Liao Qing, Li Rui, Zhou Rui, Pan Zhihua, Xu Lijun, Ding Yanqing, Zhao Liang
Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China.
Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.
Br J Cancer. 2017 Aug 8;117(4):563-571. doi: 10.1038/bjc.2017.193. Epub 2017 Jun 29.
LIM kinase 1 (LIMK1) is a key regulator of the cytoskeletal organisation involved in cell proliferation and migration. Even though LIMK1 is frequently dysregulated in epithelial cancers, the role and mechanisms of LIMK1 in colorectal cancer (CRC) remains unclear.
Immunohistochemical analysis was performed to examine the expression and clinical significance of LIMK1 in CRC samples. Loss- and gain-of-function assay was performed to investigate the effects of aberrant expression on cellular biological behaviour of CRC cells in vitro and in vivo. Immunoblotting and immunoprecipitation was used to screen LIMK1-related signalling pathways and downstream factors.
In this study, our results showed that LIMK1 was upregulated in CRC tissues and localised in both the cytoplasm and the nucleus of CRC cells. Overexpression of LIMK1 in cytoplasmic and nuclear subcellular compartments was closely related to tumour metastasis and poor prognosis of CRC patients. Enhanced expression of cytoplasmic and nuclear LIMK1 significantly increased cell proliferation and migration by driving epithelial-mesenchymal transition and activating the PI3K/Akt signal pathway in vitro as well as promoting growth and metastasis of CRC xenografts, whereas opposite effects were achieved in LIMK1-silenced cells. Furthermore, we identified two tumour metastasis-associated proteins, MYH9 and ACTN4, as direct targets of LIMK1, which were required for a LIMK1-mediated aggressive phenotype.
These findings indicate that LIMK1 plays a critical role in promoting CRC progression at subcellular level. Our findings provide new insights into the metastasis of CRC and advocate for the development of clinical intervention strategies against advanced CRC.
LIM激酶1（LIMK1）是参与细胞增殖和迁移的细胞骨架组织的关键调节因子。尽管LIMK1在上皮性癌中经常失调，但其在结直肠癌（CRC）中的作用和机制仍不清楚。
采用免疫组织化学分析检测CRC样本中LIMK1的表达及临床意义。进行功能丧失和功能获得试验，以研究异常表达对CRC细胞体外和体内细胞生物学行为的影响。采用免疫印迹和免疫沉淀法筛选LIMK1相关信号通路和下游因子。
在本研究中，我们的结果表明LIMK1在CRC组织中上调，并定位于CRC细胞的细胞质和细胞核中。LIMK1在细胞质和细胞核亚细胞区室中的过表达与CRC患者的肿瘤转移和预后不良密切相关。细胞质和细胞核LIMK1的表达增强通过驱动上皮-间质转化和激活PI3K/Akt信号通路，在体外显著增加细胞增殖和迁移，同时促进CRC异种移植瘤的生长和转移，而在LIMK1沉默的细胞中则产生相反的效果。此外，我们鉴定出两种肿瘤转移相关蛋白MYH9和ACTN4是LIMK1的直接靶点，它们是LIMK1介导的侵袭性表型所必需的。
这些发现表明LIMK1在亚细胞水平促进CRC进展中起关键作用。我们的发现为CRC的转移提供了新的见解，并提倡开发针对晚期CRC的临床干预策略。
