Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China.
Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China.
Cell Rep. 2022 Feb 15;38(7):110390. doi: 10.1016/j.celrep.2022.110390.
Tumor physical microenvironment contributes greatly to the response of tumor cells. However, the mechanism of how extracellular substrate rigidity remodels colorectal cancer (CRC) cell fate and affects CRC progression remains elusive. Here, we show that F-actin regulator KIAA1211, also known as Capping protein inhibiting regulator of actin dynamics (CRAD), negatively correlates with CRC progression, stemness, and metastasis. Mechanistically, decreased CRAD in soft substrates induces Yes-associated protein (YAP) retention in the cytoplasm, restoring the repression effect on stemness markers NANOG and OCT4, thereby promoting CRC stemness and metastasis. Furthermore, CRAD deficiency promotes colorectal tumor cell softening and regulates epithelial-mesenchymal transition (EMT) states, contributing to its metastasis potential. Clinically, CRAD expression is correlated with malignant degrees and metastasis in CRC patients. Our work uncovers a role of CRAD in anticancer and mechanical signal transduction of the extracellular matrix in CRC.
肿瘤的物理微环境对肿瘤细胞的反应有很大影响。然而，细胞外基质硬度如何重塑结直肠癌（CRC）细胞命运并影响 CRC 进展的机制仍不清楚。在这里，我们发现 F-肌动蛋白调节剂 KIAA1211（也称为肌动蛋白动力学的帽蛋白抑制调节因子（CRAD））与 CRC 进展、干性和转移呈负相关。在机制上，在软底物中减少的 CRAD 诱导 Yes 相关蛋白（YAP）在细胞质中的保留，恢复对干性标记物 NANOG 和 OCT4 的抑制作用，从而促进 CRC 干性和转移。此外，CRAD 缺乏促进结直肠肿瘤细胞变软并调节上皮-间充质转化（EMT）状态，有助于其转移潜力。临床上，CRAD 的表达与 CRC 患者的恶性程度和转移相关。我们的工作揭示了 CRAD 在 CRC 中细胞外基质的抗癌和机械信号转导中的作用。
