LINC00941 promotes CRC metastasis through preventing SMAD4 protein degradation and activating the TGF-β/SMAD2/3 signaling pathway

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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.

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Fig. 1: LINC00941 expression is significantly upregulated during CRC development.
Fig. 2: LINC00941 promotes the migratory and invasive capacities of colorectal cancer cells.
Fig. 3: LINC00941 promotes SMAD4 protein stability.
Fig. 4: LINC00941 inhibited the ubiquitination of SMAD4 by blocking the binding of SMAD4 to βTrCP.
Fig. 5: TGF-β was necessary for LINC00941-induced promotion of metastasis.

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This research was funded by the National Natural Science Foundation of China (Grant No. 61471181).

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Correspondence to Yuying Han or Bing Xu.

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Wu, N., Jiang, M., Liu, H. et al. LINC00941 promotes CRC metastasis through preventing SMAD4 protein degradation and activating the TGF-β/SMAD2/3 signaling pathway. Cell Death Differ (2020). https://doi.org/10.1038/s41418-020-0596-y

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