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ERK activation drives intestinal tumorigenesis in Apcmin/+ mice

Nature Medicine volume 16, pages 665–670 (2010)Cite this article

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Abstract

Toll-like receptor (TLR) signaling is essential for intestinal tumorigenesis in Apcmin/+ mice, but the mechanisms by which Apc enhances tumor growth are unknown. Here we show that microflora-MyD88-ERK signaling in intestinal epithelial cells (IECs) promotes tumorigenesis by increasing the stability of the c-Myc oncoprotein. Activation of ERK (extracellular signal–related kinase) phosphorylates c-Myc, preventing its ubiquitination and subsequent proteasomal degradation. Accordingly, Apcmin/+/Myd88−/− mice have lower phospho-ERK (p-ERK) levels and fewer and smaller IEC tumors than Apcmin/+ mice. MyD88 (myeloid differentiation primary response gene 88)-independent activation of ERK by epidermal growth factor (EGF) increased p-ERK and c-Myc and restored the multiple intestinal neoplasia (Min) phenotype in Apcmin/+/Myd88−/− mice. Administration of an ERK inhibitor suppressed intestinal tumorigenesis in EGF-treated Apcmin/+/Myd88−/− and Apcmin/+ mice and increased their survival. Our data reveal a new facet of oncogene-environment interaction, in which microflora-induced TLR activation regulates oncogene expression and related IEC tumor growth in a susceptible host.

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Figure 1: Genetic disruption of Myd88 in Apcmin/+ mice suppresses proliferation and enhances apoptosis of IECs.
Figure 2: Myd88 signaling in hematopoietic cells is not required for tumorigenesis in Apcmin/+ mice.
Figure 3: MyD88 regulates c-Myc expression levels.
Figure 4: TLR signaling via MyD88 stabilizes c-Myc protein in IECs through activation of ERK.
Figure 5: Activation of ERK restores the Min phenotype in Apcmin/+/Myd88−/− mice.
Figure 6: Activation of ERK is essential for the Min phenotype in Apcmin/+ mice.

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Acknowledgements

The authors thank P. Charos for animal breeding and S. Shenouda for tissue processing. This work was supported by US National Institutes of Health grants AI068685, CA133702, DK35108 and DK080506.

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Author notes

  1. Sung Hee Lee & Geom Seog Seo

    Present address: Current addresses: College of Pharmacy, Wonkwang University, Iksan, Chonbuk, Republic of Korea (S.H.L.); Wonkwang University School of Medicine, Iksan, Chonbuk, Republic of Korea (G.S.S.).,

Authors and Affiliations

  1. Department of Medicine, University of California, San Diego, La Jolla, California, USA.,

    Sung Hee Lee, Li-Li Hu, Jose Gonzalez-Navajas, Geom Seog Seo, Carol Shen, Jonathan Brick, Scott Herdman, Maripat Corr, Jongdae Lee & Eyal Raz

  2. Department of Pathology, University of California, San Diego, La Jolla, California, USA.,

    Nissi Varki

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Contributions

E.R. designed the study; S.H.L. and J.L. performed the signaling experiments; C.S., L.-L.H., S.H. and G.S.S. performed the in vivo studies; M.C. generated the bone marrow chimeras; J.B., J.L. and J.G.-N. performed immunohistochemistry and flow cytometry; S.H.L., M.C., N.V., J.L. and E.R. analyzed the data; and S.H.L., J.L. and E.R. wrote the manuscript.

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Correspondence to Eyal Raz.

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Lee, S., Hu, LL., Gonzalez-Navajas, J. et al. ERK activation drives intestinal tumorigenesis in Apcmin/+ mice. Nat Med 16, 665–670 (2010). https://doi.org/10.1038/nm.2143

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