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Constitutive IKK2 activation in intestinal epithelial cells induces intestinal tumors in mice
Katerina Vlantis, … , Tania Roskams, Manolis Pasparakis
Katerina Vlantis, … , Tania Roskams, Manolis Pasparakis
Published June 23, 2011
Citation Information: J Clin Invest. 2011;121(7):2781-2793. https://doi.org/10.1172/JCI45349.
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Research Article

Constitutive IKK2 activation in intestinal epithelial cells induces intestinal tumors in mice

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Abstract

Many cancers display increased NF-κB activity, and NF-κB inhibition is known to diminish tumor development in multiple mouse models, supporting an important role of NF-κB in carcinogenesis. NF-κB activation in premalignant or cancer cells is believed to promote tumor development mainly by protecting these cells from apoptosis. However, it remains unclear to what extent NF-κB activation exhibits additional protumorigenic functions in premalignant cells that could be sufficient to induce spontaneous tumor development. Here we show that expression of constitutively active IκB kinase 2 (IKK2ca) in mouse intestinal epithelial cells (IECs) induced spontaneous tumors in aged mice and also strongly enhanced chemical- and Apc mutation–mediated carcinogenesis. IECs expressing IKK2ca displayed altered Wnt signaling and increased proliferation and elevated expression of genes encoding intestinal stem cell–associated factors including Ascl2, Olfm4, DLK1, and Bmi-1, indicating that increased IKK2/NF-κB activation synergized with Wnt signaling to drive intestinal tumorigenesis. Moreover, IECs expressing IKK2ca produced cytokines and chemokines that induced the recruitment of myeloid cells and activated stromal fibroblasts to become myofibroblasts, thus creating a tumor-promoting microenvironment. Taken together, our results show that constitutively increased activation of IKK2/NF-κB signaling in the intestinal epithelium is sufficient to induce the full spectrum of cell-intrinsic and stromal alterations required for intestinal tumorigenesis.

Authors

Katerina Vlantis, Andy Wullaert, Yoshiteru Sasaki, Marc Schmidt-Supprian, Klaus Rajewsky, Tania Roskams, Manolis Pasparakis

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Figure 2

Immune cell infiltration and increased cytokine and chemokine expression in the gut of IKK2caIEChom mice.

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Immune cell infiltration and increased cytokine and chemokine expression...
(A) Immunohistochemical staining for Gr1 and F4/80 reveals increased numbers of granulocytes and macrophages, respectively, in colonic and SI cross sections of 6-week-old IKK2caIEChom mice. In the SI of IKK2caIEChom mice, F4/80-positive cells accumulated around the crypts, while in control mice, macrophages were mainly found in the villi. (B and C) qRT-PCR analysis shows enhanced expression of a subset of proinflammatory genes in the colon (B) and the ileum (C) of 7- to 8-week-old IKK2caIEChom mice (n ≥ 6 for each genotype; mRNA levels are presented as mean ± SD). (D) Immunohistochemical staining with antibodies recognizing α-SMA revealed the presence of increased numbers of activated myofibroblasts in colons of young (10 week old) and aged (1 year old) IKK2caIEChom mice compared with IKK2casFL littermates. Scale bars: 50 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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