LINC00941promotes CRC metastasis through preventing SMAD4 protein degradation and activating the TGF-β/SMAD2/3 signaling pathway

Abstrict LINC00941is 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 ofLINC00941in CRC metastasis.LINC00941was shown to be upregulated in CRC, and upregulatedLINC00941was associated with poor prognosis. Functionally,LINC00941promoted migratory and invasive capacities and accelerated lung metastasis in nude mice. Mechanistically,LINC00941activated 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.LINC00941was found to activate EMT by directly binding the SMAD4 protein MH2 domain and competing with beta-TrCP to prevent SMAD4 protein degradation, thus activating the TGF-beta/SMAD2/3 signaling pathway. Our data reveal the essential role ofLINC00941in metastatic CRC via activation of the TGF-beta/SMAD2/3 axis, which provides new insight into the mechanism of metastatic CRC and a novel potential therapeutic target for advanced CRC.

Automated summary

LINC00941 plays a crucial role in metastatic colorectal cancer by activating the TGF-beta/SMAD2/3 pathway to promote metastasis and invasion.