Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA, USA.
Nat Cell Biol. 2018 Nov;20(11):1303-1314. doi: 10.1038/s41556-018-0215-z. Epub 2018 Oct 22.
Epithelial integrity is maintained by the cytoskeleton and through cell adhesion. However, it is not yet known how a deregulated cytoskeleton is associated with cancer. We identified cancer-related regulator of actin dynamics (CRAD) as frequently mutated or transcriptionally downregulated in colorectal cancer. We found that CRAD stabilizes the cadherin-catenin-actin complex via capping protein inhibition. The loss of CRAD inhibits F-actin polymerization and subsequently disrupts the cadherin-catenin-actin complex, which leads to β-catenin release and Wnt signalling hyperactivation. In mice, CRAD knockout induces epithelial cell integrity loss and Wnt signalling activation, resulting in the development of intestinal mucinous adenoma. With APC mutation, CRAD knockout initiates and accelerates mucinous and invasive adenoma development in the colorectum. These results define CRAD as a tumour suppressor, the inactivation of which deregulates the cytoskeleton and hyperactivates Wnt signalling thus initiating mucinous colorectal cancer. Our study reveals the unexpected roles of an actin cytoskeletal regulator in maintaining epithelial cell integrity and suppressing tumorigenesis.
上皮完整性由细胞骨架和细胞黏附维持。然而，目前尚不清楚失调的细胞骨架如何与癌症相关。我们鉴定了与结直肠癌相关的肌动蛋白动力学调控因子（CRAD），其在结直肠癌中经常发生突变或转录下调。我们发现 CRAD 通过抑制盖帽蛋白稳定着钙粘蛋白连环蛋白肌动蛋白复合物。CRAD 的缺失抑制 F-肌动蛋白聚合，随后破坏钙粘蛋白连环蛋白肌动蛋白复合物，导致β-连环蛋白释放和 Wnt 信号过度激活。在小鼠中，CRAD 敲除诱导上皮细胞完整性丧失和 Wnt 信号激活，导致肠黏液性腺瘤的发生。随着 APC 突变，CRAD 敲除启动并加速结直肠黏液性和侵袭性腺瘤的发展。这些结果将 CRAD 定义为肿瘤抑制因子，其失活会使细胞骨架失调并过度激活 Wnt 信号，从而引发黏液性结直肠癌。我们的研究揭示了一种肌动蛋白细胞骨架调节剂在维持上皮细胞完整性和抑制肿瘤发生中的意外作用。
