A Variant of Smurf2 Protects Mice Against Colitis-Associated Colon Cancer by Inducing Transforming Growth Factor β Signaling

BACKGROUND & AIMS: Transforming growth factor (TGF)-beta signaling, which is down-regulated by the E3 ubiquitin ligase Smad ubiquitin regulating factor 2 (Smurf2), promotes development of cancer. We identified a splice variant of Smurf2 (Delta E2Smurf2) and investigated its role in colon carcinogenesis in mice. METHODS: Colitis-associated colon cancer was induced in mice by administration of azoxymethane, followed by 3 cycles of oral administration of dextran sodium sulfate. Messenger RNA levels of Smurf2 in colon tumors and control tissue were measured by quantitative polymerase chain reaction; lymphocyte and cytokine levels were measured in tumor and tissue samples. RESULTS: Tumor-infiltrating CD4(+) cells expressed higher levels of Delta E2Smurf2 than CD4(+) cells from nontumor tissues of wild-type mice. T cell-specific overexpression of Delta E2Smurf2 increased TGF-beta signaling by suppressing protein levels of Smurf2, accompanied by an increase in levels of TGF-beta receptor type II. Transgenic mice that overexpress Delta E2Smurf2 were protected against development of colitis-associated tumors and down-regulated proinflammatory cytokines such as interleukin-6. Patients with chronic inflammatory bowel disease had a significantly lower ratio of Smurf2/Delta E2Smurf2 than control individuals. CONCLUSIONS: T cell-specific Delta E2Smurf2 degrades wild-type Smurf2 and controls intestinal tumor growth in mice by up-regulating TGF-beta receptor type II, reducing proliferation and production of proinflammatory cytokines.