD) was performed in HNSCC cell lines, followed by transcriptomic, cytoskeletal, and biomechanical analyses. Functional assays, including cell motility, stiffness, and tumor growth in vitro and in syngeneic mouse models, were performed to define the tumorigenic role of FXR1 in oral cancer.
Results: FXR1 silencing significantly upregulated AHNAK, a large scaffolding protein implicated in cytoskeletal organization. This upregulation was associated with reduced F-actin polymerization, impaired lamellipodia formation, decreased cellular stiffness, and diminished invasive and migratory properties of oral cancer cells. Dual knockdown of FXR1 and AHNAK partially restored F-actin architecture, lamellipodia formation, and cell stiffness, suggesting a functional interplay between the FXR1-associated protein network. Mechanistically, further evidence demonstrated that FXR1 KD activated the Hippo signaling pathway via LATS2, leading to the cytosolic accumulation of phosphorylated YAP (P-YAP), implicating FXR1's role in mechanotransduction. In vivo, WT and FXR1 KD-derived xenografts exhibited significantly reduced tumor volume in syngeneic mouse models with immune cell activation.
Conclusions: FXR1 promotes HNSCC progression by repressing AHNAK and enhancing F-actin dynamics, thereby increasing cellular stiffness, invasion, and migration. Our findings reveal a novel FXR1-AHNAK-F-actin axis that regulates tumor biomechanics and invasiveness of oral tumors, offering new mechanistic insights and identifying FXR1 as a promising therapeutic target in HNSCC.
利益披露 Disclosure
A. Vijayakumar, None..
S. John, None..
T. Kim, None..
B. V. Howley, None..
V. Palanisamy, None.