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The FOXC1/FBP1 signaling axis promotes colorectal cancer proliferation by enhancing the Warburg effect

Oncogenevolume 38pages483496 (2019) | Download Citation

Abstract

Aberrant expression of Forkhead box (FOX) transcription factors plays vital roles in carcinogenesis. However, the function of the FOX family member FOXC1 in maintenance of colorectal cancer (CRC) malignancy is unknown. Herein, FOXC1 expression in CRC specimens in The Cancer Genome Atlas (TCGA) cohort was analyzed and validated using immunohistochemistry with a tissue microarray. The effect of FOXC1 expression on proliferation of and glycolysis in CRC cells was assessed by altering its expression in vitro and in vivo. Mechanistic investigation was carried out using cell and molecular biological approaches. Our results showed that FOXC1 expression was higher in CRC specimens than in adjacent benign tissue specimens. Univariate survival analyses of the patients from whom the study specimens were obtained, and validated cohorts indicated that ectopic FOXC1 expression was significantly correlated with shortened survival. Silencing FOXC1 expression in CRC cells inhibited their proliferation and colony formation and decreased their glucose consumption and lactate production. In contrast, FOXC1 overexpression had the opposite effect. Furthermore, increased expression of FOXC1 downregulated that of a key glycolytic enzyme, fructose-1,6-bisphosphatase 1 (FBP1). Mechanistically, FOXC1 bound directly to the promoter regions of the FBP1 gene and negatively regulated its transcriptional activity. Collectively, aberrant FBP1 expression contributed to CRC tumorigenicity, and decreased FBP1 expression coupled with increased FOXC1 expression provided better prognostic information than did FOXC1 expression alone. Therefore, the FOXC1/FBP1 axis induces CRC cell proliferation, reprograms metabolism in CRCs, and constitutes potential prognostic predictors and therapeutic targets for CRC.

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Acknowledgements

We thank Don Norwood in the Department of Scientific Publications at The University of Texas MD Anderson Cancer Center for editorial assistance and Jianping Zhang at the Center for Biomedical Imaging, Fudan University, for assistance in the mouse PET/CT study.

Author contributions

Conception and design: D. Li, K. Xie. Development of methodology: Q. Li, Y. Li, D. Xie. Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): Q. Li,M. Zhang, S. Cai, D. Li, G. Li, P. Wei, Y. Li, Y. Xu, X. Li, D. Xie. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): J Wu, P. Wei, Y. Li, D. Xie. Writing, review, and/or revision of the manuscript: Q. Li, J Wu, D. Li, K. Xie. Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): Q. Li, Y. Xu, X. Li, K. Xie. Study supervision: D. Li, P. Wei. Other (financial support): S. Cai, D. Li, K. Xie

Funding

This research was supported by grants from the National Science Foundation of China (81472222, 81702353, 81772583, 81572254, 81372646, 81302097, and 81672374) and Shanghai Rising-Star Program(17QA1400900), Shanghai Municipal Natural Science Foundation (17ZR1406400), Municipal Human Resources Development Program for Outstanding Young Talents in Medical and Health Sciences in Shanghai (2017YQ046), National Key Basic Research Program of China (2014CBA02002) and grants R01-CA129956, R01-CA148954, R01CA152309, R01CA172233, and R01CA195651 from the National Cancer Institute, National Institutes of Health.

Author information

Author notes

  1. These authors contributed equally: Qingguo Li, Ping Wei, Jitao Wu

Affiliations

  1. Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China

    • Qingguo Li
    • , Yaqi Li
    • , Ye Xu
    • , Xinxiang Li
    • , Sanjun Cai
    •  & Dawei Li
  2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China

    • Qingguo Li
    • , Ping Wei
    • , Meng Zhang
    • , Guichao Li
    • , Yaqi Li
    • , Ye Xu
    • , Xinxiang Li
    • , Sanjun Cai
    •  & Dawei Li
  3. Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China

    • Ping Wei
    •  & Meng Zhang
  4. Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China

    • Ping Wei
  5. Department of Urology, Yantai Yuhuangding Hospital, Yantai, People’s Republic of China

    • Jitao Wu
  6. Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China

    • Guichao Li
  7. Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    • Dacheng Xie
    •  & Keping Xie

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The authors declare that they have no conflict of interest.

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Correspondence to Keping Xie or Dawei Li.

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https://doi.org/10.1038/s41388-018-0469-8