Ji Zhonghe, Li Xinbao, Wang Yadong, Zhang Xinjing, Yang Zhiran, Zhang Yanbin, Yu Junhui, Gao Chao, Yan Guojun, Yan Lijun, Zhang Kai, Pan Jinghan, An Songlin
Department of Peritoneal Oncology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China.
Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.
J Cell Mol Med. 2025 Jul;29(13):e70702. doi: 10.1111/jcmm.70702.
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.
转移是导致结肠癌患者预后不良的重要因素之一。然而，促成这种细胞行为的分子机制在很大程度上仍不清楚。在此，RNA测序分析表明，纤连蛋白1（FN1）在转移性结肠癌中显著增加，这与预后不良相关。FN1在体外增强了结肠癌细胞的迁移、侵袭及上皮-间质转化（EMT），并通过RAP1B促进了裸鼠结肠癌的肝转移和肺转移。机制上，FN1可通过抑制RAP1B与E3连接酶PARK2之间的相互作用与RAP1B相互作用，减轻RAP1B的泛素化修饰并提高RAP1B蛋白稳定性。此外，FN1-RAP1B激活Akt信号通路，导致CREB磷酸化并激活。有趣的是，发现CREB分别直接与FN1和TIMP1启动子结合，并增加FN1和TIMP1转录，从而建立了一个正调控反馈环。总体而言，我们的结果阐明了FN1促进结肠癌的迁移、侵袭和转移。FN1可能用作结肠癌转移的潜在治疗靶点。
