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HGF/Met and FOXM1 form a positive feedback loop and render pancreatic cancer cells resistance to Met inhibition and aggressive phenotypes

Oncogene volume 35, pages 4708–4718 (2016)Cite this article

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Abstract

Hepatocyte growth factor (HGF)/Met signaling has critical roles in pancreatic ductal adenocarcinoma (PDA) development and progression and is considered a potential therapeutic target for this disease. However, the mechanism of aberrant activation of HGF/Met signaling and resistance to Met inhibition in PDA remains unclear. The mechanistic role of cross talk between Forkhead box M1 (FOXM1) and HGF/Met signaling in promotion of PDA growth and resistance to Met inhibition was examined using cell culture, molecular biology and mouse models; and the relevance of our experimental and mechanistic findings were validated using human PDA tissues. Met was markedly overexpressed in both PDA cell lines and pancreatic tumor specimens, and the expression of Met correlated directly with that of FOXM1 in human tumor specimens. Mechanistically, FOXM1 bound to the promoter region of the Met gene and transcriptionally increased the expression of Met. Increased expression of FOXM1 enhanced the activation of HGF/Met signaling and its downstream pathways, including retrovirus-associated DNA sequences/extracellular signal-regulated kinase 1/2, phosphoinositide 3-kinase/AKT and signal transducer and activator of transcription 3. Furthermore, activation of HGF/Met signaling increased the expression and transcriptional activity of FOXM1, and the cross talk between FOXM1 and HGF/Met signaling promoted PDA growth and resistance to Met inhibition. Collectively, our findings identified a positive feedback loop formed by FOXM1 and HGF/Met and revealed that this loop is a potentially effective therapeutic target for PDA.

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Acknowledgements

We thank Don Norwood for editorial assistance and Xuemei Wang, Associate Director of Quantitative Research at The University of Texas MD Anderson Cancer Center, for assistance with statistical analyses. This work was supported by grants R01-CA129956, R01-CA148954, R01CA152309, and R01CA172233 from the National Cancer Institute, National Institutes of Health (to K Xie).

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Authors and Affiliations

  1. Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    J Cui, Z Jia, D Wei, L Wang, M Quan & K Xie

  2. Department of Gastroenterology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, People’s Republic of China

    T Xia

  3. Department of Oncology, Shanghai Tongji University Affiliated East Hospital, Shanghai, People’s Republic of China

    D Xie, Y Gao & M Quan

  4. Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    S Huang

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Cui, J., Xia, T., Xie, D. et al. HGF/Met and FOXM1 form a positive feedback loop and render pancreatic cancer cells resistance to Met inhibition and aggressive phenotypes. Oncogene 35, 4708–4718 (2016). https://doi.org/10.1038/onc.2016.14

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