Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, Guandong, China.
Cell Death Dis. 2018 Jul 3;9(7):749. doi: 10.1038/s41419-018-0766-8.
Epithelial-mesenchymal transition (EMT)-induced metastasis contributes to human colorectal cancer (CRC) progression, especially in advanced CRC. However, the underlying mechanism of β-catenin in this process is elusive. We identified that LIM domain kinase (LIMK)2 was progressively downregulated with tumor progression from precancerous lesions to advanced cancer. Gain- and loss-of-function assays revealed that LIMK2 inhibits cell proliferation via cell cycle arrest at the G1-S transition and suppresses the ability of cell metastasis by restricting the EMT process. Reduced LIMK2 expression enhanced the nuclear accumulation of β-catenin and activated the Wnt signaling pathway, thus contributing to tumor progression. A homolog of the LIMK family, LIMK1, which was overexpressed throughout tumor progression, served as a competitive inhibitor of LIMK2 via β-catenin nuclear translocation. The imbalanced expression of LIMK1 and LIMK2 is important in CRC progression, and the combined effects provide a new insight into the mechanism of CRC progression. These findings provide a new understanding for LIMK-based anticancer therapy.
上皮-间充质转化（EMT）诱导的转移有助于人类结直肠癌（CRC）的进展，尤其是在晚期 CRC 中。然而，β-连环蛋白在这一过程中的潜在机制尚不清楚。我们发现，LIM 结构域激酶（LIMK）2随着从癌前病变到晚期癌症的肿瘤进展而逐渐下调。获得和丧失功能的实验表明，LIMK2 通过在 G1-S 期转变时的细胞周期阻滞来抑制细胞增殖，并通过限制 EMT 过程来抑制细胞转移的能力。LIMK2 表达的降低增强了 β-连环蛋白的核积累并激活了 Wnt 信号通路，从而促进了肿瘤的进展。LIMK 家族的同源物 LIMK1 在整个肿瘤进展过程中过表达，通过 β-连环蛋白核易位作为 LIMK2 的竞争性抑制剂。LIMK1 和 LIMK2 的不平衡表达在 CRC 的进展中很重要，其联合作用为 CRC 进展的机制提供了新的见解。这些发现为基于 LIMK 的抗癌治疗提供了新的认识。
