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CD98 expression modulates intestinal homeostasis, inflammation, and colitis-associated cancer in mice
Hang Thi Thu Nguyen, … , Shanthi V. Sitaraman, Didier Merlin
Hang Thi Thu Nguyen, … , Shanthi V. Sitaraman, Didier Merlin
Published April 1, 2011
Citation Information: J Clin Invest. 2011;121(5):1733-1747. https://doi.org/10.1172/JCI44631.
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Research Article Gastroenterology Article has an altmetric score of 11

CD98 expression modulates intestinal homeostasis, inflammation, and colitis-associated cancer in mice

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Abstract

Expression of the transmembrane glycoprotein CD98 (encoded by SLC3A2) is increased in intestinal inflammatory conditions, such as inflammatory bowel disease (IBD), and in various carcinomas, yet its pathogenetic role remains unknown. By generating gain- and loss-of-function mouse models with genetically manipulated CD98 expression specifically in intestinal epithelial cells (IECs), we explored the role of CD98 in intestinal homeostasis, inflammation, and colitis-associated tumorigenesis. IEC-specific CD98 overexpression induced gut homeostatic defects and increased inflammatory responses to DSS-induced colitis, promoting colitis-associated tumorigenesis in mice. Further analysis indicated that the ability of IEC-specific CD98 overexpression to induce tumorigenesis was linked to its capacity to induce barrier dysfunction and to stimulate cell proliferation and production of proinflammatory mediators. To validate these results, we constructed mice carrying conditional floxed Slc3a2 alleles and crossed them with Villin-Cre mice such that CD98 was downregulated only in IECs. These mice exhibited attenuated inflammatory responses and resistance to both DSS-induced colitis and colitis-associated tumorigenesis. Together, our data show that intestinal CD98 expression has a crucial role in controlling homeostatic and innate immune responses in the gut. Modulation of CD98 expression in IECs therefore represents a promising therapeutic strategy for the treatment and prevention of inflammatory intestinal diseases, such as IBD and colitis-associated cancer.

Authors

Hang Thi Thu Nguyen, Guillaume Dalmasso, Leif Torkvist, Jonas Halfvarson, Yutao Yan, Hamed Laroui, Doron Shmerling, Tiziano Tallone, Mauro D’Amato, Shanthi V. Sitaraman, Didier Merlin

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Figure 5

IEC-specific CD98 overexpression enhances colonic tumorigenesis in a mouse model of CAC.

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IEC-specific CD98 overexpression enhances colonic tumorigenesis in a mou...
(A) CAC induction protocol. WT and Tg littermates were intraperitoneally injected with AOM (10 mg/kg body weight) and maintained for 5 days, then subjected to 2 cycles of DSS treatment (1 cycle representing 7 days of 2.5% DSS followed by 14 days of H2O). Survival (14 of 14 WT; 14 of 19 Tg) and percent change in body weight during the CAC protocol are shown. (B) Representative colons at the end of the CAC protocol and number of tumors per mouse. (C) Tumor size, determined using a dissecting microscope (n = 14 per group). Size distribution of tumors is also shown. (D) Representative H&E-stained colonic tumors at the end of the CAC protocol. Scale bars: 100 μm. (E) Colonic MPO activity in AOM/DSS-treated mice. (F) Colonic mRNA levels of cytokines/chemokines in AOM/DSS-treated mice, quantified by qRT-PCR (n = 9 per group). Data are from 1 experiment repeated twice with similar results. *P < 0.05, **P < 0.005, ***P < 0.001 vs. WT.

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

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