Fibronectin 1 Aggravates Colon Cancer Metastasis by Regulating RAP1B Protein Stability Through Akt/CREB Signalling Pathway.

Metastasis is one of the important factors leading to poor prognosis in patients with colon cancer. However, the molecular mechanism contributing to this cellular behaviour remains largely unknown. Here, RNA-seq analysis suggested that Fibronectin 1 (FN1) was significantly increased in metastatic colon cancer, which was associated with poor prognosis. FN1 enhanced colon cancer cell migration, invasion, and epithelial to mesenchymal transition (EMT) in vitro and promoted liver and lung metastasis of colon cancer in nude mice through RAP1B. Mechanistically, FN1 could interact with RAP1B by suppressing the interaction between RAP1B and the E3 ligase PARK2, relieving RAP1B ubiquitination modification and improving RAP1B protein stability. Furthermore, FN1-RAP1B activated Akt signalling pathway, leading to the phosphorylation and activation of CREB. Interestingly, CREB was found directly bound to the FN1 and TIMP1 promoter, respectively and increased FN1 and TIMP1 transcription, thereby establishing a positive regulatory feedback loop. Overall, our results elucidated that FN1 promotes colon cancer migration, invasion, and metastasis. FN1 may be used as the potential therapeutic target for colon cancer metastasis.