Article | Published:

Forkhead box C1 promotes colorectal cancer metastasis through transactivating ITGA7 and FGFR4 expression

Oncogene (2018) | Download Citation

Abstract

Metastatic colorectal cancer (CRC) is one of the most common causes of cancer death worldwide; however, the molecular mechanism underlying CRC metastasis remains unknown. Using an integrated approach, we identified forkhead box C1 (FOXC1) as a novel regulator of CRC metastasis. Elevated expression of FOXC1 is significantly correlated with metastasis, recurrence and reduced survival. FOXC1 overexpression promotes CRC invasion and lung metastasis, whereas FOXC1 knockdown has the opposite effect. In addition, FOXC1 directly binds its target genes integrin α7 (ITGA7) and fibroblast growth factor receptor 4 (FGFR4) and activates their expression. Genetic epistasis analysis confirmed that ITGA7 and FGFR4 act downstream of FOXC1. Furthermore, pharmaceutical inhibition of FGFR4 can reverse CRC metastasis mediated by FOXC1 overexpression. These results suggest that FOXC1 is a prognostic biomarker in CRC patients and targeting the FGFR4 signaling pathway may provide a promising strategy for the treatment of FOXC1-driven CRC metastasis.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (Nos. 81522031, 81772623, 81627807, and 81421003) and the National Center for Clinical Research of Digestive Diseases (2015BAI13B07).

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Author notes

    Affiliations

    1. State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, China

      • Jian Liu
      • , Zhe Zhang
      • , Xiaowei Li
      • , Jie Chen
      • , Guodong Wang
      • , Zuhong Tian
      • , Meirui Qian
      • , Zhangqian Chen
      • , Hao Guo
      • , Guangbo Tang
      • , Wenjie Huang
      • , Yongzhan Nie
      • , Daiming Fan
      • , Kaichun Wu
      •  & Limin Xia
    2. Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, People’s Republic of China

      • Wenjie Huang
      • , Dean Tian
      • , Daowen Wang
      •  & Limin Xia

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    Correspondence to Kaichun Wu or Limin Xia.

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    https://doi.org/10.1038/s41388-018-0355-4

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