Loss of Rab25 promotes the development of intestinal neoplasia in mice and is associated with human colorectal adenocarcinomas
Ki Taek Nam, … , Robert J. Coffey, James R. Goldenring
Ki Taek Nam, … , Robert J. Coffey, James R. Goldenring
Published February 8, 2010
Citation Information: J Clin Invest. 2010;120(3):840-849. https://doi.org/10.1172/JCI40728.
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Research Article Oncology

Loss of Rab25 promotes the development of intestinal neoplasia in mice and is associated with human colorectal adenocarcinomas

Abstract

Transformation of epithelial cells is associated with loss of cell polarity, which includes alterations in cell morphology as well as changes in the complement of plasma membrane proteins. Rab proteins regulate polarized trafficking to the cell membrane and therefore represent potential regulators of this neoplastic transition. Here we have demonstrated a tumor suppressor function for Rab25 in intestinal neoplasia in both mice and humans. Human colorectal adenocarcinomas exhibited reductions in Rab25 expression independent of stage, with lower Rab25 expression levels correlating with substantially shorter patient survival. In wild-type mice, Rab25 was strongly expressed in cells luminal to the proliferating cells of intestinal crypts. While Rab25-deficient mice did not exhibit gross pathology, ApcMin/+ mice crossed onto a Rab25-deficient background showed a 4-fold increase in intestinal polyps and a 2-fold increase in colonic tumors compared with parental ApcMin/+ mice. Rab25-deficient mice had decreased β1 integrin staining in the lateral membranes of villus cells, and this pattern was accentuated in Rab25-deficient mice crossed onto the ApcMin/+ background. Additionally, Smad3+/– mice crossed onto a Rab25-deficient background demonstrated a marked increase in colonic tumor formation. Taken together, these results suggest that Rab25 may function as a tumor suppressor in intestinal epithelial cells through regulation of protein trafficking to the cell surface.

Authors

Ki Taek Nam, Hyuk-Joon Lee, J. Joshua Smith, Lynne A. Lapierre, Vidya P. Kamath, Xi Chen, Bruce J. Aronow, Timothy J. Yeatman, Sheela G. Bhartur, Benjamin C. Calhoun, Brian Condie, Nancy R. Manley, R. Daniel Beauchamp, Robert J. Coffey, James R. Goldenring

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Figure 8

Rab25 deficiency promotes colon tumor formation and neoplasia in Smad3+/– mice.

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Rab25 deficiency promotes colon tumor formation and neoplasia in Smad3+/...
(A) Smad3 heterozygote mice on a Rab25 wild-type background did not show any adenomas in their colons. (B) Higher magnification of view of A shows normal colonic mucosa. (C) Swiss roll of Smad3+/–;Rab25–/– mouse colon. Note the numerous mucin-filled cysts. The image was captured using an Ario SL-50 imager. Areas of the image in which no tissue was present appear blank. (D) In a more aggressive proximal tumor, the cancerous lesions penetrated into the serosal wall with neoplastic atypical cystic glands filled with mucin. (E) The neoplastic colonic epithelium invaded into and through the submucosa, and the neoplastic glands invaded the muscle wall. (F) Rectal area of Smad3+/–;Rab25–/– mice. The neoplastic colonic epithelium penetrated muscle wall with atypical cystic glands filled with mucin. (G) Atypical cystic glands in epithelium and penetrating the muscle wall. (H) Vagina neoplasia. In vaginal epithelium, neoplastic squamous epithelial cells invaded the muscle layer. The vaginal lesions were not specific to ApcMin/+ mice and were seen in Rab25-deficient mice on the 129 background. Scale bars: 1 mm.