Ion channel TRPV1-dependent activation of PTP1B suppresses EGFR-associated intestinal tumorigenesis
Petrus R. de Jong, … , Maripat Corr, Eyal Raz
Petrus R. de Jong, … , Maripat Corr, Eyal Raz
Published August 1, 2014
Citation Information: J Clin Invest. 2014;124(9):3793-3806. https://doi.org/10.1172/JCI72340.
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Research Article Oncology

Ion channel TRPV1-dependent activation of PTP1B suppresses EGFR-associated intestinal tumorigenesis

Abstract

The intestinal epithelium has a high rate of turnover, and dysregulation of pathways that regulate regeneration can lead to tumor development; however, the negative regulators of oncogenic events in the intestinal epithelium are not fully understood. Here we identified a feedback loop between the epidermal growth factor receptor (EGFR), a known mediator of proliferation, and the transient receptor potential cation channel, subfamily V, member 1 (TRPV1), in intestinal epithelial cells (IECs). We found that TRPV1 was expressed by IECs and was intrinsically activated upon EGFR stimulation. Subsequently, TRPV1 activation inhibited EGFR-induced epithelial cell proliferation via activation of Ca2+/calpain and resulting activation of protein tyrosine phosphatase 1B (PTP1B). In a murine model of multiple intestinal neoplasia (ApcMin/+ mice), TRPV1 deficiency increased adenoma formation, and treatment of these animals with an EGFR kinase inhibitor reversed protumorigenic phenotypes, supporting a functional association between TRPV1 and EGFR signaling in IECs. Administration of a TRPV1 agonist suppressed intestinal tumorigenesis in ApcMin/+ mice, similar to — as well as in conjunction with — a cyclooxygenase-2 (COX-2) inhibitor, which suggests that targeting both TRPV1 and COX-2 has potential as a therapeutic approach for tumor prevention. Our findings implicate TRPV1 as a regulator of growth factor signaling in the intestinal epithelium through activation of PTP1B and subsequent suppression of intestinal tumorigenesis.

Authors

Petrus R. de Jong, Naoki Takahashi, Alexandra R. Harris, Jihyung Lee, Samuel Bertin, James Jeffries, Michael Jung, Jen Duong, Amy I. Triano, Jongdae Lee, Yaron Niv, David S. Herdman, Koji Taniguchi, Chang-Whan Kim, Hui Dong, Lars Eckmann, Stephanie M. Stanford, Nunzio Bottini, Maripat Corr, Eyal Raz

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Figure 4

Physiological effects of TRPV1 signaling in intestinal organoids.

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Physiological effects of TRPV1 signaling in intestinal organoids. (A) Re...
(A) Representative live-cell microscopy images of small intestinal organoids generated from WT and Trpv1–/– mice at day 7 after passing. (B) Quantification of crypt lengths of WT and Trpv1–/– organoids (n = 8). (C) Expression of the proliferation marker Mki67 in WT and Trpv1–/– organoids, determined by Q-PCR and expressed relative to WT (n = 3). (D) Increased Mki67 expression in Trpv1–/– versus WT organoids. (E) Immunostaining for Ki67 of WT and Trpv1–/– organoids showed an increase in the proliferative zone in the latter. Confocal fluorescence microscopy is shown. (F) Q-PCR analysis of c-Fos expression in WT and Trpv1–/– organoids, normalized to Gapdh and expressed relative to WT (n = 3 per group). (G) TRPV1 deficiency reduced the exogenous EGF requirement of intestinal organoids. WT and Trpv1–/– organoids were cultured with standard medium with or without EGF (50 ng/ml) for 48 hours. Representative images of organoids by brightfield microscopy are shown. (H) Organoids as in G, stained for Ki67 and F-actin. Scale bars: 50 μm (E); 100 μm (A, G, and H). Mean ± SEM. *P < 0.05, Student’s t test. Data representative of 2–3 independent experiments.