LINC00941 is a novel lncRNA that has been found to exhibit protumorigenic and prometastatic behaviors during tumorigenesis. However, its role in metastatic CRC remains unknown. We aimed to investigate the functions and mechanisms of LINC00941 in CRC metastasis. LINC00941 was shown to be upregulated in CRC, and upregulated LINC00941 was associated with poor prognosis. Functionally, LINC00941 promoted migratory and invasive capacities and accelerated lung metastasis in nude mice. Mechanistically, LINC00941 activated EMT in CRC cells, as indicated by the increased expression of key molecular markers of cell invasion and metastasis (Vimentin, Fibronectin, and Twist1) and simultaneous decreased expression of the main invasion suppressors E-cadherin and ZO-1. LINC00941 was found to activate EMT by directly binding the SMAD4 protein MH2 domain and competing with β-TrCP to prevent SMAD4 protein degradation, thus activating the TGF-β/SMAD2/3 signaling pathway. Our data reveal the essential role of LINC00941 in metastatic CRC via activation of the TGF-β/SMAD2/3 axis, which provides new insight into the mechanism of metastatic CRC and a novel potential therapeutic target for advanced CRC.

LINC00941是一种新型 lncRNA，已被发现在肿瘤发生过程中表现出促肿瘤发生和促转移行为。然而，其在转移性结直肠癌中的作用仍不清楚。我们的目的是研究LINC00941在 CRC 转移中的功能和机制。LINC00941在 CRC 中表达上调，且LINC00941上调与不良预后相关。从功能上讲，LINC00941可促进裸鼠的迁移和侵袭能力并加速肺转移。从机制上讲，LINC00941激活 CRC 细胞中的 EMT，细胞侵袭和转移的关键分子标记物（Vimentin、Fibronectin 和 Twist1）表达增加，同时主要侵袭抑制因子 E-cadherin 和 ZO-1 表达减少。LINC00941被发现通过直接结合SMAD4蛋白MH2结构域并与β-TrCP竞争阻止SMAD4蛋白降解来激活EMT，从而激活TGF-β/SMAD2/3信号通路。我们的数据揭示了LINC00941通过激活 TGF-β/SMAD2/3 轴在转移性 CRC 中的重要作用，这为转移性 CRC 机制提供了新的见解，并为晚期 CRC 提供了新的潜在治疗靶点。